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14-September-2008 18:02:48 - Resistin Resistin Identifiers Symbols RETN; ADSF; FIZZ3; MGC126603; MGC126609; RETN1; RSTN; XCP1 External IDs OMIM: 605565 MGI: 1888506 HomoloGene: 10703 Gene ontology Molecular function: hormone activity Cellular component: extracellular region Biological process: biological_process RNA expression pattern More reference expression data Orthologs Human Mouse Entrez 56729 57264 Ensembl ENSG00000104918 ENSMUSG00000012705 Uniprot Q9HD89 Q3V2F6 Refseq NM_020415 mRNA NP_065148 protein NM_022984 mRNA NP_075360 protein Location Chr 19: 7.64 - 7.64 Mb Chr 8: 3.66 - 3.66 Mb Pubmed search 1 2 Resistin is a hormone secreted by adipose tissue. It is also known as serine/cysteine-rich adipocyte-Specific Secretory Factor ADSF or FIZZ3. The length of the resistin pre-peptide in human is 108 aminoacids in the mouse and rat it's 114 aa; the molecular weight is ~12.5 kDa. Among the hormones synthesized and released from adipose tissue adiponectin, angiotensin, estradiol, IL-6, leptin, PAI-1, TNF-α, and resistin also known as ADSF or FIZZ3, resistin is an adipocytokine whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus T2DM. Contents 1 Discovery 2 Resistin and inflammation 3 Resistin, obesity and insulin resistance 4 Controversy 5 References 6 External links Discovery Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from University of Pennsylvania School of Medicine.1 It was called resistin because of the observed insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems humans, rats, and mice.12345 Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.678 This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects. Resistin and inflammation 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 found that resistin also participates in the inflammatory response.9101112 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 fashion.1314 It has also been demonstrated that resistin upregulates intracellular adhesion molecule-1 ICAM1 vascular cell-adhesion molecule-1 VCAM1 and CCL2, all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection.15 Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,16 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.17 In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation1819 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 declined renal function and inflammation, but not with insulin resistance.20 Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance. Resistin, obesity and insulin resistance Much of what is hypothesized about a resistin role in energy metabolism and T2DM can be derived from studies showing hefty correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity.282122 Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment.23 Specifically, central obesity waistline adipose tissue seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.5 This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM.324 Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance apparently associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance.25262728 This discovery is further authenticated by studies which confirmed a direct correlation between resistin levels and subjects with T2DM.2112930 Provided that resistin is at least in part due to the insulin resistance coupled to T2DM, fabricating drugs which specifically target cascades leading to decreased serum resistin in T2DM subjects will surely deliver immense therapeutic benefits.31 Controversy The amount of evidence supporting the resistin link theory between obesity and T2DM is vast and will most likely continue to grow. Nevertheless, this theory lacks support from the entire scientific community at large as an increasingly greater number of studies presenting contradictory evidences continue to emerge.323334 Such studies found significantly decreased serum concentrations of resistin with increased adiposity353637 suggesting that not only is resistin downregulated in obese subjects but that it also presents itself as an unlikely candidate for linking obesity to T2DM. Data has also been presented contradicting the idea that weight loss coincided with decreased serum resistin concentrations finding that it instead matched up with marked increases in serum resistin 13. In reality, most all findings many times elucidated under the same experimental conditions reported by groups opposing the resistin link theory are the exact opposite from what those groups who support the theory have observed. The idea that resistin links obesity to T2DM is now under even more scrutiny as recent investigations have confirmed a rather vast expression of resistin in many tissues rather than those only characteristic of obesity such as adipocytes. With nearly as many scientists against this theory as those scientists who seem to support it, the likelihood that resistin will ever be viewed as the key node linking obesity to T2DM in the near future is very low. The very extent to which these two views oppose each other raises questions about the synchrony of methodology used in these respective groups which resulted in polar opposite results. It is unsurprising, however, that a discovery linking T2DM to obesity via resistin-mediated pathways would not go unchallenged in a highly competitive scientific world. Nevertheless, we can certainly conclude that among this giant debate lies sufficient evidence to support the idea that resistin does have some incompletely-defined role in energy homeostasis while also demonstrating properties which help to incite inflammatory responses to sites of infection. References ^ a b c Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA January 2001. The hormone resistin links obesity to diabetes. Nature 409 6818: 307-12. doi:10.1038/35053000. PMID 11201732. ^ a b Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV November 2003. Serum resistin FIZZ3 protein is increased in obese humans. J. Clin. Endocrinol. Metab. 88 11: 5452-5. doi:10.1210/jc.2002-021808. PMID 14602788. ^ a b Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N October 2002. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process?. Diabetes 51 10: 2951-8. doi:10.2337/diabetes.51.10.2951. PMID 12351432. ^ Levy JR, Davenport B, Clore JN, Stevens W March 2002. Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats. Am. J. Physiol. Endocrinol. Metab. 282 3: E626-33. doi:10.1152/ajpendo.00346.2001. PMID 11832366. ^ a b McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S January 2002. Resistin, central obesity, and type 2 diabetes. Lancet 359 9300: 46-7. doi:10.1016/S0140-67360207281-1. PMID 11809189. ^ Adeghate E October 2004. An update on the biology and physiology of resistin. Cell. Mol. Life Sci. 61 19-20: 2485-96. doi:10.1007/s00018-004-4083-2. PMID 15526156. ^ Stumvoll M, Häring H November 2002. Resistin and adiponectin--of mice and men. Obes. Res. 10 11: 1197-9. doi:10.1038/oby.2002.162. PMID 12429885. ^ a b Vendrell J, Broch M, Vilarrasa N, Molina A, Gómez JM, Gutiérrez C, Simón I, Soler J, Richart C June 2004. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obes. Res. 12 6: 962-71. doi:10.1038/oby.2004.118. PMID 15229336. ^ Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ, Frantz GD, Tumas DB, Peale FV Jr, Shelton DL, Hébert CC August 2000. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19 15: 4046-55. doi:10.1093/emboj/19.15.4046. PMID 10921885. ^ Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG January 2007. The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes. J. Clin. Endocrinol. Metab. 92 1: 270-6. doi:10.1210/jc.2006-1151. PMID 17062773. ^ Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M December 2006. Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients. Transplant. Proc. 38 10: 3434-6. doi:10.1016/j.transproceed.2006.10.140. PMID 17175295. ^ Nagaev I, Bokarewa M, Tarkowski A, Smith U 2006. Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes. PLoS ONE 1: e31. doi:10.1371/journal.pone.0000031. PMID 17183659. ^ a b Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R November 2002. Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss. Obes. Res. 10 11: 1095-103. doi:10.1038/oby.2002.149. PMID 12429872. ^ Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ September 2005. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway. Biochem. Biophys. Res. Commun. 334 4: 1092-101. doi:10.1016/j.bbrc.2005.06.202. PMID 16039994. ^ Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA August 2003. Resistin promotes endothelial cell activation: further evidence of adipokine-endothelial interaction. Circulation 108 6: 736-40. doi:10.1161/01.CIR.0000084503.91330.49. PMID 12874180. ^ Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL October 2002. Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett. 530 1-3: 158-62. PMID 12387885. ^ Wellen KE, Hotamisligil GS May 2005. Inflammation, stress, and diabetes. J. Clin. Invest. 115 5: 1111-9. doi:10.1172/JCI25102. PMID 15864338. ^ Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME April 2004. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem. Biophys. Res. Commun. 316 3: 924-9. doi:10.1016/j.bbrc.2004.02.130. PMID 15033490. ^ Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y September 2000. Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages. Blood 96 5: 1723-32. PMID 10961870. ^ Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P February 2006. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int. 69 3: 596-604. doi:10.1038/sj.ki.5000089. PMID 16395259. ^ a b Asensio C, Cettour-Rose P, Theander-Carrillo C, Rohner-Jeanrenaud F, Muzzin P May 2004. 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. Endocrinology 145 5: 2206-13. doi:10.1210/en.2003-1679. PMID 14962997. ^ Lee JH, Bullen JW, Stoyneva VL, Mantzoros CS March 2005. Circulating resistin in lean, obese, and insulin-resistant mouse models: lack of association with insulinemia and glycemia. Am. J. Physiol. Endocrinol. Metab. 288 3: E625-32. doi:10.1152/ajpendo.00184.2004. PMID 15522996. ^ Valsamakis G, McTernan PG, Chetty R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S April 2004. Modest weight loss and reduction in waist circumference after medical treatment are associated with favorable changes in serum adipocytokines. Metab. Clin. Exp. 53 4: 430-4. doi:10.1016/j.metabol.2003.11.022. PMID 15045687. ^ Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS August 2003. The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity. Diabetes Nutr. Metab. 16 4: 243-50. PMID 14768774. ^ Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS November 2002. A central role for JNK in obesity and insulin resistance. Nature 420 6913: 333-6. doi:10.1038/nature01137. PMID 12447443. ^ Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS July 2004. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 53 7: 1671-9. doi:10.2337/diabetes.53.7.1671. PMID 15220189. ^ Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ October 2003. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur. J. Endocrinol. 149 4: 331-5. doi:10.1530/eje.0.1490331. PMID 14514348. ^ Smith SR, Bai F, Charbonneau C, Janderová L, Argyropoulos G July 2003. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52 7: 1611-8. doi:10.2337/diabetes.52.7.1611. PMID 12829623. ^ 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 January 2004. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin. Chim. Acta 339 1-2: 57-63. doi:10.1016/j.cccn.2003.09.009. PMID 14687894. ^ McTernan PG, Fisher FM, Valsamakis G, et al December 2003. 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. J. Clin. Endocrinol. Metab. 88 12: 6098-106. doi:10.1210/jc.2003-030898. PMID 14671216. ^ Tjokroprawiro A 2006. New approach in the treatment of T2DM and metabolic syndrome focus on a novel insulin sensitizer. Acta Med Indones 38 3: 160-6. doi:10.1267/science.040579197. PMID 17119268. ^ Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M January 2003. Resistin release by human adipose tissue explants in primary culture. Biochem. Biophys. Res. Commun. 300 3: 674-8. doi:10.1016/S0006-291X0202864-4. PMID 12507502. ^ Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS October 2003. 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. J. Clin. Endocrinol. Metab. 88 10: 4848-56. doi:10.1210/jc.2003-030519. PMID 14557464. ^ Nagaev I, Smith U July 2001. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem. Biophys. Res. Commun. 285 2: 561-4. doi:10.1006/bbrc.2001.5173. PMID 11444881. ^ Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR' April 2004. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J. Clin. Endocrinol. Metab. 89 4: 1844-8. doi:10.1210/jc.2003-031410. PMID 15070954. ^ Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S October 2001. Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans. Diabetes 50 10: 2199-202. doi:10.2337/diabetes.50.10.2199. PMID 11574398. ^ Way JM, Görgün CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Willson TM, Kliewer SA, Hotamisligil GS July 2001. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem. 276 28: 25651-3. doi:10.1074/jbc.C100189200. PMID 11373275. External links MeSH Resistin v d e Endocrine system: hormones/endocrine glands Peptide hormones, Steroid hormones Hypothalamic-pituitary Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α FSH, LH, TSH, GH, prolactin, POMC ACTH, MSH, endorphins, lipotropin Adrenal axis Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA Thyroid axis Thyroid: thyroid hormone T3 and T4 - calcitonin - Parathyroid: PTH Gonadal axis Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin pregnancy Other end. glands Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin Non-end. glands Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Thymulin - Skeleton: Osteocalcin - Liver/other: Insulin-like growth factor IGF-1, IGF-2 Target-derived NGF, BDNF, NT-3 Retrieved from http://en..org/wiki/Resistin Categories: Genes on chromosome 19 | Human proteins | Tissues | Endocrinology | ObesityHidden category: Protein pages needing a picture Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages Deutsch Ελληνικά This page was last modified on 17 August 2008, at 21:5
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