Editing Leptin

{{short description|Hormone that inhibits hunger}}
{{distinguish|Lectin|Lecithin|Lepton}}
{{more medical citations needed|date=July 2020}}
{{Infobox_gene}}
{{Infobox protein family
| Symbol = Leptin
| Name = Leptin
| image = PDB 1ax8 EBI.jpg
| width =
| caption = Structure of the obese protein leptin-E100<ref name="pmid9144295">{{cite journal | vauthors = Zhang F, Basinski MB, Beals JM, Briggs SL, Churgay LM, Clawson DK, DiMarchi RD, Furman TC, Hale JE, Hsiung HM, Schoner BE, Smith DP, Zhang XY, Wery JP, Schevitz RW | display-authors = 6 | title = Crystal structure of the obese protein leptin-E100 | journal = Nature | volume = 387 | issue = 6629 | pages = 206–209 | date = May 1997 | pmid = 9144295 | doi = 10.1038/387206a0 | s2cid = 716518 | bibcode = 1997Natur.387..206Z }}</ref>
| Pfam = PF02024
| Pfam_clan = CL0053
| InterPro = IPR000065
| SMART =
| PROSITE = 
| SCOP = 1ax8
| TCDB =
| OPM family =
| OPM protein =
| PDB = {{PDB2|1ax8}}
 }}

'''Leptin''' (from [[Ancient Greek|Greek]] λεπτός ''leptos'', "thin" or "light" or "small"), also known as '''obese protein''',<ref name="uniprot">{{cite web |title=LEP - Leptin precursor - Homo sapiens (Human) - LEP gene & protein |url=https://www.uniprot.org/uniprot/P41159 |website=www.uniprot.org |access-date=8 May 2022 |language=en}}</ref> is a protein [[hormone]] predominantly made by [[adipocyte]]s (cells of [[adipose tissue]]). Its primary role is likely to regulate long-term [[Energy homeostasis|energy balance]].<ref name="Al-Hussaniy_2021">{{cite journal |vauthors=Al-Hussaniy HA, Alburghaif AH, Naji MA |date=2021 |title=Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions |journal=Journal of Medicine and Life |volume=14 |issue=5 |pages=600–605 |doi=10.25122/jml-2021-0153 |pmc=8742898 |pmid=35027962}}</ref> 

As one of the major signals of energy status, leptin levels influence [[appetite]], [[Hunger (physiology)|satiety]], and motivated behaviors oriented toward the maintenance of energy reserves (e.g., feeding, foraging behaviors). 

The amount of circulating leptin correlates with the amount of energy reserves, mainly [[Triglyceride|triglycerides]] stored in adipose tissue. High leptin levels are interpreted by the brain that energy reserves are high, whereas low leptin levels indicate that energy reserves are low, in the process adapting the organism to [[Starvation response|starvation]] through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes.<ref>{{cite journal | vauthors = Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, Gradl-Dietsch G, Peters T, Antel J, Lau D, Fulton S | display-authors = 6 | title = The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa | journal = Neuroscience and Biobehavioral Reviews | volume = 141 | pages = 104807 | date = October 2022 | pmid = 35931221 | doi = 10.1016/j.neubiorev.2022.104807 | s2cid = 251259742 }}</ref>

Leptin is coded for by the ''LEP'' [[gene]]. Leptin receptors are expressed by a variety of brain and peripheral cell types. These include [[cell receptor]]s in the [[arcuate nucleus|arcuate]] and [[Ventromedial nucleus of the hypothalamus|ventromedial nuclei]], as well as other parts of the [[hypothalamus]] and [[Dopamine|dopaminergic neurons]] of the [[ventral tegmental area]], consequently mediating [[Eating|feeding]].<ref name="pmid16932309">{{cite journal | vauthors = Brennan AM, Mantzoros CS | title = Drug Insight: the role of leptin in human physiology and pathophysiology--emerging clinical applications | journal = Nature Clinical Practice. Endocrinology & Metabolism | volume = 2 | issue = 6 | pages = 318–327 | date = June 2006 | pmid = 16932309 | doi = 10.1038/ncpendmet0196 | s2cid = 13118779 }}</ref><ref>{{cite journal | vauthors = Bouret S, Levin BE, Ozanne SE | title = Gene-environment interactions controlling energy and glucose homeostasis and the developmental origins of obesity | journal = Physiological Reviews | volume = 95 | issue = 1 | pages = 47–82 | date = January 2015 | pmid = 25540138 | pmc = 4281588 | doi = 10.1152/physrev.00007.2014 }}</ref>

Although regulation of fat stores is deemed to be the primary function of leptin, it also plays a role in other physiological processes, as evidenced by its many sites of synthesis other than fat cells, and the many cell types beyond hypothalamic cells that have [[leptin receptor]]s. Many of these additional functions are yet to be fully defined.<ref name="pmid7624777" /><ref name="pmid7624778" /><ref name="pmid7624776" /><ref name="pmid7584987" /><ref name="pmid7769141">{{cite journal | vauthors = Considine RV, Considine EL, Williams CJ, Nyce MR, Magosin SA, Bauer TL, Rosato EL, Colberg J, Caro JF | display-authors = 6 | title = Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity | journal = The Journal of Clinical Investigation | volume = 95 | issue = 6 | pages = 2986–2988 | date = June 1995 | pmid = 7769141 | pmc = 295988 | doi = 10.1172/JCI118007 }}</ref><ref name="pmid8532024">{{cite journal | vauthors = Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL | display-authors = 6 | title = Serum immunoreactive-leptin concentrations in normal-weight and obese humans | journal = The New England Journal of Medicine | volume = 334 | issue = 5 | pages = 292–295 | date = February 1996 | pmid = 8532024 | doi = 10.1056/NEJM199602013340503 | doi-access = free }}</ref>

In [[obesity]], a decreased sensitivity to leptin occurs (similar to [[insulin resistance]] in [[type 2 diabetes]]), resulting in an inability to detect [[satiety]] despite high energy stores and high levels of leptin.<ref>{{cite journal | vauthors = Pan H, Guo J, Su Z | title = Advances in understanding the interrelations between leptin resistance and obesity | journal = Physiology & Behavior | volume = 130 | pages = 157–169 | date = May 2014 | pmid = 24726399 | doi = 10.1016/j.physbeh.2014.04.003 | s2cid = 12502104 }}</ref> 

== {{anchor|Effects}}Effects ==
{{main|Leptin receptor|Energy expenditure}}
[[File:Fatmouse.jpg|thumb|alt=Two white mice both with similar sized ears, black eyes, and pink noses: The body of the mouse on the left, however, is about three times the width of the normal-sized mouse on the right.|A comparison of a mouse unable to produce leptin, resulting in [[obesity]], constant [[hunger]], and [[lethargy]] (left), to an active normal weight mouse (right)]] 
Predominantly, the "energy expenditure hormone" leptin is made by [[adipose cells]], and is thus labeled ''fat cell-specific''. In the context of its [[Cause and effect|effects]], the short [[Adjective|describing words]] ''central'', ''direct'', and ''primary'' are not used interchangeably. In regard to the hormone leptin, central vs peripheral refers to the [[hypothalamus|hypothalamic]] portion of the brain vs non-hypothalamic ''location of action'' of leptin; direct vs indirect refers to whether there is no intermediary, or there is an intermediary in the ''mode of action'' of leptin; and primary vs secondary is an arbitrary description of a particular ''function'' of leptin.<ref name="pmid10215564">{{cite journal | vauthors = Mantzoros CS | title = The role of leptin in human obesity and disease: a review of current evidence | journal = Annals of Internal Medicine | volume = 130 | issue = 8 | pages = 671–680 | date = April 1999 | pmid = 10215564 | doi = 10.7326/0003-4819-130-8-199904200-00014 | s2cid = 12488741 }}</ref>

;Location of action: The ''central'' location of action (''effect'') of the fat cell-specific hormone leptin is the [[hypothalamus]], a part of the [[brain]], which is a part of the central nervous system. Non-hypothalamic targets of leptin are referred to as ''peripheral'' targets. There is a different relative importance of central and peripheral leptin interactions under different [[physiology|physiologic]] states, and variations among species.<ref name=Margetic />

;Mode of action: Leptin acts ''directly'' on [[leptin receptor]]s in the [[cell membrane]] of different types of [[Cell (biology)|cells]] in the [[human body]] in particular, and in [[vertebrate]]s in general. The leptin receptor is found on a wide range of cell types. It is a ''single-transmembrane-domain'' [[type I cytokine receptor]],<ref name="pmid18821585">{{cite journal | vauthors = Cirillo D, Rachiglio AM, la Montagna R, Giordano A, Normanno N | title = Leptin signaling in breast cancer: an overview | journal = Journal of Cellular Biochemistry | volume = 105 | issue = 4 | pages = 956–964 | date = November 2008 | pmid = 18821585 | doi = 10.1002/jcb.21911 | s2cid = 25572220 }}</ref> a special class of [[cytokine receptor]]s. Further, leptin interacts with other [[hormone]]s and energy regulators, ''indirectly'' mediating the effects of: [[insulin]], [[glucagon]], [[insulin-like growth factor]], [[growth hormone]], [[glucocorticoid]]s, [[cytokine]]s, and [[metabolite]]s.<ref name=Margetic />

;Function: The ''primary'' function of the hormone leptin is the regulation of [[adipose tissue]] mass through central hypothalamus mediated effects on [[hunger]], [[food energy]] use, [[physical exercise]], and [[Energy homeostasis|energy balance]]. Outside the brain, in the periphery of the body, leptin's ''secondary'' functions are: modulation of energy expenditure, modulation between fetal and maternal metabolism, and that of a permissive factor in puberty, activator of immune cells, activator of beta islet cells, and growth factor.

=== Central nervous system ===
[[File:Classic leptin–melanocortin model.jpg|thumb|Classic leptin–melanocortin model]]
In vertebrates, the [[nervous system]] consists of two main parts, the [[central nervous system]] (CNS) and the [[peripheral nervous system]] (PNS). The primary effect of leptins is in the [[hypothalamus]], a part of the central nervous system. Leptin receptors are [[Gene expression|expressed]] not only in the hypothalamus but also in other brain regions, particularly in the [[hippocampus]]. Thus some leptin receptors in the brain are classified as ''central'' (hypothalamic) and some as ''peripheral'' (non-hypothalamic).

As scientifically known so far, the general effects of leptin in the central nervous system are:
*Deficiency of leptin has been shown to alter brain proteins and neuronal functions of obese mice that can be restored by leptin injection <ref name="pmid16293343">{{cite journal | vauthors = Farr SA, Banks WA, Morley JE | title = Effects of leptin on memory processing | journal = Peptides | volume = 27 | issue = 6 | pages = 1420–1425 | date = June 2006 | pmid = 16293343 | doi = 10.1016/j.peptides.2005.10.006 | s2cid = 42496027 }}</ref>
*Leptin receptor signaling in the hippocampus enhances learning and memory <ref name="pmid30692905" /> Treatment with leptin has been shown to enhance learning and memory in animal models.<ref name="pmid30692905" />
*In humans, low circulating plasma leptin has been associated with cognitive changes associated with anorexia,<ref name="pmid9169091">{{cite journal | vauthors = Casanueva FF, Dieguez C, Popovic V, Peino R, Considine RV, Caro JF | title = Serum immunoreactive leptin concentrations in patients with anorexia nervosa before and after partial weight recovery | journal = Biochemical and Molecular Medicine | volume = 60 | issue = 2 | pages = 116–120 | date = April 1997 | pmid = 9169091 | doi = 10.1006/bmme.1996.2564 }}</ref> depression, and Alzheimer's Disease <ref name="pmid20009056">{{cite journal | vauthors = Lieb W, Beiser AS, Vasan RS, Tan ZS, Au R, Harris TB, Roubenoff R, Auerbach S, DeCarli C, Wolf PA, Seshadri S | display-authors = 6 | title = Association of plasma leptin levels with incident Alzheimer disease and MRI measures of brain aging | journal = JAMA | volume = 302 | issue = 23 | pages = 2565–2572 | date = December 2009 | pmid = 20009056 | pmc = 2838501 | doi = 10.1001/jama.2009.1836 }}</ref>
*Studies in transgenic mouse models of Alzheimer's disease have shown that chronic administration of leptin can ameliorate brain pathology and improve cognitive performance,<ref name="pmid20308782">{{cite journal | vauthors = Greco SJ, Bryan KJ, Sarkar S, Zhu X, Smith MA, Ashford JW, Johnston JM, Tezapsidis N, Casadesus G | display-authors = 6 | title = Leptin reduces pathology and improves memory in a transgenic mouse model of Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 19 | issue = 4 | pages = 1155–1167 | year = 2010 | pmid = 20308782 | pmc = 2862270 | doi = 10.3233/JAD-2010-1308 }}</ref> by reducing b-amyloid and hyperphosphorylated Tau,<ref name="pmid22921154">{{cite journal | vauthors = Doherty GH, Beccano-Kelly D, Yan SD, Gunn-Moore FJ, Harvey J | title = Leptin prevents hippocampal synaptic disruption and neuronal cell death induced by amyloid β | journal = Neurobiology of Aging | volume = 34 | issue = 1 | pages = 226–237 | date = January 2013 | pmid = 22921154 | doi = 10.1016/j.neurobiolaging.2012.08.003 | s2cid = 24676545 }}</ref><ref name="pmid19166821">{{cite journal | vauthors = Greco SJ, Sarkar S, Johnston JM, Tezapsidis N | title = Leptin regulates tau phosphorylation and amyloid through AMPK in neuronal cells | journal = Biochemical and Biophysical Research Communications | volume = 380 | issue = 1 | pages = 98–104 | date = February 2009 | pmid = 19166821 | pmc = 2657956 | doi = 10.1016/j.bbrc.2009.01.041 }}</ref> two hallmarks of Alzheimer's pathology.

Generally, leptin is thought to enter the brain at the [[choroid plexus]], where the intense expression of a form of leptin receptor molecule could act as a transport mechanism.<ref name="pmid8645274">{{cite journal | vauthors = Lynn RB, Cao GY, Considine RV, Hyde TM, Caro JF | title = Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice | journal = Biochemical and Biophysical Research Communications | volume = 219 | issue = 3 | pages = 884–889 | date = February 1996 | pmid = 8645274 | doi = 10.1006/bbrc.1996.0328 }}</ref>

Increased levels of [[melatonin]] causes a downregulation of leptin,<ref name="pmid15311999">{{cite journal | vauthors = Kus I, Sarsilmaz M, Colakoglu N, Kukne A, Ozen OA, Yilmaz B, Kelestimur H | title = Pinealectomy increases and exogenous melatonin decreases leptin production in rat anterior pituitary cells: an immunohistochemical study | journal = Physiological Research | volume = 53 | issue = 4 | pages = 403–408 | year = 2004 | doi = 10.33549/physiolres.930478 | pmid = 15311999 | s2cid = 1664461 | doi-access = free }}</ref> however, melatonin also appears to increase leptin levels in the presence of [[insulin]], therefore causing a decrease in appetite during sleeping.<ref name="pmid15572654">{{cite journal | vauthors = Alonso-Vale MI, Andreotti S, Peres SB, Anhê GF, das Neves Borges-Silva C, Neto JC, Lima FB | title = Melatonin enhances leptin expression by rat adipocytes in the presence of insulin | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 288 | issue = 4 | pages = E805–812 | date = April 2005 | pmid = 15572654 | doi = 10.1152/ajpendo.00478.2004 | s2cid = 187830 }}</ref> Partial sleep deprivation has also been associated with decreased leptin levels.<ref>{{cite journal | vauthors = Copinschi G | title = Metabolic and endocrine effects of sleep deprivation | journal = Essential Psychopharmacology | volume = 6 | issue = 6 | pages = 341–347 | year = 2005 | pmid = 16459757 }}</ref>

Mice with type 1 diabetes treated with leptin or leptin plus insulin, compared to insulin alone had better metabolic profiles: blood sugar did not fluctuate so much; cholesterol levels decreased; less body fat formed.<ref name="pmid20194735">{{cite journal | vauthors = Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH | display-authors = 6 | title = Leptin therapy in insulin-deficient type I diabetes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 11 | pages = 4813–4819 | date = March 2010 | pmid = 20194735 | pmc = 2841945 | doi = 10.1073/pnas.0909422107| doi-access = free | bibcode = 2010PNAS..107.4813W }}*{{lay source |template=cite web|vauthors = Dotinga R|url= http://www.medicinenet.com/script/main/art.asp?articlekey=113886 |title=Hormone Outperforms Insulin in Diabetic Mice|date=March 1, 2010 |website= MedicineNet.com }}</ref>

==== Hypothalamus ====
[[File:Summary of the different ways leptin can indirectly affect POMC neurons.jpg|thumb|Summary of the different ways leptin can indirectly affect POMC neurons]]
Leptin acts on [[Leptin receptor|receptors]] in the lateral [[hypothalamus]] to inhibit hunger and the medial hypothalamus to stimulate satiety.<ref name="Elmquist_1999">{{cite journal | vauthors = Elmquist JK, Elias CF, Saper CB | title = From lesions to leptin: hypothalamic control of food intake and body weight | journal = Neuron | volume = 22 | issue = 2 | pages = 221–232 | date = February 1999 | pmid = 10069329 | doi = 10.1016/S0896-6273(00)81084-3 | s2cid = 1712670 | doi-access = free }}</ref>
*In the lateral hypothalamus, leptin inhibits hunger <ref name="pmid10482243">{{cite journal | vauthors = Elias CF, Aschkenasi C, Lee C, Kelly J, Ahima RS, Bjorbaek C, Flier JS, Saper CB, Elmquist JK | display-authors = 6 | title = Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area | journal = Neuron | volume = 23 | issue = 4 | pages = 775–786 | date = August 1999 | pmid = 10482243 | doi = 10.1016/S0896-6273(01)80035-0 | s2cid = 18748215 | doi-access = free }}</ref> by
**counteracting the effects of [[neuropeptide Y]], a potent hunger promoter secreted by cells in the gut and in the hypothalamus
**counteracting the effects of [[anandamide]], another potent hunger promoter that binds to the same receptors as [[THC]]
*In the medial hypothalamus, leptin stimulates satiety <ref>{{cite journal | vauthors = Fekete C, Légrádi G, Mihály E, Huang QH, Tatro JB, Rand WM, Emerson CH, Lechan RM | display-authors = 6 | title = alpha-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression | journal = The Journal of Neuroscience | volume = 20 | issue = 4 | pages = 1550–1558 | date = February 2000 | pmid = 10662844 | pmc = 6772359 | doi = 10.1523/JNEUROSCI.20-04-01550.2000 }}</ref> by
**promoting the synthesis of [[α-MSH]], a hunger suppressant
Thus, a lesion in the lateral hypothalamus causes anorexia (due to a lack of hunger signals) and a lesion in the medial hypothalamus causes excessive hunger (due to a lack of satiety signals).<ref name="Elmquist_1999"/>
This appetite inhibition is long-term, in contrast to the rapid inhibition of hunger by [[cholecystokinin]] (CCK) and the slower suppression of hunger between meals mediated by [[PYY3-36]]. The absence of leptin (or its receptor) leads to uncontrolled hunger and resulting obesity. Fasting or following a very-low-calorie diet lowers leptin levels.<ref>{{cite journal | vauthors = Dubuc GR, Phinney SD, Stern JS, Havel PJ | title = Changes of serum leptin and endocrine and metabolic parameters after 7 days of energy restriction in men and women | journal = Metabolism | volume = 47 | issue = 4 | pages = 429–434 | date = April 1998 | pmid = 9550541 | doi = 10.1016/S0026-0495(98)90055-5 | url = http://www.escholarship.org/uc/item/9990k8xf }}</ref><ref>{{cite journal | vauthors = Pratley RE, Nicolson M, Bogardus C, Ravussin E | title = Plasma leptin responses to fasting in Pima Indians | journal = The American Journal of Physiology | volume = 273 | issue = 3 Pt 1 | pages = E644–649 | date = September 1997 | pmid = 9316457 | doi = 10.1152/ajpendo.1997.273.3.E644 }}</ref><ref>{{cite journal | vauthors = Weigle DS, Duell PB, Connor WE, Steiner RA, Soules MR, Kuijper JL | title = Effect of fasting, refeeding, and dietary fat restriction on plasma leptin levels | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 2 | pages = 561–535 | date = February 1997 | doi = 10.1210/jcem.82.2.3757 | pmid = 9024254 | hdl = 1773/4373 | s2cid = 7959485 | url = https://digital.lib.washington.edu:443/researchworks/bitstream/1773/4373/2/JCEM_1997_Effect_Fasting_Refeeding.pdf }}</ref><ref name="Nov 26 2013">{{cite journal | vauthors = Wadden TA, Considine RV, Foster GD, Anderson DA, Sarwer DB, Caro JS | title = Short- and long-term changes in serum leptin dieting obese women: effects of caloric restriction and weight loss | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 83 | issue = 1 | pages = 214–218 | date = January 1998 | pmid = 9435444 | doi = 10.1210/jcem.83.1.4494 | s2cid = 7592234 | doi-access = free }}</ref> 
Leptin levels change more when food intake decreases than when it increases.<ref>{{cite journal | vauthors = Chin-Chance C, Polonsky KS, Schoeller DA | title = Twenty-four-hour leptin levels respond to cumulative short-term energy imbalance and predict subsequent intake | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 85 | issue = 8 | pages = 2685–2691 | date = August 2000 | doi = 10.1210/jcem.85.8.6755 | pmid = 10946866 | doi-access = free }}</ref> The dynamics of leptin due to an acute change in energy balance may be related to appetite and eventually, to food intake rather than fat stores.<ref>{{cite journal | vauthors = Keim NL, Stern JS, Havel PJ | title = Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women | journal = The American Journal of Clinical Nutrition | volume = 68 | issue = 4 | pages = 794–801 | date = October 1998 | pmid = 9771856 | doi = 10.1093/ajcn/68.4.794 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mars M, de Graaf C, de Groot CP, van Rossum CT, Kok FJ | title = Fasting leptin and appetite responses induced by a 4-day 65%-energy-restricted diet | journal = International Journal of Obesity | volume = 30 | issue = 1 | pages = 122–128 | date = January 2006 | pmid = 16158086 | doi = 10.1038/sj.ijo.0803070 | hdl = 10029/4914 | s2cid = 6769226 | hdl-access = free }}</ref>

* It controls food intake and energy expenditure by acting on receptors in the mediobasal [[hypothalamus]].<ref name="pmid19176744">{{cite journal | vauthors = Williams KW, Scott MM, Elmquist JK | title = From observation to experimentation: leptin action in the mediobasal hypothalamus | journal = The American Journal of Clinical Nutrition | volume = 89 | issue = 3 | pages = 985S–990S | date = March 2009 | pmid = 19176744 | pmc = 2667659 | doi = 10.3945/ajcn.2008.26788D }}</ref>

Leptin binds to [[neuropeptide Y]] (NPY) neurons in the [[arcuate nucleus]] in such a way as to decrease the activity of these neurons. Leptin signals to the hypothalamus which produces a feeling of satiety. Moreover, leptin signals may make it easier for people to resist the temptation of foods high in calories.<ref name="pmid17986612">{{cite journal | vauthors = Baicy K, London ED, Monterosso J, Wong ML, Delibasi T, Sharma A, Licinio J | title = Leptin replacement alters brain response to food cues in genetically leptin-deficient adults | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 46 | pages = 18276–18279 | date = November 2007 | pmid = 17986612 | pmc = 2084333 | doi = 10.1073/pnas.0706481104 |doi-access = free | bibcode = 2007PNAS..10418276B }}*{{lay source |template=cite web|vauthors = Hitti M|url= http://www.webmd.com/brain/news/20071029/hormone-leptin-tweaks-hungry-brain |title=Hormone Leptin Tweaks Hungry Brain|date=October 29, 2007 |website= WebMD }}</ref>

Leptin receptor activation inhibits neuropeptide Y and [[agouti-related peptide]] (AgRP), and activates [[α-melanocyte-stimulating hormone]] (α-MSH). The NPY neurons are a key element in the regulation of hunger; small doses of NPY injected into the brains of experimental animals stimulates feeding, while selective destruction of the NPY neurons in mice causes them to become anorexic. Conversely, α-MSH is an important mediator of satiety, and differences in the gene for the α-MSH receptor are linked to obesity in humans.

Leptin interacts with six types of receptors (Ob-Ra–Ob-Rf, or LepRa-LepRf), which in turn are encoded by a single gene, [[leptin receptor|LEPR]].<ref name="pmid8772180">{{cite journal | vauthors = Wang MY, Zhou YT, Newgard CB, Unger RH | title = A novel leptin receptor isoform in rat | journal = FEBS Letters | volume = 392 | issue = 2 | pages = 87–90 | date = August 1996 | pmid = 8772180 | doi = 10.1016/0014-5793(96)00790-9 | bibcode = 1996FEBSL.392...87W | s2cid = 28037249 }}</ref> Ob-Rb is the only receptor isoform that can signal [[intracellular]]ly via the [[JAK-STAT signaling pathway|JAK-STAT]] and [[MAPK]] [[signal transduction pathways]],<ref name="pmid16964413">{{cite journal | vauthors = Malendowicz W, Rucinski M, Macchi C, Spinazzi R, Ziolkowska A, Nussdorfer GG, Kwias Z | title = Leptin and leptin receptors in the prostate and seminal vesicles of the adult rat | journal = International Journal of Molecular Medicine | volume = 18 | issue = 4 | pages = 615–618 | date = October 2006 | pmid = 16964413 | doi = 10.3892/ijmm.18.4.615 | doi-access = free }}</ref> and is present in [[hypothalamus|hypothalamic nuclei]].<ref>{{cite web|url=http://www.neuromics.com/ittrium/visit?path=A1x66x1y1x9fx1y1x246x1y1x372x1x82y1x35d4x1x7f|title=LepRb antibody (commercial site)|access-date=2009-01-07|archive-url=https://web.archive.org/web/20110714165932/http://www.neuromics.com/ittrium/visit?path=A1x66x1y1x9fx1y1x246x1y1x372x1x82y1x35d4x1x7f|archive-date=2011-07-14|url-status=dead}}</ref>

Once leptin has bound to the Ob-Rb receptor, it activates the stat3, which is phosphorylated and travels to the nucleus to effect changes in gene expression, one of the main effects being the down-regulation of the expression of [[endocannabinoids]], responsible for increasing hunger.<ref name="pmid18563385">{{cite journal | vauthors = Di Marzo V | title = The endocannabinoid system in obesity and type 2 diabetes | journal = Diabetologia | volume = 51 | issue = 8 | pages = 1356–1367 | date = August 2008 | pmid = 18563385 | doi = 10.1007/s00125-008-1048-2 | s2cid = 21487407 | doi-access = free }}</ref> In response to leptin, receptor neurons have been shown to remodel themselves, changing the number and types of synapses that fire onto them.

=== Circulatory system ===
The role of leptin/leptin receptors in modulation of [[T cell]] activity and the innate immune system was shown in experimentation with mice. It modulates the immune response to atherosclerosis, of which obesity is a predisposing and exercise a mitigating factor.<ref name=Taleb>{{cite journal | vauthors = Taleb S, Herbin O, Ait-Oufella H, Verreth W, Gourdy P, Barateau V, Merval R, Esposito B, Clément K, Holvoet P, Tedgui A, Mallat Z | display-authors = 6 | title = Defective leptin/leptin receptor signaling improves regulatory T cell immune response and protects mice from atherosclerosis | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 27 | issue = 12 | pages = 2691–2698 | date = December 2007 | pmid = 17690315 | doi = 10.1161/ATVBAHA.107.149567 | s2cid = 17955869 | doi-access = free }}</ref><ref name="ReferenceA">{{cite journal | vauthors = Frodermann V, Rohde D, Courties G, Severe N, Schloss MJ, Amatullah H, McAlpine CS, Cremer S, Hoyer FF, Ji F, van Koeverden ID, Herisson F, Honold L, Masson GS, Zhang S, Grune J, Iwamoto Y, Schmidt SP, Wojtkiewicz GR, Lee IH, Gustafsson K, Pasterkamp G, de Jager SC, Sadreyev RI, MacFadyen J, Libby P, Ridker P, Scadden DT, Naxerova K, Jeffrey KL, Swirski FK, Nahrendorf M | display-authors = 6 | title = Exercise reduces inflammatory cell production and cardiovascular inflammation via instruction of hematopoietic progenitor cells | journal = Nature Medicine | volume = 25 | issue = 11 | pages = 1761–1771 | date = November 2019 | pmid = 31700184 | pmc = 6858591 | doi = 10.1038/s41591-019-0633-x }}</ref>

Exogenous leptin can promote [[angiogenesis]] by increasing [[vascular endothelial growth factor]] levels.

Hyperleptinemia produced by infusion or adenoviral gene transfer decreases blood pressure in rats.<ref name=Zhang>{{cite journal | vauthors = Zhang W, Telemaque S, Augustyniak RA, Anderson P, Thomas GD, An J, Wang Z, Newgard CB, Victor RG | display-authors = 6 | title = Adenovirus-mediated leptin expression normalises hypertension associated with diet-induced obesity | journal = Journal of Neuroendocrinology | volume = 22 | issue = 3 | pages = 175–180 | date = March 2010 | pmid = 20059648 | doi = 10.1111/j.1365-2826.2010.01953.x | s2cid = 25716300 }}</ref><ref name=Knight>{{cite journal | vauthors = Knight WD, Seth R, Boron J, Overton JM | title = Short-term physiological hyperleptinemia decreases arterial blood pressure | journal = Regulatory Peptides | volume = 154 | issue = 1–3 | pages = 60–68 | date = April 2009 | pmid = 19323984 | doi = 10.1016/j.regpep.2009.02.001 | s2cid = 3221720 }}</ref>

Leptin microinjections into the [[nucleus of the solitary tract]] (NTS) have been shown to elicit sympathoexcitatory responses, and potentiate the cardiovascular responses to activation of the chemoreflex.<ref>{{cite journal | vauthors = Ciriello J, Moreau JM | title = Systemic administration of leptin potentiates the response of neurons in the nucleus of the solitary tract to chemoreceptor activation in the rat | journal = Neuroscience | volume = 229 | pages = 88–99 | date = January 2013 | pmid = 23159310 | doi = 10.1016/j.neuroscience.2012.10.065 | s2cid = 22852202 }}</ref>

=== Fetal lung ===
In [[fetal lung]], leptin is induced in the alveolar interstitial fibroblasts ("lipofibroblasts") by the action of [[PTHrP]] secreted by formative alveolar epithelium ([[endoderm]]) under moderate stretch. The leptin from the [[mesenchyme]], in turn, acts back on the epithelium at the leptin receptor carried in the alveolar type II pneumocytes and induces surfactant expression, which is one of the main functions of these type II pneumocytes.<ref name="pmid16940239">{{cite journal | vauthors = Torday JS, Rehan VK | title = Up-regulation of fetal rat lung parathyroid hormone-related protein gene regulatory network down-regulates the Sonic Hedgehog/Wnt/betacatenin gene regulatory network | journal = Pediatric Research | volume = 60 | issue = 4 | pages = 382–388 | date = October 2006 | pmid = 16940239 | doi = 10.1203/01.pdr.0000238326.42590.03 | s2cid = 21101408 | doi-access = free }}</ref>

=== Reproductive system ===
==== Ovulatory cycle ====
In mice, and to a lesser extent in humans, leptin is required for male and female [[fertility]]. Ovulatory cycles in females are linked to energy balance (positive or negative depending on whether a female is losing or gaining weight) and energy flux (how much energy is consumed and expended) much more than energy status (fat levels). When energy balance is highly negative (meaning the woman is starving) or energy flux is very high (meaning the woman is exercising at extreme levels, but still consuming enough calories), the ovarian cycle stops and females stop menstruating. Only if a female has an extremely low body fat percentage does energy status affect menstruation. Leptin levels outside an ideal range may have a negative effect on egg quality and outcome during ''in vitro'' fertilization.<ref name="pmid15798029">{{cite journal | vauthors = Anifandis G, Koutselini E, Louridas K, Liakopoulos V, Leivaditis K, Mantzavinos T, Sioutopoulou D, Vamvakopoulos N | display-authors = 6 | title = Estradiol and leptin as conditional prognostic IVF markers | journal = Reproduction | volume = 129 | issue = 4 | pages = 531–534 | date = April 2005 | pmid = 15798029 | doi = 10.1530/rep.1.00567 | s2cid = 11398376 | doi-access = free }}</ref> Leptin is involved in reproduction by stimulating [[gonadotropin-releasing hormone]] from the [[hypothalamus]].<ref name="pmid24173881">{{cite journal | vauthors = Comninos AN, Jayasena CN, Dhillo WS | title = The relationship between gut and adipose hormones, and reproduction | journal = Human Reproduction Update | volume = 20 | issue = 2 | pages = 153–174 | year = 2014 | pmid = 24173881 | doi = 10.1093/humupd/dmt033 | s2cid = 18645125 | doi-access = free }}</ref>

==== Pregnancy ====
The placenta produces leptin.<ref>{{cite journal | vauthors = Zhao J, Townsend KL, Schulz LC, Kunz TH, Li C, Widmaier EP | title = Leptin receptor expression increases in placenta, but not hypothalamus, during gestation in Mus musculus and Myotis lucifugus | journal = Placenta | volume = 25 | issue = 8–9 | pages = 712–722 | year = 2004 | pmid = 15450389 | doi = 10.1016/j.placenta.2004.01.017 }}</ref> Leptin levels rise during pregnancy and fall after childbirth. Leptin is also expressed in fetal membranes and the uterine tissue. Uterine contractions are inhibited by leptin.<ref>{{cite journal | vauthors = Moynihan AT, Hehir MP, Glavey SV, Smith TJ, Morrison JJ | title = Inhibitory effect of leptin on human uterine contractility in vitro | journal = American Journal of Obstetrics and Gynecology | volume = 195 | issue = 2 | pages = 504–509 | date = August 2006 | pmid = 16647683 | doi = 10.1016/j.ajog.2006.01.106 }}</ref> Leptin plays a role in [[hyperemesis gravidarum]] (severe [[morning sickness]] of pregnancy),<ref>{{cite journal | vauthors = Aka N, Atalay S, Sayharman S, Kiliç D, Köse G, Küçüközkan T | title = Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum | journal = The Australian & New Zealand Journal of Obstetrics & Gynaecology | volume = 46 | issue = 4 | pages = 274–277 | date = August 2006 | pmid = 16866785 | doi = 10.1111/j.1479-828X.2006.00590.x | s2cid = 72562308 }}</ref> in [[polycystic ovary syndrome]],<ref>{{cite journal | vauthors = Cervero A, Domínguez F, Horcajadas JA, Quiñonero A, Pellicer A, Simón C | title = The role of the leptin in reproduction | journal = Current Opinion in Obstetrics & Gynecology | volume = 18 | issue = 3 | pages = 297–303 | date = June 2006 | pmid = 16735830 | doi = 10.1097/01.gco.0000193004.35287.89 | s2cid = 7681765 }}</ref><!-- to check: literature is controversial --> and hypothalamic leptin is implicated in bone growth in mice.<ref>{{cite journal | vauthors = Iwaniec UT, Boghossian S, Lapke PD, Turner RT, Kalra SP | title = Central leptin gene therapy corrects skeletal abnormalities in leptin-deficient ob/ob mice | journal = Peptides | volume = 28 | issue = 5 | pages = 1012–1019 | date = May 2007 | pmid = 17346852 | pmc = 1986832 | doi = 10.1016/j.peptides.2007.02.001 }}</ref>

==== Lactation ====
Immunoreactive leptin has been found in human breast milk; and leptin from mother's milk has been found in the blood of suckling infant animals.<ref name="pmid9398752">{{cite journal | vauthors = Casabiell X, Piñeiro V, Tomé MA, Peinó R, Diéguez C, Casanueva FF | title = Presence of leptin in colostrum and/or breast milk from lactating mothers: a potential role in the regulation of neonatal food intake | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 12 | pages = 4270–4273 | date = December 1997 | pmid = 9398752 | doi = 10.1210/jcem.82.12.4590 | doi-access = free }}</ref>

==== Puberty ====
Leptin along with [[kisspeptin]] controls the onset of puberty.<ref name="pmid23998663">{{cite journal | vauthors = Sanchez-Garrido MA, Tena-Sempere M | title = Metabolic control of puberty: roles of leptin and kisspeptins | journal = Hormones and Behavior | volume = 64 | issue = 2 | pages = 187–194 | date = July 2013 | pmid = 23998663 | doi = 10.1016/j.yhbeh.2013.01.014 | s2cid = 27078496 }}</ref> High levels of leptin, as usually observed in obese females, can trigger neuroendocrine cascade resulting in early menarche.<ref name="pmid9329346">{{cite journal | vauthors = Matkovic V, Ilich JZ, Skugor M, Badenhop NE, Goel P, Clairmont A, Klisovic D, Nahhas RW, Landoll JD | display-authors = 6 | title = Leptin is inversely related to age at menarche in human females | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 10 | pages = 3239–3345 | date = October 1997 | doi = 10.1210/jcem.82.10.4280 | pmid = 9329346 | s2cid = 24926542 | doi-access = free }}</ref> This may eventually lead to shorter [[Human stature|stature]] as [[oestrogen]] secretion starts during menarche and causes early closure of [[epiphyses]].

=== Bone ===
Leptin's role in regulating bone mass was identified in 2000.<ref name="Dance">{{cite journal |vauthors = Dance A |title=Fun facts about bones: More than just scaffolding |journal=Knowable Magazine |date=23 February 2022 |doi=10.1146/knowable-022222-1|doi-access=free |url=https://knowablemagazine.org/article/health-disease/2022/fun-facts-about-bones-more-just-scaffolding |access-date=8 March 2022}}</ref><ref name="pmid10660043">{{cite journal | vauthors = Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G | display-authors = 6 | title = Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass | journal = Cell | volume = 100 | issue = 2 | pages = 197–207 | date = January 2000 | pmid = 10660043 | doi = 10.1016/S0092-8674(00)81558-5 | s2cid = 17873790 | doi-access = free }}</ref> Leptin can affect [[bone metabolism]] via direct signalling from the brain. Leptin decreases [[cancellous bone]], but increases [[cortical bone]]. This "cortical-cancellous dichotomy" may represent a mechanism for enlarging bone size, and thus bone resistance, to cope with increased body weight.<ref name="pmid17924050">{{cite journal | vauthors = Hamrick MW, Ferrari SL | title = Leptin and the sympathetic connection of fat to bone | journal = Osteoporosis International | volume = 19 | issue = 7 | pages = 905–912 | date = July 2008 | pmid = 17924050 | doi = 10.1007/s00198-007-0487-9 | s2cid = 8825233 }}</ref>

Bone metabolism can be regulated by central sympathetic outflow, since sympathetic pathways innervate bone tissue.<ref name="Allison_2006">{{cite book | vauthors = Allison SJ, Herzog H | title = NPY Family of Peptides in Neurobiology, Cardiovascular and Metabolic Disorders: From Genes to Therapeutics | chapter = NPY and bone | journal = Exs | volume = 95 | issue = 95 | pages = 171–182 | year = 2006 | pmid = 16383006 | doi = 10.1007/3-7643-7417-9_13 | isbn = 3-7643-7155-2 | series = Experientia Supplementum }}</ref> A number of brain-signalling molecules ([[neuropeptides]] and [[neurotransmitters]]) have been found in bone, including [[adrenaline]], [[noradrenaline]], [[serotonin]], [[calcitonin gene-related peptide]], [[vasoactive intestinal peptide]], and [[neuropeptide Y]].<ref name="Allison_2006"/><ref name="pmid12577304">{{cite journal | vauthors = Gordeladze JO, Reseland JE | title = A unified model for the action of leptin on bone turnover | journal = Journal of Cellular Biochemistry | volume = 88 | issue = 4 | pages = 706–712 | date = March 2003 | pmid = 12577304 | doi = 10.1002/jcb.10385 | s2cid = 35669344 }}</ref> Leptin binds to its receptors in the hypothalamus, where it acts through the [[sympathetic nervous system]] to regulate bone metabolism.<ref name="pmid12419242">{{cite journal | vauthors = Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G | display-authors = 6 | title = Leptin regulates bone formation via the sympathetic nervous system | journal = Cell | volume = 111 | issue = 3 | pages = 305–317 | date = November 2002 | pmid = 12419242 | doi = 10.1016/S0092-8674(02)01049-8 | s2cid = 11171580 | doi-access = free }}</ref> Leptin may also act directly on bone metabolism via a balance between energy intake and the IGF-I pathway.<ref name="pmid17924050"/><ref name="pmid17431002">{{cite journal | vauthors = Martin A, David V, Malaval L, Lafage-Proust MH, Vico L, Thomas T | title = Opposite effects of leptin on bone metabolism: a dose-dependent balance related to energy intake and insulin-like growth factor-I pathway | journal = Endocrinology | volume = 148 | issue = 7 | pages = 3419–3425 | date = July 2007 | pmid = 17431002 | doi = 10.1210/en.2006-1541 | doi-access = free }}</ref> There is a potential for treatment of diseases of bone formation - such as impaired fracture healing - with leptin.<ref name="pmid24343796">{{cite journal | vauthors = Rőszer T, Józsa T, Kiss-Tóth ED, De Clerck N, Balogh L | title = Leptin receptor deficient diabetic (db/db) mice are compromised in postnatal bone regeneration | journal = Cell and Tissue Research | volume = 356 | issue = 1 | pages = 195–206 | date = April 2014 | pmid = 24343796 | doi = 10.1007/s00441-013-1768-6 | s2cid = 2422805 }}</ref>

=== Immune system ===
Factors that acutely affect leptin levels are also factors that influence other markers of inflammation, e.g., testosterone, sleep, emotional stress, caloric restriction, and body fat levels. While it is well-established that leptin is involved in the regulation of the [[Inflammation|inflammatory]] response,<ref name="pmid9732873">{{cite journal | vauthors = Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI | title = Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression | journal = Nature | volume = 394 | issue = 6696 | pages = 897–901 | date = August 1998 | pmid = 9732873 | doi = 10.1038/29795 | s2cid = 4431600 | bibcode = 1998Natur.394..897L }}</ref><ref name="Fantuzzi_2000">{{cite journal | vauthors = Fantuzzi G, Faggioni R | title = Leptin in the regulation of immunity, inflammation, and hematopoiesis | journal = Journal of Leukocyte Biology | volume = 68 | issue = 4 | pages = 437–446 | date = October 2000 | doi = 10.1189/jlb.68.4.437 | pmid = 11037963 | s2cid = 8680598 | doi-access = free }}</ref><ref name="Caldefie-Chezet 2001">{{cite journal | vauthors = Caldefie-Chezet F, Poulin A, Tridon A, Sion B, Vasson MP | title = Leptin: a potential regulator of polymorphonuclear neutrophil bactericidal action? | journal = Journal of Leukocyte Biology | volume = 69 | issue = 3 | pages = 414–418 | date = March 2001 | doi = 10.1189/jlb.69.3.414 | pmid = 11261788 | s2cid = 15787413 }}</ref> it has been further theorized that leptin's role as an inflammatory marker is to respond specifically to adipose-derived inflammatory [[cytokines]].

In terms of both structure and function, leptin resembles [[Interleukin 6|IL-6]] and is a member of the cytokine [[Protein family|superfamily]].<ref name="pmid9144295"/><ref name="Fantuzzi_2000"/><ref name="Madej_1995">{{cite journal | author1 = Madej T| author2 =Boguski MS|author-link2=Mark Boguski|author3 = Bryant SH | title = Threading analysis suggests that the obese gene product may be a helical cytokine | journal = FEBS Letters | volume = 373 | issue = 1 | pages = 13–18 | date = October 1995 | pmid = 7589424 | doi = 10.1016/0014-5793(95)00977-H | bibcode =1995FEBSL.373...13M| s2cid = 25961554 | citeseerx = 10.1.1.467.3817 }}</ref> Circulating leptin seems to affect the [[Hypothalamic–pituitary–adrenal axis|HPA axis]], suggesting a role for leptin in stress response.<ref name="pmid9275075">{{cite journal | vauthors = Heiman ML, Ahima RS, Craft LS, Schoner B, Stephens TW, Flier JS | title = Leptin inhibition of the hypothalamic-pituitary-adrenal axis in response to stress | journal = Endocrinology | volume = 138 | issue = 9 | pages = 3859–3863 | date = September 1997 | pmid = 9275075 | doi = 10.1210/endo.138.9.5366 | s2cid = 7601046 | doi-access = free }}</ref> Elevated leptin concentrations are associated with elevated white blood cell counts in both men and women.<ref name="pmid15724240">{{cite journal | vauthors = Mabuchi T, Yatsuya H, Tamakoshi K, Otsuka R, Nagasawa N, Zhang H, Murata C, Wada K, Ishikawa M, Hori Y, Kondo T, Hashimoto S, Toyoshima H | display-authors = 6 | title = Association between serum leptin concentration and white blood cell count in middle-aged Japanese men and women | journal = Diabetes/Metabolism Research and Reviews | volume = 21 | issue = 5 | pages = 441–447 | year = 2005 | pmid = 15724240 | doi = 10.1002/dmrr.540 | s2cid = 10320501 }}</ref>

Similar to what is observed in chronic inflammation, chronically elevated leptin levels are associated with obesity, overeating, and inflammation-related diseases, including [[hypertension]], [[metabolic syndrome]], and [[cardiovascular disease]]. While leptin is associated with body fat mass, the size of individual fat cells, and overeating, it is not affected by exercise (for comparison, [[Inflammation#Post-inflammatory muscle growth and repair|IL-6 is released in response to muscular contractions]]). Thus, it is speculated that leptin responds specifically to adipose-derived inflammation.<ref name="pmid7585224">{{cite journal | vauthors = Hamilton BS, Paglia D, Kwan AY, Deitel M | title = Increased obese mRNA expression in omental fat cells from massively obese humans | journal = Nature Medicine | volume = 1 | issue = 9 | pages = 953–956 | date = September 1995 | pmid = 7585224 | doi = 10.1038/nm0995-953 | s2cid = 24211050 }}</ref> Leptin is a pro-angiogenic, pro-inflammatory, and mitogenic factor, the actions of which are reinforced through crosstalk with IL-1 family cytokines in cancer.<ref name="pmid19111549">{{cite journal | vauthors = Perrier S, Caldefie-Chézet F, Vasson MP | title = IL-1 family in breast cancer: potential interplay with leptin and other adipocytokines | journal = FEBS Letters | volume = 583 | issue = 2 | pages = 259–265 | date = January 2009 | pmid = 19111549 | doi = 10.1016/j.febslet.2008.12.030 | s2cid = 30801028 | doi-access = free | bibcode = 2009FEBSL.583..259P }}</ref> High leptin levels have been also demonstrated in patients with COVID-19 pneumonia.<ref>{{cite journal | vauthors = Tonon F, Di Bella S, Giudici F, Zerbato V, Segat L, Koncan R, Misin A, Toffoli B, D'Agaro P, Luzzati R, Fabris B, Bernardi S | display-authors = 6 | title = Discriminatory Value of Adiponectin to Leptin Ratio for COVID-19 Pneumonia | journal = International Journal of Endocrinology | volume = 2022 | pages = 9908450 | date = 2022-04-26 | pmid = 35529082 | pmc = 9072020 | doi = 10.1155/2022/9908450 | veditors = Salvador J | doi-access = free }}</ref>

Taken as such, increases in leptin levels (in response to caloric intake) function as an acute pro-inflammatory response mechanism to prevent excessive cellular stress induced by overeating. When high caloric intake overtaxes the ability of fat cells to [[hypertrophy|grow larger]] or [[hyperplasia|increase in number]] in step with caloric intake, the ensuing stress response leads to inflammation at the cellular level and ectopic fat storage, i.e., the unhealthy storage of body fat within internal organs, arteries, and/or muscle. The insulin increase in response to the caloric load provokes a dose-dependent rise in leptin, an effect potentiated by high cortisol levels.<ref name="pmid8826983">{{cite journal | vauthors = Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H | display-authors = 6 | title = Insulin and cortisol promote leptin production in cultured human fat cells | journal = Diabetes | volume = 45 | issue = 10 | pages = 1435–1438 | date = October 1996 | pmid = 8826983 | doi = 10.2337/diabetes.45.10.1435 }}</ref> (This insulin-leptin relationship is notably similar to insulin's effect on the increase of IL-6 gene expression and secretion from [[adipocytes|preadipocytes]] in a time- and dose-dependent manner.)<ref name="pmid18617614">{{cite journal | vauthors = LaPensee CR, Hugo ER, Ben-Jonathan N | title = Insulin stimulates interleukin-6 expression and release in LS14 human adipocytes through multiple signaling pathways | journal = Endocrinology | volume = 149 | issue = 11 | pages = 5415–5422 | date = November 2008 | pmid = 18617614 | pmc = 2584585 | doi = 10.1210/en.2008-0549 }}</ref> Furthermore, plasma leptin concentrations have been observed to gradually increase when [[acipimox]] is administered to prevent [[lipolysis]], concurrent hypocaloric dieting and weight loss notwithstanding.<ref name="pmid11022182">{{cite journal | vauthors = Worm D, Vinten J, Vaag A, Henriksen JE, Beck-Nielsen H | title = The nicotinic acid analogue acipimox increases plasma leptin and decreases free fatty acids in type 2 diabetic patients | journal = European Journal of Endocrinology | volume = 143 | issue = 3 | pages = 389–395 | date = September 2000 | pmid = 11022182 | doi = 10.1530/eje.0.1430389 | doi-access = free }}</ref> Such findings appear to demonstrate high caloric loads in excess of storage rate capacities of fat cells lead to stress responses that induce an increase in leptin, which then operates as an adipose-derived inflammation stopgap signaling for the cessation of food intake so as to prevent adipose-derived inflammation from reaching elevated levels. This response may then protect against the harmful process of ectopic fat storage, which perhaps explains the connection between chronically elevated leptin levels and ectopic fat storage in obese individuals.<ref name="pmid8866547"/>

Leptin increases the production of leukocytes via actions on the hematopoietic niche, a pathway that is more active in sedentary mice and humans when compared to individuals who are physically active.<ref name="ReferenceA"/>

== Location of gene and structure of hormone ==
The ''Ob(Lep)'' gene (Ob for obese, Lep for leptin) is located on [[chromosome 7]] in humans.<ref name="pmid8717050">{{cite journal | vauthors = Green ED, Maffei M, Braden VV, Proenca R, DeSilva U, Zhang Y, Chua SC, Leibel RL, Weissenbach J, Friedman JM | display-authors = 6 | title = The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7 | journal = Genome Research | volume = 5 | issue = 1 | pages = 5–12 | date = August 1995 | pmid = 8717050 | doi = 10.1101/gr.5.1.5 | doi-access = free }}</ref> Human leptin is a 16-kDa protein of 167 amino acids.

== Mutations ==
A human mutant leptin was first described in 1997,<ref name="pmid9202122">{{cite journal | vauthors = Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S | display-authors = 6 | title = Congenital leptin deficiency is associated with severe early-onset obesity in humans | journal = Nature | volume = 387 | issue = 6636 | pages = 903–908 | date = June 1997 | pmid = 9202122 | doi = 10.1038/43185 | s2cid = 205032762 | bibcode = 1997Natur.387..903M | doi-access = free }}</ref> and subsequently six additional mutations were described. All of those affected were from Eastern countries; and all had variants of leptin not detected by the standard immunoreactive technique, so leptin levels were low or undetectable. The most recently described eighth mutation reported in January 2015, in a child with Turkish parents, is unique in that it ''is'' detected by the standard immunoreactive technique, where leptin levels are elevated; but the leptin does not turn on the leptin receptor, hence the patient has functional leptin deficiency.<ref name="Wabitsch_2015">{{cite journal | vauthors = Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM, Vatter P, Gierschik P, Moepps B, Fischer-Posovszky P | display-authors = 6 | title = Biologically inactive leptin and early-onset extreme obesity | journal = The New England Journal of Medicine | volume = 372 | issue = 1 | pages = 48–54 | date = January 2015 | pmid = 25551525 | doi = 10.1056/NEJMoa1406653 | doi-access = free }}</ref> These eight mutations all cause extreme obesity in infancy, with [[hyperphagia]].<ref name="Wabitsch_2015"/>

=== Nonsense ===
A [[nonsense mutation]] in the leptin gene that results in a [[stop codon]] and lack of leptin production was first observed in mice. In the mouse gene, arginine-105 is encoded by CGA and only requires one nucleotide change to create the stop codon TGA. The corresponding amino acid in humans is encoded by the sequence CGG and would require two nucleotides to be changed to produce a stop codon, which is much less likely to happen.<ref name="pmid7769141" />

=== Frameshift ===
A recessive [[frameshift mutation]] resulting in a reduction of leptin has been observed in two [[consanguineous]] children with juvenile obesity. A 2001 study of 13 people with a heterozygous frameshift mutation known as delta-G133 found that they had lower blood leptin levels than controls. There was an increased rate of obesity in these individuals, with 76% having a BMI of more than 30 compared to 26% in the control group.<ref>{{cite journal | vauthors = Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R, Jebb SA, Lip GY, O'Rahilly S | display-authors = 6 | title = Partial leptin deficiency and human adiposity | journal = Nature | volume = 414 | issue = 6859 | pages = 34–35 | date = November 2001 | pmid = 11689931 | doi = 10.1038/35102112 | s2cid = 4344492 | bibcode = 2001Natur.414...34F }}</ref>

=== Polymorphisms ===
A Human Genome Equivalent (HuGE) review in 2004 looked at studies of the connection between genetic mutations affecting leptin regulation and obesity. They reviewed a common polymorphism in the leptin gene (A19G; frequency 0.46), three mutations in the [[leptin receptor]] gene (Q223R, K109R, and K656N) and two mutations in the ''[[PPARG]]'' gene (P12A and C161T). They found no association between any of the polymorphisms and obesity.<ref name="pmid15972940">{{cite journal | vauthors = Paracchini V, Pedotti P, Taioli E | title = Genetics of leptin and obesity: a HuGE review | journal = American Journal of Epidemiology | volume = 162 | issue = 2 | pages = 101–114 | date = July 2005 | pmid = 15972940 | doi = 10.1093/aje/kwi174 | doi-access = free }}</ref>

A 2006 study found a link between the common LEP-2548 G/A genotype and morbid obesity in [[Taiwanese aborigines]],<ref name="pmid16571841">{{cite journal | vauthors = Wang TN, Huang MC, Chang WT, Ko AM, Tsai EM, Liu CS, Lee CH, Ko YC | display-authors = 6 | title = G-2548A polymorphism of the leptin gene is correlated with extreme obesity in Taiwanese aborigines | journal = Obesity | volume = 14 | issue = 2 | pages = 183–187 | date = February 2006 | pmid = 16571841 | doi = 10.1038/oby.2006.23 | s2cid = 24231672 }}</ref><ref name="pmid24564125">{{cite journal | vauthors = Zhang L, Lu M, Yuan L, Lai W, Wang Y | title = [Association of leptin gene-2548 G/A polymorphism with obesity: a meta-analysis] | language = zh | journal = Wei Sheng Yan Jiu = Journal of Hygiene Research | volume = 43 | issue = 1 | pages = 128–132 | date = January 2014 | pmid = 24564125 }}</ref> but a 2014 meta-analysis did not,<ref name="pmid24564125"/> however, this polymorphism has been associated with weight gain in patients taking antipsychotics.<ref name="pmid15864111">{{cite journal | vauthors = Templeman LA, Reynolds GP, Arranz B, San L | title = Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis | journal = Pharmacogenetics and Genomics | volume = 15 | issue = 4 | pages = 195–200 | date = April 2005 | pmid = 15864111 | doi = 10.1097/01213011-200504000-00002 | s2cid = 10584758 }}</ref><ref name="pmid17804136">{{cite journal | vauthors = Kang SG, Lee HJ, Park YM, Choi JE, Han C, Kim YK, Kim SH, Lee MS, Joe SH, Jung IK, Kim L | display-authors = 6 | title = Possible association between the -2548A/G polymorphism of the leptin gene and olanzapine-induced weight gain | journal = Progress in Neuro-Psychopharmacology & Biological Psychiatry | volume = 32 | issue = 1 | pages = 160–163 | date = January 2008 | pmid = 17804136 | doi = 10.1016/j.pnpbp.2007.08.002 | s2cid = 53181942 }}</ref><ref name="pmid21937795">{{cite journal | vauthors = Wu R, Zhao J, Shao P, Ou J, Chang M | title = Genetic predictors of antipsychotic-induced weight gain: a case-matched multi-gene study | journal = Zhong Nan da Xue Xue Bao. Yi Xue Ban = Journal of Central South University. Medical Sciences | volume = 36 | issue = 8 | pages = 720–723 | date = August 2011 | pmid = 21937795 | doi = 10.3969/j.issn.1672-7347.2011.08.003 }}</ref>

The LEP-2548 G/A polymorphism has been linked with an increased risk of prostate cancer,<ref name="pmid15042602">{{cite journal | vauthors = Ribeiro R, Vasconcelos A, Costa S, Pinto D, Morais A, Oliveira J, Lobo F, Lopes C, Medeiros R | display-authors = 6 | title = Overexpressing leptin genetic polymorphism (-2548 G/A) is associated with susceptibility to prostate cancer and risk of advanced disease | journal = The Prostate | volume = 59 | issue = 3 | pages = 268–274 | date = May 2004 | pmid = 15042602 | doi = 10.1002/pros.20004 | s2cid = 22787605 }}</ref> gestational diabetes,<ref name="pmid18850205">{{cite journal | vauthors = Vaskú JA, Vaskú A, Dostálová Z, Bienert P | title = Association of leptin genetic polymorphism -2548 G/A with gestational diabetes mellitus | journal = Genes & Nutrition | volume = 1 | issue = 2 | pages = 117–123 | date = June 2006 | pmid = 18850205 | pmc = 3454683 | doi = 10.1007/BF02829953 }}</ref> and osteoporosis.<ref name="pmid23460508">{{cite journal | vauthors = Ye XL, Lu CF | title = Association of polymorphisms in the leptin and leptin receptor genes with inflammatory mediators in patients with osteoporosis | journal = Endocrine | volume = 44 | issue = 2 | pages = 481–488 | date = October 2013 | pmid = 23460508 | doi = 10.1007/s12020-013-9899-9 | s2cid = 19769251 }}</ref>

Other rare polymorphisms have been found, but their association with obesity are not consistent.<ref name="pmid15972940"/>

=== Transversion ===
A single case of a homozygous [[transversion mutation]] of the gene encoding for leptin was reported in January 2015.<ref name="Wabitsch_2015"/> It leads to functional leptin deficiency with high leptin levels in circulation. The transversion of (c.298G → T) changed [[aspartic acid]] to [[tyrosine]] at position 100 (p.D100Y). The mutant leptin could neither bind to nor activate the leptin receptor ''in vitro'', nor in leptin-deficient mice ''in vivo''. It was found in a two-year-old boy with extreme obesity with recurrent ear and pulmonary infections. Treatment with metreleptin led to "rapid change in eating behavior, a reduction in daily energy intake, and substantial weight loss."<ref name="Wabitsch_2015"/>

== Sites of synthesis ==
Leptin is produced primarily in the adipocytes of [[white adipose tissue]]. It also is produced by [[brown adipose tissue]], [[placenta]] (syncytiotrophoblasts), [[ovaries]], [[skeletal muscle]], [[stomach]] (the lower part of the [[fundic glands]]), [[mammary gland|mammary]] [[epithelial cell]]s, [[bone marrow]],<ref name=Margetic>{{cite journal | vauthors = Margetic S, Gazzola C, Pegg GG, Hill RA | title = Leptin: a review of its peripheral actions and interactions | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 26 | issue = 11 | pages = 1407–1433 | date = November 2002 | pmid = 12439643 | doi = 10.1038/sj.ijo.0802142 | s2cid = 6611022 }}</ref> [[gastric chief cell]]s, and [[P/D1 cell]]s.<ref name="pmid9723619">{{cite journal | vauthors = Bado A, Levasseur S, Attoub S, Kermorgant S, Laigneau JP, Bortoluzzi MN, Moizo L, Lehy T, Guerre-Millo M, Le Marchand-Brustel Y, Lewin MJ | display-authors = 6 | title = The stomach is a source of leptin | journal = Nature | volume = 394 | issue = 6695 | pages = 790–793 | date = August 1998 | pmid = 9723619 | doi = 10.1038/29547 | s2cid = 4367948 | bibcode = 1998Natur.394..790B }}</ref>

[[File:Diagram representing where leptin is produced in the human body, where it goes, and what it causes.svg|thumb|Diagram representing where leptin is produced in the human body, where it goes, and what it causes]]

== Blood levels ==
Leptin circulates in blood in free form and bound to proteins.<ref name="pmid8823291">{{cite journal | vauthors = Sinha MK, Opentanova I, Ohannesian JP, Kolaczynski JW, Heiman ML, Hale J, Becker GW, Bowsher RR, Stephens TW, Caro JF | display-authors = 6 | title = Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting | journal = The Journal of Clinical Investigation | volume = 98 | issue = 6 | pages = 1277–1282 | date = September 1996 | pmid = 8823291 | pmc = 507552 | doi = 10.1172/JCI118913 }}</ref>

=== Physiologic variation ===
Leptin levels vary exponentially, not linearly, with fat mass.<ref name="Lönnqvist_1995">{{cite journal | vauthors = Lönnqvist F, Arner P, Nordfors L, Schalling M | title = Overexpression of the obese (ob) gene in adipose tissue of human obese subjects | journal = Nature Medicine | volume = 1 | issue = 9 | pages = 950–953 | date = September 1995 | pmid = 7585223 | doi = 10.1038/nm0995-950 | s2cid = 2661056 }}</ref><ref name = "Madej_1998">{{cite journal | vauthors = Madej T | title = Considerations in the use of lipid-based drug products | journal = Journal of Intravenous Nursing | volume = 21 | issue = 6 | pages = 326 | year = 1998 | pmid = 10392096 }}</ref> Leptin levels in blood are higher between midnight and early morning, perhaps suppressing appetite during the night.<ref name="pmid8636448">{{cite journal | vauthors = Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF | display-authors = 6 | title = Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects | journal = The Journal of Clinical Investigation | volume = 97 | issue = 5 | pages = 1344–1347 | date = March 1996 | pmid = 8636448 | pmc = 507189 | doi = 10.1172/JCI118551 }}</ref> The diurnal rhythm of blood leptin levels may be modified by meal-timing.<ref name="pmid9312190">{{cite journal | vauthors = Schoeller DA, Cella LK, Sinha MK, Caro JF | title = Entrainment of the diurnal rhythm of plasma leptin to meal timing | journal = The Journal of Clinical Investigation | volume = 100 | issue = 7 | pages = 1882–1887 | date = October 1997 | pmid = 9312190 | pmc = 508375 | doi = 10.1172/JCI119717 }}</ref>

=== In specific conditions ===
In humans, many instances are seen where leptin dissociates from the strict role of communicating nutritional status between body and brain and no longer correlates with body fat levels:
* Leptin plays a critical role in the adaptive response to starvation.<ref name="pmid8717038">{{cite journal | vauthors = Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS | title = Role of leptin in the neuroendocrine response to fasting | journal = Nature | volume = 382 | issue = 6588 | pages = 250–252 | date = July 1996 | pmid = 8717038 | doi = 10.1038/382250a0 | s2cid = 4331304 | bibcode = 1996Natur.382..250A }}</ref><ref name="pmid19190071">{{cite journal | vauthors = Friedman JM | title = Leptin at 14 y of age: an ongoing story | journal = The American Journal of Clinical Nutrition | volume = 89 | issue = 3 | pages = 973S–979S | date = March 2009 | pmid = 19190071 | pmc = 2667654 | doi = 10.3945/ajcn.2008.26788B }}</ref>
* Leptin level is decreased after short-term [[fasting]] (24–72 hours), even when changes in fat mass are not observed.<ref name="pmid12727933">{{cite journal | vauthors = Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS | title = The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men | journal = The Journal of Clinical Investigation | volume = 111 | issue = 9 | pages = 1409–1421 | date = May 2003 | pmid = 12727933 | pmc = 154448 | doi = 10.1172/JCI17490 }}</ref><ref name="pmid8866554">{{cite journal | vauthors = Kolaczynski JW, Considine RV, Ohannesian J, Marco C, Opentanova I, Nyce MR, Myint M, Caro JF | display-authors = 6 | title = Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves | journal = Diabetes | volume = 45 | issue = 11 | pages = 1511–1515 | date = November 1996 | pmid = 8866554 | doi = 10.2337/diab.45.11.1511 | s2cid = 27173749 }}</ref><ref name="pmid8923877">{{cite journal | vauthors = Kolaczynski JW, Ohannesian JP, Considine RV, Marco CC, Caro JF | title = Response of leptin to short-term and prolonged overfeeding in humans | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 81 | issue = 11 | pages = 4162–41625 | date = November 1996 | pmid = 8923877 | doi = 10.1210/jcem.81.11.8923877 | s2cid = 25314527 | doi-access = free }}</ref>
* Serum level of leptin is reduced by [[sleep deprivation]].<ref name="pmid24732925">{{cite book | vauthors = Copinschi G, Leproult R, Spiegel K | title = How Gut and Brain Control Metabolism | chapter = The Important Role of Sleep in Metabolism | series = Frontiers of Hormone Research | volume = 42 | pages = 59–72 | year = 2014 | pmid = 24732925 | doi = 10.1159/000358858 | isbn = 978-3-318-02638-2 }}</ref><ref name="pmid17442599">{{cite journal | vauthors = Knutson KL, Spiegel K, Penev P, Van Cauter E | title = The metabolic consequences of sleep deprivation | journal = Sleep Medicine Reviews | volume = 11 | issue = 3 | pages = 163–178 | date = June 2007 | pmid = 17442599 | pmc = 1991337 | doi = 10.1016/j.smrv.2007.01.002 }}</ref>
* Leptin levels are paradoxically increased in [[obesity]].<ref name="pmid8866547">{{cite journal | vauthors = Caro JF, Sinha MK, Kolaczynski JW, Zhang PL, Considine RV | title = Leptin: the tale of an obesity gene | journal = Diabetes | volume = 45 | issue = 11 | pages = 1455–1462 | date = November 1996 | pmid = 8866547 | doi = 10.2337/diab.45.11.1455 | s2cid = 5142768 }}</ref>
* Leptin level is increased by [[emotional stress]].<ref name="pmid17062814">{{cite journal | vauthors = Otsuka R, Yatsuya H, Tamakoshi K, Matsushita K, Wada K, Toyoshima H | title = Perceived psychological stress and serum leptin concentrations in Japanese men | journal = Obesity | volume = 14 | issue = 10 | pages = 1832–1838 | date = October 2006 | pmid = 17062814 | doi = 10.1038/oby.2006.211 | s2cid = 6208047 | doi-access = free }}</ref>
* Leptin level is chronically reduced by [[physical exercise]] [[training]].<ref name="pmid20432196">{{cite journal | vauthors = de Salles BF, Simão R, Fleck SJ, Dias I, Kraemer-Aguiar LG, Bouskela E | title = Effects of resistance training on cytokines | journal = International Journal of Sports Medicine | volume = 31 | issue = 7 | pages = 441–450 | date = July 2010 | pmid = 20432196 | doi = 10.1055/s-0030-1251994 | s2cid = 11273036 | doi-access = free }}</ref><ref name="pmid8944684">{{cite journal | vauthors = Hickey MS, Considine RV, Israel RG, Mahar TL, McCammon MR, Tyndall GL, Houmard JA, Caro JF | display-authors = 6 | title = Leptin is related to body fat content in male distance runners | journal = The American Journal of Physiology | volume = 271 | issue = 5 Pt 1 | pages = E938-940 | date = November 1996 | pmid = 8944684 | doi = 10.1152/ajpendo.1996.271.5.E938 }}</ref><ref name="pmid9142875">{{cite journal | vauthors = Hickey MS, Houmard JA, Considine RV, Tyndall GL, Midgette JB, Gavigan KE, Weidner ML, McCammon MR, Israel RG, Caro JF | display-authors = 6 | title = Gender-dependent effects of exercise training on serum leptin levels in humans | journal = The American Journal of Physiology | volume = 272 | issue = 4 Pt 1 | pages = E562–566 | date = April 1997 | pmid = 9142875 | doi = 10.1152/ajpendo.1997.272.4.E562 }}</ref>
* Leptin level is decreased by increases in [[testosterone]] levels and increased by increases in [[estrogen]] levels.<ref name="pmid10845097">{{cite journal | vauthors = Ahima RS, Flier JS | title = Leptin | journal = Annual Review of Physiology | volume = 62 | issue = 1 | pages = 413–437 | year = 2000 | pmid = 10845097 | doi = 10.1146/annurev.physiol.62.1.413 }}</ref>
* Leptin level is increased by [[insulin]].<ref name="pmid8621027">{{cite journal | vauthors = Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF | display-authors = 6 | title = Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro | journal = Diabetes | volume = 45 | issue = 5 | pages = 699–701 | date = May 1996 | pmid = 8621027 | doi = 10.2337/diabetes.45.5.699 }}</ref>
* Leptin release is increased by [[dexamethasone]].<ref name="pmid9136082">{{cite journal | vauthors = Considine RV, Nyce MR, Kolaczynski JW, Zhang PL, Ohannesian JP, Moore JH, Fox JW, Caro JF | display-authors = 6 | title = Dexamethasone stimulates leptin release from human adipocytes: unexpected inhibition by insulin | journal = Journal of Cellular Biochemistry | volume = 65 | issue = 2 | pages = 254–258 | date = May 1997 | pmid = 9136082 | doi = 10.1002/(SICI)1097-4644(199705)65:2<254::AID-JCB10>3.0.CO;2-I | s2cid = 29205104 }}</ref>
* In obese patients with [[obstructive sleep apnea]], leptin level is increased, but decreased after the administration of [[continuous positive airway pressure]].<ref name="pmid21358603">{{cite journal | vauthors = Zirlik S, Hauck T, Fuchs FS, Neurath MF, Konturek PC, Harsch IA | title = Leptin, obestatin and apelin levels in patients with obstructive sleep apnoea syndrome | journal = Medical Science Monitor | volume = 17 | issue = 3 | pages = CR159-164 | date = February 2011 | pmid = 21358603 | pmc = 3524733 | doi = 10.12659/MSM.881450 }}</ref><ref name="pmid12952256">{{cite journal | vauthors = Harsch IA, Konturek PC, Koebnick C, Kuehnlein PP, Fuchs FS, Pour Schahin S, Wiest GH, Hahn EG, Lohmann T, Ficker JH | display-authors = 6 | title = Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment | journal = The European Respiratory Journal | volume = 22 | issue = 2 | pages = 251–257 | date = August 2003 | pmid = 12952256 | doi = 10.1183/09031936.03.00010103 | s2cid = 7924198 | doi-access = free }}</ref> In non-obese individuals, however, restful sleep (i.e., 8–12 hours of unbroken sleep) can increase leptin to normal levels.

=== In mutations ===
All known leptin mutations except one are associated with low to undetectable immunoreactive leptin blood levels. The exception is a mutant leptin reported in January 2015 that is not functional, but is detected with standard immunoreactive methods. It was found in a massively obese {{frac|2|1|2}}-year-old boy who had high levels of circulating leptin that had no effect on leptin receptors, so he was functionally leptin-deficient.<ref name="Wabitsch_2015"/>

== Role in disease ==
=== Obesity ===
[[File:Energy Balance.png|thumbnail|300 px|Leptin and Ghrelin on the metabolism control]]
Although leptin reduces appetite as a circulating signal, obese individuals generally exhibit a higher circulating concentration of leptin than normal weight individuals due to their higher [[Body fat percentage|percentage body fat]].<ref name="pmid8532024" /> These people show resistance to leptin, similar to [[Insulin resistance|resistance of insulin]] in [[type 2 diabetes]], with the elevated levels failing to control hunger and modulate their weight. A number of explanations have been proposed to explain this. An important contributor to leptin resistance is changes to leptin receptor signalling, particularly in the [[arcuate nucleus]], however, deficiency of, or major changes to, the leptin receptor itself are not thought to be a major cause. [[Triglyceride]]s crossing the [[blood brain barrier]] (BBB) can induce leptin and insulin resistance in the hypothalamus.<ref name="pmid30692905">{{cite journal | vauthors = Forny-Germano L, De Felice FG, Vieira MN | title = The Role of Leptin and Adiponectin in Obesity-Associated Cognitive Decline and Alzheimer's Disease | journal = Frontiers in Neuroscience | volume = 12 | pages = 1027 | year = 2019 | pmid = 30692905 | pmc = 6340072 | doi = 10.3389/fnins.2018.01027 | doi-access = free }}</ref> Triglycerides can also impair leptin transport across the BBB.<ref name="pmid30692905" />

Studies on leptin [[cerebrospinal fluid]] (CSF) levels provide evidence for the reduction in leptin crossing the BBB and reaching obesity-relevant targets, such as the hypothalamus, in obese people.<ref name="pmid24039946">{{cite journal | vauthors = Veyrat-Durebex C, Poher AL, Caillon A, Somm E, Vallet P, Charnay Y, Rohner-Jeanrenaud F | title = Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat | journal = PLOS ONE | volume = 8 | issue = 9 | pages = e73452 | year = 2013 | pmid = 24039946 | pmc = 3765307 | doi = 10.1371/journal.pone.0073452 | doi-access = free | bibcode = 2013PLoSO...873452V }}</ref> In humans it has been observed that the ratio of leptin in the CSF compared to the blood is lower in obese people than in people of a normal weight.<ref name="pmid8684156">{{cite journal | vauthors = Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV | display-authors = 6 | title = Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance | journal = Lancet | volume = 348 | issue = 9021 | pages = 159–161 | date = July 1996 | pmid = 8684156 | doi = 10.1016/S0140-6736(96)03173-X | s2cid = 22084041 }}</ref> The reason for this may be high levels of [[triglycerides]] affecting the transport of leptin across the BBB or due to the leptin transporter becoming saturated.<ref name="pmid24039946"/> Although deficits in the transfer of leptin from the plasma to the CSF is seen in obese people, they are still found to have 30% more leptin in their CSF than lean individuals.<ref name="pmid8684156"/> These higher CSF levels fail to prevent their obesity. Since the amount and quality of leptin receptors in the hypothalamus appears to be normal in the majority of obese humans (as judged from leptin-mRNA studies),<ref name="pmid8666155">{{cite journal | vauthors = Considine RV, Considine EL, Williams CJ, Hyde TM, Caro JF | title = The hypothalamic leptin receptor in humans: identification of incidental sequence polymorphisms and absence of the db/db mouse and fa/fa rat mutations | journal = Diabetes | volume = 45 | issue = 7 | pages = 992–994 | date = July 1996 | pmid = 8666155 | doi = 10.2337/diabetes.45.7.992 }}</ref> it is likely that the leptin resistance in these individuals is due to a post leptin-receptor deficit, similar to the post-insulin receptor defect seen in type 2 diabetes.<ref name="pmid9451823">{{cite journal | vauthors = Considine RV, Caro JF | title = Leptin and the regulation of body weight | journal = The International Journal of Biochemistry & Cell Biology | volume = 29 | issue = 11 | pages = 1255–1272 | date = November 1997 | pmid = 9451823 | doi = 10.1016/S1357-2725(97)00050-2 }}</ref>

When leptin binds with the leptin receptor, it activates a number of pathways. Leptin resistance may be caused by defects in one or more parts of this process, particularly the [[Janus kinase 1|JAK]]/[[STAT protein|STAT]] pathway. Mice with a mutation in the leptin receptor gene that prevents the activation of [[STAT3]] are obese and exhibit hyperphagia. The [[Phosphoinositide 3-kinase|PI3K]] pathway may also be involved in leptin resistance, as has been demonstrated in mice by artificial blocking of PI3K signalling. The PI3K pathway also is activated by the insulin receptor and is therefore an important area where leptin and insulin act together as part of energy homeostasis. The insulin-pI3K pathway can cause [[POMC]] neurons to become insensitive to leptin through [[Hyperpolarization (biology)|hyperpolarization]].<ref name="pmid19644451"/>
 
Leptin is known to interact with [[amylin]], a hormone involved in gastric emptying and creating a feeling of fullness. When both leptin and amylin were given to obese, leptin-resistant rats, sustained weight loss was seen. Due to its apparent ability to reverse leptin resistance, amylin has been suggested as possible therapy for obesity.<ref name="pmid18458326">{{cite journal | vauthors = Roth JD, Roland BL, Cole RL, Trevaskis JL, Weyer C, Koda JE, Anderson CM, Parkes DG, Baron AD | display-authors = 6 | title = Leptin responsiveness restored by amylin agonism in diet-induced obesity: evidence from nonclinical and clinical studies | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 20 | pages = 7257–7262 | date = May 2008 | pmid = 18458326 | pmc = 2438237 | doi = 10.1073/pnas.0706473105 | doi-access = free | bibcode = 2008PNAS..105.7257R }}</ref>

It has been suggested that the main role of leptin is to act as a starvation signal when levels are low, to help maintain fat stores for survival during times of starvation, rather than a satiety signal to prevent overeating. Leptin levels signal when an animal has enough stored energy to spend it in pursuits besides acquiring food.<ref name="pmid19644451">{{cite journal | vauthors = Oswal A, Yeo G | title = Leptin and the control of body weight: a review of its diverse central targets, signaling mechanisms, and role in the pathogenesis of obesity | journal = Obesity | volume = 18 | issue = 2 | pages = 221–229 | date = February 2010 | pmid = 19644451 | doi = 10.1038/oby.2009.228 | s2cid = 9158376 | doi-access = free }}</ref><ref name="pmid16781741">{{cite journal | vauthors = Banks WA, Farr SA, Morley JE | title = The effects of high fat diets on the blood-brain barrier transport of leptin: failure or adaptation? | journal = Physiology & Behavior | volume = 88 | issue = 3 | pages = 244–248 | date = June 2006 | pmid = 16781741 | doi = 10.1016/j.physbeh.2006.05.037 | s2cid = 37806313 }}</ref> This would mean that leptin resistance in obese people is a normal part of mammalian physiology and possibly, could confer a survival advantage.<ref name="pmid17937601">{{cite journal | vauthors = Myers MG, Cowley MA, Münzberg H | title = Mechanisms of leptin action and leptin resistance | journal = Annual Review of Physiology | volume = 70 | issue = 1 | pages = 537–556 | year = 2008 | pmid = 17937601 | doi = 10.1146/annurev.physiol.70.113006.100707 | s2cid = 7572231 }}</ref> Leptin resistance (in combination with insulin resistance and weight gain) is seen in rats after they are given unlimited access to palatable, energy-dense foods.<ref name="pmid11723062">{{cite journal | vauthors = Wang J, Obici S, Morgan K, Barzilai N, Feng Z, Rossetti L | title = Overfeeding rapidly induces leptin and insulin resistance | journal = Diabetes | volume = 50 | issue = 12 | pages = 2786–2791 | date = December 2001 | pmid = 11723062 | doi = 10.2337/diabetes.50.12.2786 | doi-access = free }}</ref> This effect is reversed when the animals are put back on a low-energy diet.<ref name="pmid17339026">{{cite journal | vauthors = Enriori PJ, Evans AE, Sinnayah P, Jobst EE, Tonelli-Lemos L, Billes SK, Glavas MM, Grayson BE, Perello M, Nillni EA, Grove KL, Cowley MA | display-authors = 6 | title = Diet-induced obesity causes severe but reversible leptin resistance in arcuate melanocortin neurons | journal = Cell Metabolism | volume = 5 | issue = 3 | pages = 181–194 | date = March 2007 | pmid = 17339026 | doi = 10.1016/j.cmet.2007.02.004 | doi-access = free }}</ref> This also may have an evolutionary advantage: allowing energy to be stored efficiently when food is plentiful would be advantageous in populations where food frequently may be scarce.<ref name="pmid12970158">{{cite journal | vauthors = Obici S, Rossetti L | title = Minireview: nutrient sensing and the regulation of insulin action and energy balance | journal = Endocrinology | volume = 144 | issue = 12 | pages = 5172–5178 | date = December 2003 | pmid = 12970158 | doi = 10.1210/en.2003-0999 | s2cid = 2006530 | doi-access = free }}</ref>

A [[fad diet]], the [[Rosedale diet]] is based on ideas about how leptin might affect weight. It is based on unsound science and marketed with unevidenced claims of health benefits.<ref name=sbm>{{cite web |author=Harriet Hall |date=2 June 2015 |publisher=[[Science-Based Medicine]] |title=The Rosedale Diet: Here We Go Again |url=https://sciencebasedmedicine.org/the-rosedale-diet-here-we-go-again/}}</ref>

=== Role in osteoarthritis with obesity ===

==== Obesity and osteoarthritis ====
Osteoarthritis and obesity are closely linked. Obesity is one of the most important preventable factors for the development of osteoarthritis.

Originally, the relationship between osteoarthritis and obesity was considered to be exclusively biomechanically based, according to which the excess weight caused the joint to become worn down more quickly. However, today we recognise that there is also a metabolic component which explains why obesity is a risk factor for osteoarthritis, not only for weight-bearing joints (for example, the knees), but also for joints that do not bear weight (for example, the hands).<ref name="pmid19487215">{{cite journal | vauthors = Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, van Osch G, Middeldorp S, Huizinga TW, Kloppenburg M | display-authors = 6 | title = Association between weight or body mass index and hand osteoarthritis: a systematic review | journal = Annals of the Rheumatic Diseases | volume = 69 | issue = 4 | pages = 761–765 | date = April 2010 | pmid = 19487215 | doi = 10.1136/ard.2008.106930 | s2cid = 43044428 | hdl = 1765/17588 | url = http://repub.eur.nl/pub/17588 | hdl-access = free }}</ref> Consequently, it has been shown that decreasing body fat lessens osteoarthritis to a greater extent than weight loss per se.<ref name="pmid20485173">{{cite journal | vauthors = Sowers MR, Karvonen-Gutierrez CA | title = The evolving role of obesity in knee osteoarthritis | journal = Current Opinion in Rheumatology | volume = 22 | issue = 5 | pages = 533–537 | date = September 2010 | pmid = 20485173 | pmc = 3291123 | doi = 10.1097/BOR.0b013e32833b4682 }}</ref> This metabolic component related with the release of systemic factors, of a pro-inflammatory nature, by the adipose tissues, which frequently are critically associated with the development of osteoarthritis.<ref name="pmid11297982">{{cite journal | vauthors = Aspden RM, Scheven BA, Hutchison JD | title = Osteoarthritis as a systemic disorder including stromal cell differentiation and lipid metabolism | journal = Lancet | volume = 357 | issue = 9262 | pages = 1118–1120 | date = April 2001 | pmid = 11297982 | doi = 10.1016/S0140-6736(00)04264-1 | s2cid = 21487529 }}</ref><ref name="pmid17038451">{{cite journal | vauthors = Pottie P, Presle N, Terlain B, Netter P, Mainard D, Berenbaum F | title = Obesity and osteoarthritis: more complex than predicted! | journal = Annals of the Rheumatic Diseases | volume = 65 | issue = 11 | pages = 1403–1405 | date = November 2006 | pmid = 17038451 | pmc = 1798356 | doi = 10.1136/ard.2006.061994 }}</ref><ref name="pmid18836239">{{cite journal | vauthors = Griffin TM, Guilak F | title = Why is obesity associated with osteoarthritis? Insights from mouse models of obesity | journal = Biorheology | volume = 45 | issue = 3–4 | pages = 387–398 | year = 2008 | pmid = 18836239 | pmc = 2748656 | doi = 10.3233/BIR-2008-0485 }}</ref><ref name="pmid19473582">{{cite journal | vauthors = Masuko K, Murata M, Suematsu N, Okamoto K, Yudoh K, Nakamura H, Kato T | title = A metabolic aspect of osteoarthritis: lipid as a possible contributor to the pathogenesis of cartilage degradation | journal = Clinical and Experimental Rheumatology | volume = 27 | issue = 2 | pages = 347–353 | year = 2009 | pmid = 19473582 }}</ref><ref name="pmid20480243">{{cite journal | vauthors = Hu PF, Bao JP, Wu LD | title = The emerging role of adipokines in osteoarthritis: a narrative review | journal = Molecular Biology Reports | volume = 38 | issue = 2 | pages = 873–878 | date = February 2011 | pmid = 20480243 | doi = 10.1007/s11033-010-0179-y | s2cid = 1801387 }}</ref>

Thus, the deregulated production of adipokines and inflammatory mediators, hyperlipidaemia, and the increase of systemic oxidative stress are conditions frequently associated with obesity, which can favour joint degeneration. Furthermore, many regulation factors have been implicated in the development, maintenance, and function, both of adipose tissues, as well as of the cartilage and other joint tissues. Alterations in these factors can be the additional link between obesity and osteoarthritis.

==== Leptin and osteoarthritis ====
Adipocytes interact with other cells through producing and secreting a variety of signalling molecules, including the cell signalling proteins known as adipokines. Certain adipokines can be considered as hormones, as they regulate the functions of organs at a distance, and several of them have been specifically involved in the physiopathology of joint diseases. In particular, there is one, leptin, which has been the focus of attention for research in recent years.

The circulating leptin levels are positively correlated with the Body Mass Index (BMI), more specifically with fatty mass, and obese individuals have higher leptin levels in their blood circulation, compared with non-obese individuals.<ref name="pmid8532024" /> In obese individuals, the increased circulating leptin levels induce unwanted responses, that is, reduced food intake or losing body weight does not occur as there is a resistance to leptin (ref 9). In addition to the function of regulating energy homeostasis, leptin carries out a role in other physiological functions such as neuroendocrine communication, reproduction, angiogenesis, and bone formation. More recently, leptin has been recognised as a cytokine factor as well as with pleiotropic actions also in the immune response and inflammation.<ref name="pmid22935803">{{cite journal | vauthors = Coppari R, Bjørbæk C | title = Leptin revisited: its mechanism of action and potential for treating diabetes | journal = Nature Reviews. Drug Discovery | volume = 11 | issue = 9 | pages = 692–708 | date = September 2012 | pmid = 22935803 | pmc = 4019022 | doi = 10.1038/nrd3757 }}</ref><ref name="pmid17560812">{{cite journal | vauthors = Gualillo O | title = Further evidence for leptin involvement in cartilage homeostases | journal = Osteoarthritis and Cartilage | volume = 15 | issue = 8 | pages = 857–860 | date = August 2007 | pmid = 17560812 | doi = 10.1016/j.joca.2007.04.015 | doi-access = free }}</ref><ref name="pmid21252989">{{cite journal | vauthors = Ouchi N, Parker JL, Lugus JJ, Walsh K | title = Adipokines in inflammation and metabolic disease | journal = Nature Reviews. Immunology | volume = 11 | issue = 2 | pages = 85–97 | date = February 2011 | pmid = 21252989 | pmc = 3518031 | doi = 10.1038/nri2921 }}</ref><ref name="pmid23906693">{{cite journal | vauthors = Scotece M, Conde J, Vuolteenaho K, Koskinen A, López V, Gómez-Reino J, Lago F, Moilanen E, Gualillo O | display-authors = 6 | title = Adipokines as drug targets in joint and bone disease | journal = Drug Discovery Today | volume = 19 | issue = 3 | pages = 241–258 | date = March 2014 | pmid = 23906693 | doi = 10.1016/j.drudis.2013.07.012 }}</ref> For example, leptin can be found in the [[synovial fluid]] in correlation with the body mass index, and the leptin receptors are expressed in the cartilage, where leptin mediates and modulates many inflammatory responses that can damage cartilage and other joint tissues. Leptin has thus emerged as a candidate to link obesity and osteoarthritis and serves as an apparent objective as a nutritional treatment for osteoarthritis.

As in the plasma, the leptin levels in the synovial fluid are positively correlated with BMI.<ref name="Dumond_2003">{{cite journal | vauthors = Dumond H, Presle N, Terlain B, Mainard D, Loeuille D, Netter P, Pottie P | title = Evidence for a key role of leptin in osteoarthritis | journal = Arthritis and Rheumatism | volume = 48 | issue = 11 | pages = 3118–3129 | date = November 2003 | pmid = 14613274 | doi = 10.1002/art.11303 }}</ref><ref name="Simopoulou_2007">{{cite journal | vauthors = Simopoulou T, Malizos KN, Iliopoulos D, Stefanou N, Papatheodorou L, Ioannou M, Tsezou A | title = Differential expression of leptin and leptin's receptor isoform (Ob-Rb) mRNA between advanced and minimally affected osteoarthritic cartilage; effect on cartilage metabolism | journal = Osteoarthritis and Cartilage | volume = 15 | issue = 8 | pages = 872–883 | date = August 2007 | pmid = 17350295 | doi = 10.1016/j.joca.2007.01.018 | doi-access = free }}</ref><ref name="pmid22689314">{{cite journal | vauthors = Vuolteenaho K, Koskinen A, Moilanen T, Moilanen E | title = Leptin levels are increased and its negative regulators, SOCS-3 and sOb-R are decreased in obese patients with osteoarthritis: a link between obesity and osteoarthritis | journal = Annals of the Rheumatic Diseases | volume = 71 | issue = 11 | pages = 1912–1913 | date = November 2012 | pmid = 22689314 | doi = 10.1136/annrheumdis-2011-201242 | s2cid = 37657650 }}</ref><ref name="pmid19780190">{{cite journal | vauthors = Gandhi R, Takahashi M, Syed K, Davey JR, Mahomed NN | title = Relationship between body habitus and joint leptin levels in a knee osteoarthritis population | journal = Journal of Orthopaedic Research | volume = 28 | issue = 3 | pages = 329–333 | date = March 2010 | pmid = 19780190 | doi = 10.1002/jor.21000 | s2cid = 30527738 | doi-access = free }}</ref> The leptin of the synovial fluid is synthesised at least partially in the joint and may originate in part in the circulation. Leptin has been shown to be produced by chondrocytes, as well as by other tissues in the joints, including the synovial tissue, osteophytes, the meniscus, and bone.<ref name="Dumond_2003" /><ref name="Simopoulou_2007" /><ref name="pmid16527497">{{cite journal | vauthors = Presle N, Pottie P, Dumond H, Guillaume C, Lapicque F, Pallu S, Mainard D, Netter P, Terlain B | display-authors = 6 | title = Differential distribution of adipokines between serum and synovial fluid in patients with osteoarthritis. Contribution of joint tissues to their articular production | journal = Osteoarthritis and Cartilage | volume = 14 | issue = 7 | pages = 690–695 | date = July 2006 | pmid = 16527497 | doi = 10.1016/j.joca.2006.01.009 | doi-access = free }}</ref><ref name="pmid15447688">{{cite journal | vauthors = Morroni M, De Matteis R, Palumbo C, Ferretti M, Villa I, Rubinacci A, Cinti S, Marotti G | display-authors = 6 | title = In vivo leptin expression in cartilage and bone cells of growing rats and adult humans | journal = Journal of Anatomy | volume = 205 | issue = 4 | pages = 291–296 | date = October 2004 | pmid = 15447688 | pmc = 1571344 | doi = 10.1111/j.0021-8782.2004.00333.x }}</ref><ref name="pmid18565249">{{cite journal | vauthors = Järvinen K, Vuolteenaho K, Nieminen R, Moilanen T, Knowles RG, Moilanen E | title = Selective iNOS inhibitor 1400W enhances anti-catabolic IL-10 and reduces destructive MMP-10 in OA cartilage. Survey of the effects of 1400W on inflammatory mediators produced by OA cartilage as detected by protein antibody array | journal = Clinical and Experimental Rheumatology | volume = 26 | issue = 2 | pages = 275–282 | year = 2008 | pmid = 18565249 }}</ref><ref name="Distel_2009">{{cite journal | vauthors = Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X, Benelli C | title = The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor | journal = Arthritis and Rheumatism | volume = 60 | issue = 11 | pages = 3374–3377 | date = November 2009 | pmid = 19877065 | doi = 10.1002/art.24881 | s2cid = 29783077 }}</ref> An infrapatellar fat pad located extrasynovially within the knee joint is also adjacent to the synovial membrane and cartilage, and has recently been highly appreciated as an important source of leptin, as well as other adipokines and mediators that contribute to the pathogenesis of osteoarthritis <ref name="Distel_2009" /><ref name="pmid20417297">{{cite journal | vauthors = Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJ, Van Offel JF, Verhaar JA, De Clerck LS, Somville J | display-authors = 6 | title = The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review | journal = Osteoarthritis and Cartilage | volume = 18 | issue = 7 | pages = 876–882 | date = July 2010 | pmid = 20417297 | doi = 10.1016/j.joca.2010.03.014 | doi-access = free }}</ref><ref name="pmid21242232">{{cite journal | vauthors = Klein-Wieringa IR, Kloppenburg M, Bastiaansen-Jenniskens YM, Yusuf E, Kwekkeboom JC, El-Bannoudi H, Nelissen RG, Zuurmond A, Stojanovic-Susulic V, Van Osch GJ, Toes RE, Ioan-Facsinay A | display-authors = 6 | title = The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype | journal = Annals of the Rheumatic Diseases | volume = 70 | issue = 5 | pages = 851–857 | date = May 2011 | pmid = 21242232 | doi = 10.1136/ard.2010.140046 | s2cid = 23009219 | url = https://pure.eur.nl/en/publications/dd47861b-3124-46bf-921b-c1f5430d29c5 }}</ref><ref name="pmid22072016">{{cite journal | vauthors = Hui W, Litherland GJ, Elias MS, Kitson GI, Cawston TE, Rowan AD, Young DA | title = Leptin produced by joint white adipose tissue induces cartilage degradation via upregulation and activation of matrix metalloproteinases | journal = Annals of the Rheumatic Diseases | volume = 71 | issue = 3 | pages = 455–462 | date = March 2012 | pmid = 22072016 | doi = 10.1136/annrheumdis-2011-200372 | s2cid = 29600605 | url = https://eprint.ncl.ac.uk/fulltext.aspx?url=183525/443FB0D8-858E-4A45-80F6-56B5809DA906.pdf&pub_id=183525 }}</ref>

The risk of suffering osteoarthritis can be decreased with weight loss. This reduction of risk is related in part with the decrease of the load on the joint, but also in the decrease of fatty mass, the central adipose tissue and the low-level inflammation associated with obesity and systemic factors. {{Citation needed|date=January 2022}}

This growing evidence points to leptin as a cartilage degradation factor in the pathogenesis of osteoarthritis, and as a potential biomarker in the progression of the disease, which suggests that leptin, as well as regulation and signalling mechanisms, can be a new and promising target in the treatment of osteoarthritis, especially in obese patients. {{Citation needed|date=January 2022}}

Obese individuals are predisposed to developing osteoarthritis, not only due to the excess mechanical load, but also due to the excess expression of soluble factors, that is, leptin and pro-inflammatory cytokines, which contribute to joint inflammation and cartilage destruction. As such, obese individuals are in an altered state, due to a metabolic insufficiency, which requires specific nutritional treatment capable of normalising the leptin production and reducing the systematic low-level inflammation, in order to reduce the harmful impact of these systematic mediators on the joint health. {{Citation needed|date=January 2022}}

There are nutritional supplements and pharmacological agents capable of directing these factors and improving both conditions. {{Citation needed|date=January 2022}}

== Therapeutic use ==

=== Leptin===

Leptin was approved in the United States in 2014 for use in congenital leptin deficiency and generalized [[lipodystrophy]].<ref name="pmid24714458">{{cite journal | vauthors = Sinha G | title = Leptin therapy gains FDA approval | journal = Nature Biotechnology | volume = 32 | issue = 4 | pages = 300–302 | date = April 2014 | pmid = 24714458 | doi = 10.1038/nbt0414-300b | s2cid = 205267285 }}</ref>

=== Analog metreleptin===
{{main|Metreleptin}}

An analog of human leptin [[metreleptin]] (trade names Myalept, Myalepta) was first approved in Japan in 2013, in the United States in February 2014, and in Europe in 2018. In the US it is indicated as a treatment for complications of leptin deficiency, and for the diabetes and [[hypertriglyceridemia]] associated with congenital or acquired generalized [[lipodystrophy]].<ref>{{cite journal | vauthors = Chou K, Perry CM | title = Metreleptin: first global approval | journal = Drugs | volume = 73 | issue = 9 | pages = 989–997 | date = June 2013 | pmid = 23740412 | doi = 10.1007/s40265-013-0074-7 | s2cid = 7740045 }}</ref><ref name="fda">{{cite web | url=https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm387060.htm | archive-url=https://web.archive.org/web/20140302120246/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm387060.htm | url-status=dead | archive-date=March 2, 2014 | title=FDA approves Myalept to treat rare metabolic disease | publisher=FDA | date=25 February 2014 | access-date=30 April 2014}}</ref> In Europe based on [[European Medicines Agency|EMA]], metreleptin should be used in addition to diet to treat lipodystrophy, where patients have loss of fatty tissue under the skin and build-up of fat elsewhere in the body such as in the liver and muscles. The medicine is used in adults and children above the age of 2 years with [[Generalized lipodystrophy|generalised lipodystrophy]] ([[Berardinelli-Seip syndrome]] and [[Acquired generalized lipodystrophy|Lawrence syndrome]]); and in adults and children above the age of 12 years with [[partial lipodystrophy]] (including [[Barraquer–Simons syndrome|Barraquer-Simons syndrome]]), when standard treatments have failed.<ref>{{Cite web|url=https://www.ema.europa.eu/en/medicines/human/EPAR/myalepta|title=Myalepta {{!}} European Medicines Agency|website=www.ema.europa.eu|access-date=2019-01-09|date=2018-09-17}}</ref>

The National Health Service in England will commission metreleptin treatment for all with congenital leptin deficiency regardless of age beginning on April 1, 2019.<ref>{{Cite web|url=https://www.england.nhs.uk/publication/metreleptin-for-congenital-leptin-deficiency-all-ages/|title=NHS England » Metreleptin for congenital leptin deficiency (all ages)|website=www.england.nhs.uk|date=21 December 2018 |access-date=2019-01-18}}</ref>

== Research ==
Leptin is currently being evaluated as a potential target for the treatment of anorexia nervosa.<ref>{{cite journal |display-authors=6 |vauthors=Hebebrand J, Hildebrandt T, Schlögl H, Seitz J, Denecke S, Vieira D, Gradl-Dietsch G, Peters T, Antel J, Lau D, Fulton S |date=October 2022 |title=The role of hypoleptinemia in the psychological and behavioral adaptation to starvation: Implications for anorexia nervosa |journal=Neuroscience and Biobehavioral Reviews |volume=141 |pages=104807 |doi=10.1016/j.neubiorev.2022.104807 |pmid=35931221 |s2cid=251259742}}</ref> It is hypothesized that the gradual loss of body fat mass, and more specifically the ensuing low leptin levels, escalate the preexisting drive for thinness into an obsessive-compulsive-like and addictive-like state. It was shown that short-term metreleptin treatment of patients with anorexia nervosa had rapid on-set of beneficial cognitive, emotional, and behavioral effects. Among other things, depression, drive for activity, repetitive thoughts of food, inner restlessness, and weight phobia decreased rapidly. Whether metreleptin (or another leptin analogue) is a suitable treatment for anorexia nervosa is currently unknown. Potential side effects are weight loss and the development of anti-metreleptin antibodies.<ref>{{cite journal | vauthors = Milos G, Antel J, Kaufmann LK, Barth N, Koller A, Tan S, Wiesing U, Hinney A, Libuda L, Wabitsch M, von Känel R, Hebebrand J | display-authors = 6 | title = Short-term metreleptin treatment of patients with anorexia nervosa: rapid on-set of beneficial cognitive, emotional, and behavioral effects | journal = Translational Psychiatry | volume = 10 | issue = 1 | pages = 303 | date = August 2020 | pmid = 32855384 | doi = 10.1038/s41398-020-00977-1 | pmc = 7453199 }}</ref>

== History ==
The leptin was discovered by Jeffrey Friedman in 1994 after several decades of research conducted by others institutions since 1950 on obese mouse models.<ref>{{Cite web|url=http://centennial.rucares.org/index.php?page=Discovery_Leptin|title=The Rockefeller University » Hospital Centennial|website=centennial.rucares.org|language=en|access-date=2018-10-11}}</ref>

=== Identification of the encoding gene ===
In 1949, a non-obese mouse colony being studied at the [[Jackson Laboratory]] produced a strain of obese offspring, suggesting that a mutation had occurred in a hormone regulating hunger and energy expenditure. Mice homozygous for the so-called ob mutation (ob/ob) ate voraciously and were massively obese.<ref>{{cite journal | vauthors = Dickie MM, Lane PW | journal = Mouse News Lett. | title = Plus letter to Roy Robinson 7/7/70 | year = 1957 | issue = 17 | page = 52}}</ref> In the 1960s, a second mutation causing obesity and a similar phenotype was identified by [[Douglas L. Coleman|Douglas Coleman]], also at the Jackson Laboratory, and was named diabetes (db), as both ob/ob and db/db were obese.<ref name="pmid7906968">{{cite journal | vauthors = Bahary N, Siegel DA, Walsh J, Zhang Y, Leopold L, Leibel R, Proenca R, Friedman JM | display-authors = 6 | title = Microdissection of proximal mouse chromosome 6: identification of RFLPs tightly linked to the ob mutation | journal = Mammalian Genome | volume = 4 | issue = 9 | pages = 511–515 | date = September 1993 | pmid = 7906968 | doi = 10.1007/BF00364786 | s2cid = 2130385 }}</ref><ref name="pmid1686014">{{cite journal | vauthors = Friedman JM, Leibel RL, Siegel DS, Walsh J, Bahary N | title = Molecular mapping of the mouse ob mutation | journal = Genomics | volume = 11 | issue = 4 | pages = 1054–1062 | date = December 1991 | pmid = 1686014 | doi = 10.1016/0888-7543(91)90032-A }}</ref><ref name="pmid7984236">{{cite journal | vauthors = Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM | title = Positional cloning of the mouse obese gene and its human homologue | journal = Nature | volume = 372 | issue = 6505 | pages = 425–432 | date = December 1994 | pmid = 7984236 | doi = 10.1038/372425a0 | s2cid = 4359725 | bibcode = 1994Natur.372..425Z }}</ref> In 1990 [[Rudolph Leibel]] and [[Jeffrey M. Friedman]] reported mapping of the ''db'' gene.<ref name="pmid1973864">{{cite book | vauthors = Leibel RL, Bahary N, Friedman JM | title = Genetic variation and nutrition in obesity: approaches to the molecular genetics of obesity | chapter = Genetic Variation and Nutrition in Obesity: Approaches to the Molecular Genetics of Obesity1 | journal = World Rev Nutr Diet. | volume = 63 | issue = 1 | pages = 90–101 | date = January 1990 | pmid = 1973864 | doi = 10.1159/000418501 | series = World Review of Nutrition and Dietetics | isbn = 978-3-8055-5126-7 }}</ref><ref name="pmid1978328">{{cite journal | vauthors = Bahary N, Leibel RL, Joseph L, Friedman JM | title = Molecular mapping of the mouse db mutation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 87 | issue = 21 | pages = 8642–8646 | date = November 1990 | pmid = 1978328 | pmc = 55013 | doi = 10.1073/pnas.87.21.8642 | doi-access = free | bibcode =  1990PNAS...87.8642B}}</ref><ref name="pmid8357496">{{cite journal | vauthors = Leibel RL, Bahary N, Friedman JM | title = Strategies for the molecular genetic analysis of obesity in humans | journal = Critical Reviews in Food Science and Nutrition | volume = 33 | issue = 4–5 | pages = 351–358 | date = January 1993 | pmid = 8357496 | doi = 10.1080/10408399309527632 }}</ref>

Consistent with Coleman's and Leibel's hypothesis, several subsequent studies from Leibel's and Friedman's labs and other groups confirmed that the ob gene encoded a novel hormone that circulated in blood and that could suppress food intake and body weight in ob and wild type mice, but not in db mice.<ref name="pmid7624777">{{cite journal | vauthors = Halaas JL, Gajiwala KS, Maffei M, Cohen SL, Chait BT, Rabinowitz D, Lallone RL, Burley SK, Friedman JM | display-authors = 6 | title = Weight-reducing effects of the plasma protein encoded by the obese gene | journal = Science | volume = 269 | issue = 5223 | pages = 543–546 | date = July 1995 | pmid = 7624777 | doi = 10.1126/science.7624777 | bibcode = 1995Sci...269..543H }}</ref><ref name="pmid7624778">{{cite journal | vauthors = Campfield LA, Smith FJ, Guisez Y, Devos R, Burn P | title = Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks | journal = Science | volume = 269 | issue = 5223 | pages = 546–549 | date = July 1995 | pmid = 7624778 | doi = 10.1126/science.7624778 | bibcode = 1995Sci...269..546C }}</ref><ref name="pmid7624776">{{cite journal | vauthors = Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F | title = Effects of the obese gene product on body weight regulation in ob/ob mice | journal = Science | volume = 269 | issue = 5223 | pages = 540–543 | date = July 1995 | pmid = 7624776 | doi = 10.1126/science.7624776 | bibcode = 1995Sci...269..540P }}</ref><ref name="pmid7584987">{{cite journal | vauthors = Maffei M, Halaas J, Ravussin E, Pratley RE, Lee GH, Zhang Y, Fei H, Kim S, Lallone R, Ranganathan S | display-authors = 6 | title = Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects | journal = Nature Medicine | volume = 1 | issue = 11 | pages = 1155–1161 | date = November 1995 | pmid = 7584987 | doi = 10.1038/nm1195-1155 | s2cid = 19066834 }}</ref>

In 1994, Friedman's laboratory reported the identification of the gene.<ref name="pmid7984236"/> In 1995, [[Jose F. Caro]]'s laboratory provided evidence that the mutations in the mouse ob gene did not occur in humans. Furthermore, since ob gene expression was increased, not decreased, in human obesity, it suggested resistance to leptin to be a possibility.<ref name="pmid7769141" /> At the suggestion of [[Roger Guillemin]], Friedman named this new hormone "leptin" from the Greek ''lepto'' meaning thin.<ref name="pmid7624777" /><ref name=Neill_2010>{{cite journal | vauthors = Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH | display-authors = 6 | title = Leptin therapy in insulin-deficient type I diabetes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 11 | pages = 4813–4819 | date = March 2010 | doi=10.1073/pnas.0909422107  | pmid = 20194735 | pmc = 2841945 | bibcode = 2010PNAS..107.4813W | doi-access = free }}</ref> Leptin was the first fat cell-derived hormone ([[adipokine]]) to be discovered.<ref name="pmid22038756">{{cite journal | vauthors = Conde J, Scotece M, Gómez R, López V, Gómez-Reino JJ, Lago F, Gualillo O | title = Adipokines: biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity | journal = BioFactors | volume = 37 | issue = 6 | pages = 413–420 | year = 2011 | pmid = 22038756 | doi = 10.1002/biof.185 }}</ref>

Subsequent studies in 1995 confirmed that the db gene encodes the [[leptin receptor]], and that it is expressed in the [[hypothalamus]], a region of the brain known to regulate the sensation of hunger and body weight.<ref name="pmid8548812">{{cite journal | vauthors = Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Wool EA, Monroe CA, Tepper RI | display-authors = 6 | title = Identification and expression cloning of a leptin receptor, OB-R | journal = Cell | volume = 83 | issue = 7 | pages = 1263–1271 | date = December 1995 | pmid = 8548812 | doi = 10.1016/0092-8674(95)90151-5 | s2cid = 6534085 | doi-access = free }}</ref><ref name="pmid8608603">{{cite journal | vauthors = Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP | display-authors = 6 | title = Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice | journal = Cell | volume = 84 | issue = 3 | pages = 491–495 | date = February 1996 | pmid = 8608603 | doi = 10.1016/S0092-8674(00)81294-5 | s2cid = 13885070 | doi-access = free }}</ref><ref name="pmid8628397">{{cite journal | vauthors = Lee GH, Proenca R, Montez JM, Carroll KM, Darvishzadeh JG, Lee JI, Friedman JM | title = Abnormal splicing of the leptin receptor in diabetic mice | journal = Nature | volume = 379 | issue = 6566 | pages = 632–635 | date = February 1996 | pmid = 8628397 | doi = 10.1038/379632a0 | s2cid = 4359340 | bibcode = 1996Natur.379..632L }}</ref><ref name="pmid8584938">{{cite journal | vauthors = Chua SC, Chung WK, Wu-Peng XS, Zhang Y, Liu SM, Tartaglia L, Leibel RL | title = Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor | journal = Science | volume = 271 | issue = 5251 | pages = 994–996 | date = February 1996 | pmid = 8584938 | doi = 10.1126/science.271.5251.994 | s2cid = 33646952 | bibcode = 1996Sci...271..994C }}</ref>

=== Recognition of scientific advances ===
Coleman and Friedman have been awarded numerous prizes acknowledging their roles in discovery of leptin, including the [[Gairdner Foundation International Award]] (2005),<ref>{{cite web | author = Bonner J | year = 2005 | title = Jeffrey Friedman, discoverer of leptin, receives Gairdner, Passano awards | url = http://newswire.rockefeller.edu/2005/04/13/jeffrey-friedman-discoverer-of-leptin-receives-gairdner-passano-awards/ | work = Newswire | publisher = The Rockefeller University | access-date = 2013-08-08 | archive-url = https://web.archive.org/web/20130829091938/http://newswire.rockefeller.edu/2005/04/13/jeffrey-friedman-discoverer-of-leptin-receives-gairdner-passano-awards/ | archive-date = 2013-08-29 | url-status = dead }}</ref> the [[Shaw Prize]] (2009),<ref>{{cite web | website = News-Medical.net | year = 2009 | title = Jeffrey Friedman receives Shaw Prize for discovery of leptin | url = http://www.news-medical.net/news/20090616/Jeffrey-Friedman-receives-Shaw-Prize-for-discovery-of-leptin.aspx}}</ref> the [[Lasker Award]],<ref name="urlThe Lasker Foundation - 2010 Awards">{{cite web | url = http://www.laskerfoundation.org/awards/2010_b_description.htm | title = The Lasker Foundation – 2010 Awards | year = 2010 | publisher = Lasker Foundation | access-date = 2013-08-08 | archive-date = 2016-02-24 | archive-url = https://web.archive.org/web/20160224094920/http://www.laskerfoundation.org/awards/2010_b_description.htm | url-status = dead }}</ref> the [[BBVA Foundation Frontiers of Knowledge Award]]<ref name="urlBBVA Foundation Frontiers of Knowledge Awards">{{cite web | url = http://www.fbbva.es/TLFU/tlfu/ing/microsites/premios/fronteras/galardonados/2012/biomedicina.jsp | title = BBVA Foundation Frontiers of Knowledge Awards | year = 2012 | publisher = BBVA Foundation | access-date = 2013-08-08 | archive-url = https://web.archive.org/web/20161006010639/http://www.fbbva.es/TLFU/tlfu/ing/microsites/premios/fronteras/galardonados/2012/biomedicina.jsp | archive-date = 2016-10-06 | url-status = dead }}</ref> and the [[King Faisal International Prize]],<ref name="urlKFF - KFIP - Winners 2013 - Medicine">{{cite web | url = http://www.kff.com/en01/kfip/1434H2013G/KFIPWinners4MED1434H2013G.html | title = KFF – KFIP – Winners 2013 – Medicine | year = 2013 | publisher = King Faisal Foundation | access-date = 2013-08-08 | archive-date = 2013-12-02 | archive-url = https://web.archive.org/web/20131202022141/http://www.kff.com/en01/kfip/1434H2013G/KFIPWinners4MED1434H2013G.html | url-status = dead }}</ref> Leibel has not received the same level of recognition from the discovery because he was omitted as a co-author of a scientific paper published by Friedman that reported the discovery of the gene. The various theories surrounding Friedman's omission of Leibel and others as co-authors of this paper have been presented in a number of publications, including [[Ellen Ruppel Shell]]’s 2002 book ''[[The Hungry Gene]]''.<ref name="Shell2002">{{cite book |author = Shell E | title = The Hungry Gene: The Inside Story of the Obesity Industry | publisher = Atlantic Monthly Press | year=2002 | chapter =On the Cutting Edge | isbn = 978-1-4223-5243-4 }}{{page needed| date = November 2013}}</ref><ref name="Shell2002a">{{cite book |author = Shell E | title = The Hungry Gene: The Inside Story of the Obesity Industry | publisher = Atlantic Monthly Press | year = 2002 | chapter = Hunger | isbn = 978-1-4223-5243-4}} {{page needed| date = November 2013}}</ref>

The discovery of leptin also is documented in a series of books including ''Fat: Fighting the Obesity Epidemic'' by Robert Pool,<ref>{{Cite book | author = Pool R | title = Fat: fighting the obesity epidemic | year = 2001 | publisher = Oxford University Press | location = New York | isbn = 978-0-19-511853-7 | url = https://archive.org/details/fatfightingobesi00pool }} {{page needed| date = November 2013}}</ref> ''[[The Hungry Gene]]'' by Ellen Ruppel Shell, and ''Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting'' by [[Gina Kolata]].<ref>{{cite book | author = Kolata GB | title = Rethinking thin: the new science of weight loss – and the myths and realities of dietin | year = 2007 | publisher = Farrar | location = New York | isbn = 978-0-374-10398-9 | url = https://archive.org/details/rethinkingthinne00kola }} {{page needed| date = November 2013}}</ref><ref>{{cite book |vauthors=Castracane VD, Henson MC | chapter = The Obese (Ob/Ob) Mouse and the Discovery of Leptin | chapter-url = https://books.google.com/books?id=nQNSJ6XvL6AC&pg=PA1 | pages = 1–9 | doi = 10.1007/978-0-387-31416-7_1 | year = 2006 |veditors=Castracane VD, Henson MC | title = Leptin | series = Endocrine Updates | volume = 25 | isbn = 978-0-387-31415-0 }}</ref> ''Fat: Fighting the Obesity Epidemic'' and ''Rethinking Thin: The New Science of Weight Loss and the Myths and Realities of Dieting'' review the work in the Friedman laboratory that led to the cloning of the ob gene, while The ''Hungry Gene'' draws attention to the contributions of Leibel.{{citation needed|date=August 2016}}

== See also ==
* [[Ghrelin]]
* [[NAPEs]]
* [[Raptin]]
* [[Teleost leptins]]

== References ==
{{reflist}}

== External links ==
*[https://web.archive.org/web/20060627212342/http://neuroendo.org.uk/index.php/content/view/8/11/ Leptin: Your brain, appetite and obesity by the British Society of Neuroendocrinology]
*[https://web.archive.org/web/20111026031421/http://www.vivo.colostate.edu/hbooks/pathphys/endocrine/bodyweight/leptin.html Leptin by Colorado State University] – last updated 1998
*[http://www.3dchem.com/molecules.asp?ID=154 Leptin at 3Dchem.com], description and structure diagrams
* {{PDBe-KB2|P41159|Leptin}}
<!-- * [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8742898/ Leptin hormone and its effectiveness in reproduction, metabolism, immunity, diabetes, hopes and ambitions] --><!-- already in reference section -->

{{Hormones}}
{{Diets}}
{{Commons category|Leptin (obesity protein)|Leptin}}

[[Category:Leptin receptor agonists]]
[[Category:Peptide hormones]]
[[Category:Mutated genes]]
[[Category:Obesity]]