Editing Leptin (section)

== {{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"/>