Resistin is a
hormonesecreted 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 mouseand ratit's 114 aa); the molecular weightis ~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 adipocytokinewhose physiologic role has been the subject of much controversy regarding its involvement with obesityand type II diabetes mellitus(T2DM).
Resistin was discovered in
2001by the group of Dr Mitchell A. Lazar from University of PennsylvaniaSchool of Medicine.cite journal | author = 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 = 307–12 | year = 2001 | month = January | pmid = 11201732 | doi = 10.1038/35053000 | url = | issn = ] It was called "resistin" because of the observed insulinresistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrinefunctions likely involved in insulin resistance. This idea primarily stems from studies demonstrating that serumresistin levels increase with obesity in several model systems (humans, rats, and mice).cite journal | author = Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV | title = Serum resistin (FIZZ3) protein is increased in obese humans | journal = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 11 | pages = 5452–5 | year = 2003 | month = November | pmid = 14602788 | doi = 10.1210/jc.2002-021808 | url = | issn = ] cite journal | author = Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N | title = Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? | journal = Diabetes | volume = 51 | issue = 10 | pages = 2951–8 | year = 2002 | month = October | pmid = 12351432 | doi = 10.2337/diabetes.51.10.2951 | url = | issn = ] cite journal | author = Levy JR, Davenport B, Clore JN, Stevens W | title = Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats | journal = Am. J. Physiol. Endocrinol. Metab. | volume = 282 | issue = 3 | pages = E626–33 | year = 2002 | month = March | pmid = 11832366 | doi = 10.1152/ajpendo.00346.2001 | url = | issn = ] cite journal | author = McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S | title = Resistin, central obesity, and type 2 diabetes | journal = Lancet | volume = 359 | issue = 9300 | pages = 46–7 | year = 2002 | month = January | pmid = 11809189 | doi = 10.1016/S0140-6736(02)07281-1 | url = | issn = ] Since these observations, further research has linked resistin to other physiological systems such as inflammationand energy homeostasis.cite journal | author = Adeghate E | title = An update on the biology and physiology of resistin | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 19-20 | pages = 2485–96 | year = 2004 | month = October | pmid = 15526156 | doi = 10.1007/s00018-004-4083-2 | url = | issn = ] cite journal | author = Stumvoll M, Häring H | title = Resistin and adiponectin--of mice and men | journal = Obes. Res. | volume = 10 | issue = 11 | pages = 1197–9 | year = 2002 | month = November | pmid = 12429885 | doi = 10.1038/oby.2002.162 | url = | issn = ] cite journal | author = 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 = Obes. Res. | volume = 12 | issue = 6 | pages = 962–71 | year = 2004 | month = June | pmid = 15229336 | doi = 10.1038/oby.2004.118 | url = | issn = ]
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 responseto infectionor irritationresulting from leukocyte( neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenicchemicals such as histamine, prostaglandinand pro-inflammatory cytokines. As cited, it has recently been found that resistin also participates in the inflammatory response.cite journal | author = 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 | title = FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family | journal = EMBO J. | volume = 19 | issue = 15 | pages = 4046–55 | year = 2000 | month = August | pmid = 10921885 | pmc = 306596 | doi = 10.1093/emboj/19.15.4046 | url = | issn = ] cite journal | author = 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 = J. Clin. Endocrinol. Metab. | volume = 92 | issue = 1 | pages = 270–6 | year = 2007 | month = January | pmid = 17062773 | doi = 10.1210/jc.2006-1151 | url = | issn = ] cite journal | author = 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 = Transplant. Proc. | volume = 38 | issue = 10 | pages = 3434–6 | year = 2006 | month = December | pmid = 17175295 | doi = 10.1016/j.transproceed.2006.10.140 | url = | issn = ] cite journal | author = Nagaev I, Bokarewa M, Tarkowski A, Smith U | title = Human resistin is a systemic immune-derived proinflammatory cytokine targeting both leukocytes and adipocytes | journal = PLoS ONE | volume = 1 | issue = | pages = e31 | year = 2006 | pmid = 17183659 | pmc = 1762367 | doi = 10.1371/journal.pone.0000031 | url = | issn = ]
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.cite journal | author = Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G, Vettor R | title = Resistin and adiponectin expression in visceral fat of obese rats: effect of weight loss | journal = Obes. Res. | volume = 10 | issue = 11 | pages = 1095–103 | year = 2002 | month = November | pmid = 12429872 | doi = 10.1038/oby.2002.149 | url = | issn = ] cite journal | author = 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 = Biochem. Biophys. Res. Commun. | volume = 334 | issue = 4 | pages = 1092–101 | year = 2005 | month = September | pmid = 16039994 | doi = 10.1016/j.bbrc.2005.06.202 | url = | issn = ] It has also been demonstrated that resistin upregulates intracellular adhesionmolecule-1 ( ICAM1) vascular cell-adhesion molecule-1 ( VCAM1) and CCL2, all of which are occupied in chemotacticpathways involved in leukocyterecruitment to sites of infection.cite journal | author = 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 = 736–40 | year = 2003 | month = August | pmid = 12874180 | doi = 10.1161/01.CIR.0000084503.91330.49 | url = | issn = ] Resistin itself can be upregulated by interleukins and also by microbialantigens such as lipopolysaccharide,cite journal | author = Lu SC, Shieh WY, Chen CY, Hsu SC, Chen HL | title = Lipopolysaccharide increases resistin gene expression in vivo and in vitro | journal = FEBS Lett. | volume = 530 | issue = 1-3 | pages = 158–62 | year = 2002 | month = October | pmid = 12387885 | doi = | url = http://linkinghub.elsevier.com/retrieve/pii/S0014579302034506 | issn = ] 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.cite journal | author = Wellen KE, Hotamisligil GS | title = Inflammation, stress, and diabetes | journal = J. Clin. Invest. | volume = 115 | issue = 5 | pages = 1111–9 | year = 2005 | month = May | pmid = 15864338 | pmc = 1087185 | doi = 10.1172/JCI25102 | url = | issn = ] 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 inflammationin 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 inflammationcite journal | author = Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME | title = Adiponectin differentially regulates cytokines in porcine macrophages | journal = Biochem. Biophys. Res. Commun. | volume = 316 | issue = 3 | pages = 924–9 | year = 2004 | month = April | pmid = 15033490 | doi = 10.1016/j.bbrc.2004.02.130 | url = | issn = ] cite journal | author = Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y | title = Adiponectin, a new member of the family of soluble defense collagens, negatively regulates the growth of myelomonocytic progenitors and the functions of macrophages | journal = Blood | volume = 96 | issue = 5 | pages = 1723–32 | year = 2000 | month = September | pmid = 10961870 | doi = | url = http://www.bloodjournal.org/cgi/pmidlookup?view=long&pmid=10961870 | issn = ] 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 diseaseare associated with declined renal function and inflammation, but not with insulin resistance.cite journal | author = Axelsson J, Bergsten A, Qureshi AR, Heimbürger O, Bárány P, Lönnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P | title = Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance | journal = Kidney Int. | volume = 69 | issue = 3 | pages = 596–604 | year = 2006 | month = February | pmid = 16395259 | doi = 10.1038/sj.ki.5000089 | url = | issn = ] 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 diseaseswith or without associated insulin resistance.
Resistin, obesity and insulin resistance
Much of what is
hypothesizedabout a resistin role in energy metabolismand 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 serumresistin levels will increase with increased adiposity.cite journal | author = 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 = 2206–13 | year = 2004 | month = May | pmid = 14962997 | doi = 10.1210/en.2003-1679 | url = | issn = ] cite journal | author = 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 = Am. J. Physiol. Endocrinol. Metab. | volume = 288 | issue = 3 | pages = E625–32 | year = 2005 | month = March | pmid = 15522996 | doi = 10.1152/ajpendo.00184.2004 | url = | issn = ] Conversely, serum resistin levels have been found to decline with decreased adiposity following medicaltreatment.cite journal | author = 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 = Metab. Clin. Exp. | volume = 53 | issue = 4 | pages = 430–4 | year = 2004 | month = April | pmid = 15045687 | doi = 10.1016/j.metabol.2003.11.022 | url = | issn = ] Specifically, central obesity(waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.cite journal | author = 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 = J. Clin. Endocrinol. Metab. | volume = 87 | issue = 5 | pages = 2407 | year = 2002 | month = May | pmid = 11994397 | doi = 10.1210/jc.87.5.2407 | url = | issn = ] This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM.cite journal | author = 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 Nutr. Metab. | volume = 16 | issue = 4 | pages = 243–50 | year = 2003 | month = August | pmid = 14768774 | doi = | url = | issn = ] Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistanceapparently 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.cite journal | author = 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 = 333–6 | year = 2002 | month = November | pmid = 12447443 | doi = 10.1038/nature01137 | url = http://www.hsph.harvard.edu/GSH-LAB/tnf-ins.html | issn = ] cite journal | author = 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 = 1671–9 | year = 2004 | month = July | pmid = 15220189 | doi = 10.2337/diabetes.53.7.1671 | url = | issn = ] cite journal | author = 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 = Eur. J. Endocrinol. | volume = 149 | issue = 4 | pages = 331–5 | year = 2003 | month = October | pmid = 14514348 | doi = 10.1530/eje.0.1490331 | url = | issn = ] cite journal | author = 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 = 1611–8 | year = 2003 | month = July | pmid = 12829623 | doi = 10.2337/diabetes.52.7.1611 | url = | issn = ] This discovery is further authenticated by studies which confirmed a direct correlation between resistin levels and subjects with T2DM.cite journal | author = 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 = Clin. Chim. Acta | volume = 339 | issue = 1-2 | pages = 57–63 | year = 2004 | month = January | pmid = 14687894 | doi = 10.1016/j.cccn.2003.09.009 | url = | issn = ] cite journal | author = McTernan PG, Fisher FM, Valsamakis G, "et al" | 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 = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 12 | pages = 6098–106 | year = 2003 | month = December | pmid = 14671216 | doi = 10.1210/jc.2003-030898 | url = | issn = ] 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.cite journal | author = Tjokroprawiro A | title = New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer) | journal = Acta Med Indones | volume = 38 | issue = 3 | pages = 160–6 | year = 2006 | pmid = 17119268 | doi = 10.1267/science.040579197 | url = | issn = ]
The amount of
evidencesupporting the resistin link theory between obesity and T2DM is vast and will most likely continue to grow. Nevertheless, this theorylacks support from the entire scientific communityat large as an increasingly greater number of studies presenting contradictory evidences continue to emerge.cite journal | author = Fain JN, Cheema PS, Bahouth SW, Lloyd Hiler M | title = Resistin release by human adipose tissue explants in primary culture | journal = Biochem. Biophys. Res. Commun. | volume = 300 | issue = 3 | pages = 674–8 | year = 2003 | month = January | pmid = 12507502 | doi = 10.1016/S0006-291X(02)02864-4 | url = | issn = ] cite journal | author = 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 = J. Clin. Endocrinol. Metab. | volume = 88 | issue = 10 | pages = 4848–56 | year = 2003 | month = October | pmid = 14557464 | doi = 10.1210/jc.2003-030519 | url = | issn = ] cite journal | author = Nagaev I, Smith U | title = Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle | journal = Biochem. Biophys. Res. Commun. | volume = 285 | issue = 2 | pages = 561–4 | year = 2001 | month = July | pmid = 11444881 | doi = 10.1006/bbrc.2001.5173 | url = | issn = ] Such studies found significantly decreased serum concentrations of resistin with increased adipositycite journal | author = Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR' | title = Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects | journal = J. Clin. Endocrinol. Metab. | volume = 89 | issue = 4 | pages = 1844–8 | year = 2004 | month = April | pmid = 15070954 | doi = 10.1210/jc.2003-031410 | url = | issn = ] cite journal | author = Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, O'Rahilly S | title = Resistin / Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-gamma action in humans | journal = Diabetes | volume = 50 | issue = 10 | pages = 2199–202 | year = 2001 | month = October | pmid = 11574398 | doi = 10.2337/diabetes.50.10.2199 | url = | issn = ] cite journal | author = Way JM, Görgün CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Willson TM, Kliewer SA, Hotamisligil GS | title = Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists | journal = J. Biol. Chem. | volume = 276 | issue = 28 | pages = 25651–3 | year = 2001 | month = July | pmid = 11373275 | doi = 10.1074/jbc.C100189200 | url = | issn = ] suggesting that not only is resistin downregulated in obese subjects but that it also presents itself as an unlikely candidate for linking obesityto 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 . In reality, most all findings (many times elucidated under the same experimental conditions) reported by groups opposing the resistin link theoryare the exact opposite from what those groups who support the theoryhave observed. The idea that resistin links obesityto 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
scientistsagainst this theoryas those scientists who seem to support it, the likelihood that resistin will ever be viewed as the key node linking obesityto T2DM in the near future is very low. The very extent to which these two views oppose each other raises questions about the synchronyof methodologyused in these respective groups which resulted in polar opposite results. It is unsurprising, however, that a “ discovery” linking T2DM to obesityvia resistin-mediated pathways would not go unchallenged in a highly competitivescientific world. Nevertheless, we can certainly conclude that among this giant debatelies sufficient evidenceto support the idea that resistin does have some incompletely-defined role in energy homeostasiswhile also demonstrating properties which help to incite inflammatory responsesto sites of infection.
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