Resistin

{{Short description|Mammalian protein, acts as a multifunctional hormone}} {{Redirect|RETN|the internet service provider|RETN Networks}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{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">{{cite journal | vauthors = Wang H, Chu WS, Hemphill C, Elbein SC | title = Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 6 | pages = 2520–2524 | date = June 2002 | pmid = 12050208 | doi = 10.1210/jcem.87.6.8528 | doi-access = free }}</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">{{cite journal | vauthors = Lazar MA | title = Resistin- and Obesity-associated metabolic diseases | journal = Hormone and Metabolic Research | volume = 39 | issue = 10 | pages = 710–716 | date = October 2007 | pmid = 17952831 | doi = 10.1055/s-2007-985897 | doi-access = free }}</ref>

== Discovery and structure == 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">{{cite journal | vauthors = Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA | title = The hormone resistin links obesity to diabetes | journal = Nature | volume = 409 | issue = 6818 | pages = 307–312 | date = January 2001 | pmid = 11201732 | doi = 10.1038/35053000 | bibcode = 2001Natur.409..307S | s2cid = 4358808 }}</ref> Specifically, elevated resistin levels appear to interfere with the action of insulin on adipose cells.<ref name="Steppan_2001" /><ref name="Levy_2002">{{cite journal | vauthors = Levy JR, Davenport B, Clore JN, Stevens W | title = Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 282 | issue = 3 | pages = E626–E633 | date = March 2002 | pmid = 11832366 | doi = 10.1152/ajpendo.00346.2001 | s2cid = 25303054 }}</ref><ref name="McTernan_2002">{{cite journal | vauthors = McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S | title = Resistin, central obesity, and type 2 diabetes | journal = Lancet | location = London, England | volume = 359 | issue = 9300 | pages = 46–47 | date = January 2002 | pmid = 11809189 | doi = 10.1016/S0140-6736(02)07281-1 | s2cid = 21927880 }}</ref> Subsequent studies noted a link between resistin and activation of pro-inflammatory cytokines.<ref name="Adeghate_2004">{{cite journal | vauthors = Adeghate E | title = An update on the biology and physiology of resistin | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 19–20 | pages = 2485–2496 | date = October 2004 | pmid = 15526156 | pmc = 11924563 | doi = 10.1007/s00018-004-4083-2 | s2cid = 22832421 }}</ref><ref name="Vendrell_2004">{{cite journal | vauthors = Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C | title = Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity | journal = Obesity Research | volume = 12 | issue = 6 | pages = 962–971 | date = June 2004 | pmid = 15229336 | doi = 10.1038/oby.2004.118 | doi-access = free }}</ref>

{{Infobox protein family | Symbol = Resistin | Name = Resistin | image = | width = | caption = | Pfam= PF06954 | InterPro= IPR009714 | SMART= | Prosite = | SCOP = 1rgx | TCDB = | OPM family= 384 | OPM protein= 1rgx | PDB= }} 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">{{cite journal | vauthors = Li Y, Yang Q, Cai D, Guo H, Fang J, Cui H, Gou L, Deng J, Wang Z, Zuo Z | title = Resistin, a Novel Host Defense Peptide of Innate Immunity | journal = Frontiers in Immunology | volume = 12 | article-number = 699807 | date = 2021 | pmid = 34220862 | pmc = 8253364 | doi = 10.3389/fimmu.2021.699807 | doi-access = free }}</ref><ref name="Patel_2004">{{cite journal | vauthors = Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L | title = Disulfide-dependent multimeric assembly of resistin family hormones | journal = Science | location = New York, N.Y. | volume = 304 | issue = 5674 | pages = 1154–1158 | date = May 2004 | pmid = 15155948 | doi = 10.1126/science.1093466 | bibcode = 2004Sci...304.1154P }}</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" /> 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 family of peptide hormones.<ref name="Li_2021" /><ref name="Patel_2004" />

== Function ==

Resistin is a multifunctional 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">{{cite journal | vauthors = Lee S, Lee HC, Kwon YW, Lee SE, Cho Y, Kim J, Lee S, Kim JY, Lee J, Yang HM, Mook-Jung I, Nam KY, Chung J, Lazar MA, Kim HS | title = Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes | journal = Cell Metabolism | volume = 19 | issue = 3 | pages = 484–97 | date = March 2014 | pmid = 24606903 | pmc = 3969988 | doi = 10.1016/j.cmet.2014.01.013 | url = }}</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 significance ==

=== Obesity and insulin resistance ===

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="Vendrell_2004" /><ref name="Asensio_2004">{{cite journal | vauthors = Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P | title = Changes in glycemia by leptin administration or high- fat feeding in rodent models of obesity/type 2 diabetes suggest a link between resistin expression and control of glucose homeostasis | journal = Endocrinology | volume = 145 | issue = 5 | pages = 2206–2213 | date = May 2004 | pmid = 14962997 | doi = 10.1210/en.2003-1679 | doi-access = free }}</ref><ref name="Lee_2005">{{cite journal | vauthors = Lee JH, Bullen JW, Stoyneva VL, Mantzoros CS | title = Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia | journal = American Journal of Physiology. Endocrinology and Metabolism | volume = 288 | issue = 3 | pages = E625–E632 | date = March 2005 | pmid = 15522996 | doi = 10.1152/ajpendo.00184.2004 | s2cid = 20609673 }}</ref> Conversely, serum resistin levels decline with decreased adiposity following medical treatment.<ref name="Valsamakis_2004">{{cite journal | vauthors = Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S | title = Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines | journal = Metabolism: Clinical and Experimental | volume = 53 | issue = 4 | pages = 430–434 | date = April 2004 | pmid = 15045687 | doi = 10.1016/j.metabol.2003.11.022 }}</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">{{cite journal | vauthors = McTernan PG, McTernan CL, Chetty R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S | title = Increased resistin gene and protein expression in human abdominal adipose tissue | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 87 | issue = 5 | page = 2407 | date = May 2002 | pmid = 11994397 | doi = 10.1210/jcem.87.5.8627 | doi-access = free }}</ref> This is significant, considering the link between central obesity and insulin resistance, two marked peculiarities of T2DM.<ref name="Duman_2003">{{cite journal | vauthors = Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS | title = The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity | journal = Diabetes, Nutrition & Metabolism | volume = 16 | issue = 4 | pages = 243–250 | date = August 2003 | pmid = 14768774 }}</ref> On the other hand, at least one study has found no correlation between resistin levels and obesity or insulin resistance in humans,<ref name="Lee_2003">{{cite journal | vauthors = Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS | title = Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 10 | pages = 4848–4856 | date = October 2003 | pmid = 14557464 | doi = 10.1210/jc.2003-030519 | doi-access = free }}</ref> so the resistin–insulin resistance connection may be regarded as somewhat unsettled.

Although resistin levels increase with obesity, it is questioned whether this increase is responsible for the insulin resistance associated with increased adiposity. Several reports have shown a positive correlation between resistin levels and insulin resistance.<ref name="Hirosumi_2002">{{cite journal | vauthors = Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS | title = A central role for JNK in obesity and insulin resistance | journal = Nature | volume = 420 | issue = 6913 | pages = 333–336 | date = November 2002 | pmid = 12447443 | doi = 10.1038/nature01137 | bibcode = 2002Natur.420..333H | url = http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html | s2cid = 1659156 | url-access = subscription }}</ref><ref name="Rajala_2004">{{cite journal | vauthors = Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS | title = Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting | journal = Diabetes | volume = 53 | issue = 7 | pages = 1671–1679 | date = July 2004 | pmid = 15220189 | doi = 10.2337/diabetes.53.7.1671 | doi-access = free }}</ref><ref name="Silha_2003">{{cite journal | vauthors = Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ | title = Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance | journal = European Journal of Endocrinology | volume = 149 | issue = 4 | pages = 331–335 | date = October 2003 | pmid = 14514348 | doi = 10.1530/eje.0.1490331 | doi-access = free }}</ref><ref name="Smith_2003">{{cite journal | vauthors = Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G | title = A promoter genotype and oxidative stress potentially link resistin to human insulin resistance | journal = Diabetes | volume = 52 | issue = 7 | pages = 1611–1618 | date = July 2003 | pmid = 12829623 | doi = 10.2337/diabetes.52.7.1611 | doi-access = free }}</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">{{cite journal | vauthors = Fujinami A, Obayashi H, Ohta K, Ichimura T, Nishimura M, Matsui H, Kawahara Y, Yamazaki M, Ogata M, Hasegawa G, Nakamura N, Yoshikawa T, Nakano K, Ohta M | title = Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 339 | issue = 1–2 | pages = 57–63 | date = January 2004 | pmid = 14687894 | doi = 10.1016/j.cccn.2003.09.009 }}</ref><ref name="McTernan_2003">{{cite journal | vauthors = McTernan PG, Fisher FM, Valsamakis G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S | title = Resistin and type 2 diabetes: regulation of resistin expression by insulin and rosiglitazone and the effects of recombinant resistin on lipid and glucose metabolism in human differentiated adipocytes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 88 | issue = 12 | pages = 6098–6106 | date = December 2003 | pmid = 14671216 | doi = 10.1210/jc.2003-030898 | doi-access = free }}</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">{{cite journal | vauthors = Tjokroprawiro A | title = New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer) | journal = Acta Medica Indonesiana | volume = 38 | issue = 3 | pages = 160–166 | year = 2006 | pmid = 17119268 }}</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">{{Cite web | title = Canadian scientists discover cause of high cholesterol | date = October 28, 2012 | url = https://www.sciencecodex.com/canadian_scientists_discover_cause_of_high_cholesterol-101029 | website = Science Codex }}</ref> In the liver, resistin increases LDL production and degrades LDL receptors, impairing the ability to process LDL.

=== Inflammation ===

Beyond its role as a hormone, resistin also contributes to inflammation.<ref name="Kusminski_2007">{{cite journal | vauthors = Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG | title = The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 92 | issue = 1 | pages = 270–276 | date = January 2007 | pmid = 17062773 | doi = 10.1210/jc.2006-1151 | doi-access = free }}</ref><ref name="Malyszko_2006">{{cite journal | vauthors = Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M | title = Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients | journal = Transplantation Proceedings | volume = 38 | issue = 10 | pages = 3434–3436 | date = December 2006 | pmid = 17175295 | doi = 10.1016/j.transproceed.2006.10.140 }}</ref><ref name="Nagaev_2006">{{cite journal | vauthors = Nagaev I, Bokarewa M, Tarkowski A, Smith U | veditors = Valcarcel J | title = Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting both Leukocytes and Adipocytes | journal = PLOS ONE | volume = 1 | issue = 1 | article-number = e31 | date = Dec 2006 | pmid = 17183659 | pmc = 1762367 | doi = 10.1371/journal.pone.0000031 | bibcode = 2006PLoSO...1...31N | doi-access = free }}</ref> Interleukin-12 (IL-12) and tumor necrosis factor-α (TNF-α) are up-regulated by resistin in an NF-κB-mediated fashion.<ref name="Silswal_2005">{{cite journal | vauthors = Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ | title = Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway | journal = Biochemical and Biophysical Research Communications | volume = 334 | issue = 4 | pages = 1092–1101 | date = September 2005 | pmid = 16039994 | doi = 10.1016/j.bbrc.2005.06.202 | bibcode = 2005BBRC..334.1092S | s2cid = 29273978 }}</ref> Likewise, in vitro studies show Toll-like receptor 2 expression is increased by resistin.<ref name="Kusminski_2007" /> It has also been demonstrated that resistin upregulates vascular cell-adhesion molecule-1 (VCAM1), involved in chemotactic movement of leukocytes to sites of infection.<ref name="Verma_2003">{{cite journal | vauthors = Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA | title = Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction | journal = Circulation | volume = 108 | issue = 6 | pages = 736–740 | date = August 2003 | pmid = 12874180 | doi = 10.1161/01.CIR.0000084503.91330.49 | doi-access = free }}</ref> Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,<ref name="Lu_2002">{{cite journal | vauthors = Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL | title = Lipopolysaccharide increases resistin gene expression in vivo and in vitro | journal = FEBS Letters | volume = 530 | issue = 1–3 | pages = 158–162 | date = October 2002 | pmid = 12387885 | doi = 10.1016/S0014-5793(02)03450-6 | bibcode = 2002FEBSL.530..158L | s2cid = 45491974 }}</ref> which are recognized by leukocytes. Together, these findings suggest resistin may be a link in the well-known association between inflammation and insulin resistance.<ref name="Wellen_2005">{{cite journal | vauthors = Wellen KE, Hotamisligil GS | title = Inflammation, stress, and diabetes | journal = The Journal of Clinical Investigation | volume = 115 | issue = 5 | pages = 1111–1119 | date = May 2005 | pmid = 15864338 | pmc = 1087185 | doi = 10.1172/JCI25102 }}</ref>

Resistin also seems to be a marker of inflammation in semen. Resistin levels correlate positively with those of proinflammatory mediators such as interleukin-6 (IL-6), elastase and tumor necrosis factor-α (TNF-α) in seminal plasma. 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">{{cite journal | vauthors = Elfassy Y, Bastard JP, McAvoy C, Fellahi S, Dupont J, Levy R | title = Adipokines in Semen: Physiopathology and Effects on Spermatozoas | journal = International Journal of Endocrinology | volume = 2018 | article-number = 3906490 | date = 2018 | pmid = 29971101 | pmc = 6008818 | doi = 10.1155/2018/3906490 | doi-access = free }}</ref> One study showed that there was a negative correlation between the concentrations of seminal resistin and spermatic motility and vitality.<ref name="Moretti_2019">{{cite journal | vauthors = Moretti E, Micheli L, Noto D, Fiaschi AI, Menchiari A, Cerretani D | title = Resistin in Human Seminal Plasma: Relationship with Lipid Peroxidation, CAT Activity, GSH/GSSG Ratio, and Semen Parameters | journal = Oxidative Medicine and Cellular Longevity | volume = 2019 | article-number = 2192093 | date = 2019 | pmid = 31772701 | pmc = 6854241 | doi = 10.1155/2019/2192093 | doi-access = free }}</ref>

== References == {{Reflist|2}} <!-- This was reference 12, couldn't find any reference to it, although there were two references to ref. 22 so perhaps one of them should be to this one

{{cite journal | vauthors = Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR | title = Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro | journal = Biochemical and Biophysical Research Communications | volume = 309 | issue = 2 | pages = 286–90 | date = September 2003 | pmid = 12951047 | doi = 10.1016/j.bbrc.2003.07.003 }} -->

==External links== * {{MeshName|Resistin}}

{{Hormones}}

Category:Tissues (biology) Category:Endocrinology Category:Obesity