Resistin
Template:Redirect Template:Short description Template:Cs1 config Template:Infobox gene Resistin, also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1), is a cysteine-rich peptide hormone that is derived from adipose tissue and, in humans, is encoded by the RETN gene.<ref name="Wang_2002">Template:Cite journal</ref>
In primates, pigs, and dogs, resistin is secreted primarily by immune and epithelial cells, whereas in rodents, it is mainly secreted by adipose tissue. The human resistin pre-peptide consists of 108 amino acid residues, while in mice and rats it is 114 amino acids in length; the molecular weight is approximately 12.5 kDa. Resistin is classified as an adipose-derived hormone (similar to a cytokine), and its physiological role has been widely debated, particularly regarding its involvement in obesity and type II diabetes mellitus (T2DM).<ref name="Lazar_2007">Template:Cite journal</ref>
DiscoveryEdit
Resistin was discovered in 2001 and identified as a hormone produced by adipose tissue, with a role in promoting insulin resistance.<ref name="Steppan_2001">Template:Cite journal</ref> Elevated resistin levels were linked to insulin resistance and were shown to increase with obesity, supporting its role in metabolic dysfunction.<ref name="Steppan_2001" /><ref name="DegawaYamauchi_2003">Template:Cite journal</ref><ref name="Gabriely_2002">Template:Cite journal</ref><ref name="Levy_2002">Template:Cite journal</ref><ref name="McTernan_2002">Template:Cite journal</ref>
Subsequent studies highlighted resistin’s involvement in inflammatory processes and energy homeostasis, indicating a broader physiological role beyond insulin resistance.<ref name="Adeghate_2004">Template:Cite journal</ref><ref name="Stumvoll_2002">Template:Cite journal</ref><ref name="Vendrell_2004">Template:Cite journal</ref>
Recent reviews have synthesized these findings, supporting resistin’s proposed role in mediating the link between obesity and insulin resistance, as well as its potential contributions to inflammation and metabolic diseases.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
StructureEdit
Template:Infobox protein family Resistin is a cysteine-rich, secreted peptide hormone characterized by a unique multimeric structure. Each resistin monomer consists of a C-terminal, disulfide-rich beta-sandwich "head" domain and an N-terminal alpha-helical "tail" segment.<ref name="Li_2021">Template:Cite journal</ref><ref name="Patel_2004">Template:Cite journal</ref> The head domain adopts a six-stranded jelly-roll topology, forming two three-stranded antiparallel beta-sheets, while the tail segments associate to create three-stranded coiled coils.<ref name="Li_2021" /><ref name="Patel_2004" /> These monomers assemble into trimers, and further interchain disulfide linkages mediate the formation of tail-to-tail hexamers, resulting in a multimeric assembly stabilized by disulfide bonds.<ref name="Li_2021" /><ref name="Patel_2004" /> The C-terminal head domain is notable for its positive electrostatic surface and exposed hydrophobic residues, which may contribute to the protein’s biological activity, including its antimicrobial properties.<ref name="Li_2021" /> In circulation, resistin exists in multiple assembly states, including high-molecular-mass hexamers and lower-molecular-mass trimers, with the oligomeric form in humans showing greater proinflammatory activity.<ref name="Li_2021" /> This structural organization is highly conserved within the resistin-like molecule (RELM) family and is thought to underpin resistin’s diverse physiological roles.<ref name="Li_2021" /><ref name="Patel_2004" />
FunctionEdit
Resistin is a multifunctional, cysteine-rich peptide hormone that plays critical roles in metabolic regulation, inflammation, and innate immunity. In humans, resistin is primarily expressed by immune cells such as monocytes and macrophages, where it acts as a pro-inflammatory cytokine by stimulating the production of cytokines including IL-6, IL-1β, and TNF-α through activation of signaling pathways involving the TLR4 and CAP1 receptors.<ref name="Li_2021" /><ref name=":1">Template:Cite journal</ref> Beyond its pro-inflammatory effects, resistin also demonstrates direct antimicrobial activity by damaging bacterial membranes, and it modulates immune responses by recruiting and activating immune cells, promoting chemokine production, and enhancing the formation of neutrophil extracellular traps (NETs).<ref name="Li_2021" /> Notably, resistin exhibits bidirectional immunomodulatory properties: while it can amplify inflammation in response to certain stimuli, it can also attenuate excessive inflammatory responses triggered by bacterial products such as lipopolysaccharide (LPS), potentially by competing for TLR4 binding or directly neutralizing LPS.<ref name="Li_2021" /> This dual functionality positions resistin as an important regulator of host defense and inflammatory balance in both health and disease.<ref name="Li_2021" />
Clinical significanceEdit
InflammationEdit
Inflammation is the first innate immune response to infection or irritation resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine, prostaglandin, and pro-inflammatory cytokines. As cited, it has recently been discovered that resistin also participates in the inflammatory response.<ref name="Holcomb_2000">Template:Cite journal</ref><ref name="Kusminski_2007">Template:Cite journal</ref><ref name="Malyszko_2006">Template:Cite journal</ref><ref name="Nagaev_2006">Template:Cite journal</ref>
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion.<ref name="Milan_2002">Template:Cite journal</ref><ref name="Silswal_2005">Template:Cite journal</ref> It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection.<ref name="Verma_2003">Template:Cite journal</ref> Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,<ref name="Lu_2002">Template:Cite journal</ref> which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.<ref name="Wellen_2005">Template:Cite journal</ref>
In accordance, it is expected that, if resistin does serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then proportional increases in chronic inflammation in association with obesity and insulin resistance should be observed. Recent data has shown that this is possible by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation,<ref name="WulsterRadcliffe_2004">Template:Cite journal</ref><ref name="Yokota_2000">Template:Cite journal</ref> which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with lowered renal function and inflammation, but not with insulin resistance.<ref name="Axelsson_2006">Template:Cite journal</ref> Notwithstanding, regarding resistin and the inflammatory response, it can be concluded that resistin does bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
This adipokine is associated with markers of inflammation in seminal plasma and the concentrations of seminal resistin correlate positively with those of proinflammatory mediators such as interleukin-6 (IL-6), elastase and tumor necrosis factor-α (TNF-α). During inflammation, the concentrations of cytokines and ROS increase, and this may have a deleterious effect on the male reproductive function.<ref name="Elfassy_2018">Template:Cite journal</ref> One study showed that there was a negative correlation between the concentrations of seminal resistin and spermatic motility and vitality. (The seminal concentrations of resistin were significantly higher in cases of leukocyte spermia or if the patients were smokers.)<ref name="Moretti_2019">Template:Cite journal</ref>
Obesity and insulin resistanceEdit
Arguments forEdit
Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing strong correlations between resistin and obesity. The premise being that serum resistin levels increase with increased adiposity.<ref name="DegawaYamauchi_2003" /><ref name="Vendrell_2004" /><ref name="Asensio_2004">Template:Cite journal</ref><ref name="Lee_2005">Template:Cite journal</ref> Conversely, serum resistin levels to decline with decreased adiposity following medical treatment.<ref name="Valsamakis_2004">Template:Cite journal</ref> Specifically, central obesity (waistline adipose tissue) is the region of adipose tissue that contributes most to rising levels of serum resistin.<ref name="McTernan_2002a">Template:Cite journal</ref> This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.<ref name="Gabriely_2002" /><ref name="Duman_2003">Template:Cite journal</ref>
Although resistin levels increase with obesity, it is questioned whether this increase is responsible for the insulin resistance associated with increased adiposity.Template:Citation needed Several reports have shown a positive correlation between resistin levels and insulin resistance.<ref name="Hirosumi_2002">Template:Cite journal</ref><ref name="Rajala_2004">Template:Cite journal</ref><ref name="Silha_2003">Template:Cite journal</ref><ref name="Smith_2003">Template:Cite journal</ref> This is supported by reports of correlation between resistin levels and subjects with T2DM.<ref name="Steppan_2001" /><ref name="Asensio_2004" /><ref name="Fujinami_2004">Template:Cite journal</ref><ref name="McTernan_2003">Template:Cite journal</ref> If resistin contributes to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects may deliver therapeutic benefits.<ref name="Tjokroprawiro_2006">Template:Cite journal</ref>
Resistin can increase levels of circulating low-density lipoprotein (LDL) and accelerates LDL accumulation in arteries, increasing risk of heart disease has an adverse impact on the efficacy of statins, the primary drug used to reduce cholesterol in fighting of cardiovascular disease.<ref name="Canadian scientists discover cause of high cholesterol">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> In the liver, resistin increases LDL production and degrades LDL receptors, impairing the ability to process LDL.
Arguments againstEdit
The amount of evidence supporting the resistin link theory between obesity and T2DM is vast.Template:Citation needed Nevertheless, this theory lacks support from the entire scientific community, as a number of studies present evidence against it.<ref name="Fain_2003">Template:Cite journal</ref><ref name="Lee_2003">Template:Cite journal</ref><ref name="Nagaev_2001">Template:Cite journal</ref> Such studies have found significantly decreased serum concentrations of resistin with increased adiposity,<ref name="Heilbronn_2004">Template:Cite journal</ref><ref name="Savage_2001">Template:Cite journal</ref><ref name="Way_2001">Template:Cite journal</ref> suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin.<ref name="Milan_2002" /> The idea that resistin links obesity to T2DM is under scrutiny, reports have been made of ubiquitous resistin expression in many tissues, rather than only those characteristic of obesity, such as adipocytes Template:Citation needed.
Although nearly as many scientists oppose the theory as those who support it Template:Citation needed, there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.