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Crystallographic structure of a hexamer of mouse resistin (rainbow colored, N-terminus = blue, C-terminus = red).[1]
Available structures
1rfx, 1rgx
Symbols RETN; ADSF; FIZZ3; MGC126603; MGC126609; RETN1; RSTN; XCP1
External IDs OMIM605565 MGI1888506 HomoloGene10703 GeneCards: RETN Gene
RNA expression pattern
PBB GE RETN 220570 at tn.png
More reference expression data
Species Human Mouse
Entrez 56729 57264
Ensembl ENSG00000104918 ENSMUSG00000012705
UniProt Q9HD89 Q3V2F6
RefSeq (mRNA) NM_020415 NM_022984
RefSeq (protein) NP_065148 NP_075360
Location (UCSC) Chr 19:
7.64 - 7.64 Mb
Chr 8:
3.66 - 3.66 Mb
PubMed search [1] [2]

Resistin is a cysteine-rich protein secreted by adipose tissue of mice and rats. In other mammals, at least primates, pigs and dogs, resistin is secreted by immune and epithelial cells. Resistin is also known as CEBPE regulated myeloid-specific secreted cysteine-rich protein precursor 1 (XCP1), found in inflammatory zone 3 (FIZZ3), or "adipocyte-specific secretory factor" (ADSF). 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 proteins synthesized and released from adipose tissue (adiponectin, angiotensin, estradiol, IL-6 , leptin, PAI-1, TNF-α), resistin is a cytokine whose physiologic role has been the subject of much controversy regarding its involvement with obesity and type II diabetes mellitus (T2DM).



Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine.[2] 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).[2][3][4][5][6] Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.[7][8][9]

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.


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.[10][11][12][13]

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.[14][15] 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.[16] Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide,[17] 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.[18]

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 inflammation[19][20] 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.[21] 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.

Obesity and insulin resistance


Arguments for

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.[3][9][22][23] Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment.[24] Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin.[6] This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM.[4][25]

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.[26][27][28][29] This discovery is further authenticated by studies which confirmed a direct correlation between resistin levels and subjects with T2DM.[2][22][30][31] 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.[32]

Arguments against

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.[33][34][35] Such studies found significantly decreased serum concentrations of resistin with increased adiposity[36][37][38] 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 [14]. 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.


Resistin has a high sequence identity (43% in a mature protein). Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions which make up its structure.[1] Each protein subunit comprises a carboxy-terminal disulfide-rich Beta-sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coiled coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern with be conserved.

The interchain disulfide bonds of resistin and RELMß are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds of 9.9%, and of 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.

The experiment was performed by the Department of Biochemistry and Molecular Biophysics at Columbia University, New York. They decided to assess the biological relevance of the novel multimeric assembly reported, and the hexamer-forming disulfide bonds in particular. The team analyzed mouse serum for the presence of hexamer and other forms of resistin. They injected a wild-type resistin and Cys6Ser mutant during pancreatic clamp studies to determine its effects on the mouse and its bioactivity. The Cys6Ser mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect an mandatory step toward activation. The results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.[1]

Ramachandran Plot [3]


  1. ^ a b c PDB 1rfx; Patel SD, Rajala MW, Rossetti L, Scherer PE, Shapiro L (May 2004). "Disulfide-dependent multimeric assembly of resistin family hormones". Science (journal) 304 (5674): 1154–8. doi:10.1126/science.1093466. PMID 15155948.  
  2. ^ 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.  
  3. ^ 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.  
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  14. ^ 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.  
  15. ^ 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.  
  16. ^ 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.  
  17. ^ 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. doi:10.1016/S0014-5793(02)03450-6. PMID 12387885.  
  18. ^ Wellen KE, Hotamisligil GS (May 2005). "Inflammation, stress, and diabetes". J. Clin. Invest. 115 (5): 1111–9. doi:10.1172/JCI25102. PMID 15864338.  
  19. ^ 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.  
  20. ^ 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.  
  21. ^ 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/ PMID 16395259.  
  22. ^ 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.  
  23. ^ 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.  
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  28. ^ 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.  
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  34. ^ 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.  
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  36. ^ 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.  
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