Resistin

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Resistin
Identifiers
Symbol(s) RETN; ADSF; FIZZ3; MGC126603; MGC126609; RETN1; RSTN; XCP1
External IDs OMIM: 605565 MGI1888506 Homologene10703
RNA expression pattern

PBB GE RETN 220570 at tn.png

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]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3] Phone:617-632-7753



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). Resistin was first discovered in 2001 (30) and was originally 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) (4, 8, 16, 19, and 30). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis (1, 31, and 34). 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.

Discovery

Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from University of Pennsylvania School of Medicine. It was called "resistin" because of the observed insulin resistance in mice injected with resistin (Steppan et al).

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 (11, 13, 18, and 23). 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 NFқB-mediated fashion (22, 28). 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 (35). 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 (37).

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 (38, 39) 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 (3). 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 (2, 4, 14, and 34). Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment (33). Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin (19, 21). This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM (5, 8).

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 (10, 25, 27, and 29). This discovery is further authenticated by studies which confirmed a direct correlation between resistin levels and subjects with T2DM (2, 7, 20, and 30). 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).

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 (6, 15 and 24). Such studies found significantly decreased serum concentrations of resistin with increased adiposity (9, 26, and 36) 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 (22). 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

1.) Adeghate E. An update on the biology and physiology of resistin. Cellular and Molecular Life Sciences. 61: 2485–2496, 2004.

2.) Asensio, C., Cettour-Rose, P., Theander-Carrillo, C., Rohner-Jeanrenaud, F. and Muzzin, P. 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: 2206–2213, 2004.

3.) Axelsson J, Bergsten A, Qureshi AR, Heimburger O, Barany P, Lonnqvist F, Lindholm B, Nordfors L, Alvestrand A, Stenvinkel P. Elevate 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, 2006.

4.) Degawa-Yamauchi MBJE, Juliar BE, Watson W, Kerr K, Jones RM, Zhu Q & Considine RV. Serum resistin (FIZZ3) protein is increased in obese humans. Journal of Clinical Endocrinology and Metabolism. 88: 5452–5455, 2003.

5.) Duman BS, Turkoglu C, Gunay D, Cagatay P, Demiroglu C, Buyukdevrim AS. The interrelationship between insulin secretion and action in type 2 diabetes mellitus with different degrees of obesity: evidence supporting central obesity. Diabetes Butr Metab. 16(4): 243-250, 2003.

6.) Fain JN, Cheema PS, Bahouth SW & Lloyd Hiler M. Resistin release by human adipose tissue explants in primary culture. Biochemical and Biophysical Research Communications. 300: 674–678, 2003.

7.) 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. Enzyme-linked immunosorbent assay for circulating human resistin: resistin concentrations in normal subjects and patients with type 2 diabetes. Clin. Chim. Acta. 339: 57–63, 2004.

8.) Gabriely, I., Ma, X. H., Yang, X. M., Atzmon G, Rajala MW, berg AH, Sherer P, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes. 51: 2951–2958, 2002.

9.) Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR. Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab. 89(4):1844-1848, 2004.

10.) Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature. 420: 333-336, 2002. [4]

11.) Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W. Nelson C. Lowman HB, Wright BD, Skelton NJ, Franta GD, Tumas DB, Peale FV Jr, Shelton DL, Hebert CC. FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19(15): 4046-4055, 2000.

12.) Kaser S, Kaser A, Sandhofer A, Ebenbichler CF, Tilg H, Patsch JR. Resistin messenger-RNA expression is increased by proinflammatory cytokines in vitro. Biochem Biophys Res Commun. 309(2): 286-290, 2003.

13.) Kusminski CM, da Silva NF, Creely SJ, Fisher FM, Harte AL, Baker AR, Kumar S, McTernan PG. The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes. J Clin endocrinol Metab. 92(1): 270-276, 2007.

14.) Lee, J. H., Bullen, Jr, J. W., Stoyneva, V. L. and Mantzoros, C. S. Circulating resistin in lean, obese and insulin-resistant mouse models: lack of association with insulinemia and glycemia. Am. J. Physiol. Endocrinol. Metab. 288: E625–E632, 2005.

15.) Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. 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):4848-4856, 2003.

16.) Levy, J. R., Davenport, B., Clore, J. N. and Stevens, W. Lipid metabolism and resistin gene expression in insulin-resistant Fischer 344 rats. Am. J. Physiol. Endocrinol. Metab. 282: E626–E633, 2002.

17.) Lu SC, Shieh WY, Chen CY, HSU SC, Chen HL. Lipopolysaccharide increases resistin gene expression in vivo and in vitro. FEBS Lett. 530(1-3): 158-162, 2002.

18.) Malyszko J, Malyszko JS, Pawlak K, Mysliwiec M. Resistin, a new adipokine, is related to inflammation and renal function in kidney allograft recipients. Transpant Proc. 38(10): 3434-3436, 2006.

19.) McTernan, C. L., McTernan, P. G., Harte, A. L., Levick, P. L., Barnett, A. H. and Kumar, S. Resistin, central obesity, and type 2 diabetes. Lancet. 359: 46–47, 2002.

20.) McTernan, P. G., Fisher, F. M., Valsamakis, G, Chetty R, Harte A, McTernan CL, Clark PM, Smith SA, Barnett AH, Kumar S. 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: 6098–6106, 2003.

21.) McTernan, P. G., McTernan, C. L., Chetty, R, Jenner K, Fisher FM, Lauer MN, Crocker J, Barnett AH, Kumar S. Increased resistin gene and protein expression in human abdominal adipose tissue. J. Clin. Endocrinol. Metab. 87: 2407, 2002.

22.) Milan G, Granzotto M, Scarda A, Calcagno A, Pagano C, Federspil G & Vettor R. Regional adipose tissue differences of resistin and adiponectin expression in genetically obese rats: effect of weight loss. Obesity Research. 10: 1095–1103, 2002.

23.) Nagaev I, Bokarewa M, Tarkowski A, Smith U. Human Resistin Is a Systemic Immune-Derived Proinflammatory Cytokine Targeting Both Leukocytes and Adipocytes. PLoS ONE. 1: e31, 2006.

24.) Nagaev I, Smith U. Insulin resistance and type 2 diabetes are not related to resistin expression in human fat cells or skeletal muscle. Biochem. Biophys. Res. Commun. 285: 561–564, 2001.

25.) Rajala, M. W., Qi, Y., Patel, H. R., Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes. 53: 1671–1679, 2004.

26.) Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV & O’Rahilly S. Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator activated receptor-gamma action in humans. Diabetes. 50: 2199–2202, 2001.

27.) Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL and Murphy LJ. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur. J. Endocrinol. 149: 331-335, 2003.

28.) Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependant pathway. Biochem Biochys Res Commun. 334(4): 1092-1101, 2005.

29.) Smith, S. R., Bai, F., Charbonneau, C., Janderova, L. and Argyropoulos, G. A promoter genotype and oxidative stress potentially link resistin to human insulin resistance. Diabetes 52, 1611–1618, 2003.

30.) Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature. 409:307-312, 2001.

31.) Stumvoll M & Haring H. Resistin and adiponectin – of mice and men. Obesity Research. 11: 1197–1199, 2002.

32.) Tjokroprawiro A. New approach in the treatment of T2DM and metabolic syndrome (focus on a novel insulin sensitizer). Acta Med Indones. 38(3): 160-166, 2006.

33.) Valsamakis, G., McTernan, P. G., Chetty, R, Al Daghri N, Field A, Hanif W, Barnett AH, Kumar S. Modest weight loss and reduction in waist circumference after medical treatment are associated with favourable changes in serum adipocytokines. Metab. Clin. Exp. 53:430–434, 2004.

34.) Vendrell J, Broch M, Vilarrasa N, Molina A, Gomez JM, Gutierrez C, Simon I, Soler J & Richart C. Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity. Obesity Research. 12: 962–971, 2004.

35.) Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD, Mickle DA. Resistin promotes endothelial cell activation: further evidnce of adipokine-endothelial interaction. Circulation. 108(6): 736-740, 2003.

36.) Way JM, Gorgun CZ, Tong Q, Uysal KT, Brown KK, Harrington WW, Oliver WR Jr, Wilson TM, Kliewer SA & Hotamisligil GS. Adipose tissue resistin expression is severely suppressed in obesity and stimulated by peroxisome proliferator-activated receptor gamma agonists. Journal of Biological Chemistry. 276: 25651–25653, 2001. [5]

37.) Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 115(5): 1111-1119, 2005. [6]

38.) Wulster-Radcliffe, M. C., Ajuwon, K. M., Wang, J., Christian, J. A. and Spurlock, M. E. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem. Biophys. Res. Commun. 316: 924–929, 2004.

39.) Yokota, T., Oritani, K., Takahashi, I., Ishikawa J, Matsuyama A, Ouchi N, Kihara S, Funahashi T, Tenner AJ, Tomiyama Y, Matsuzawa Y. 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: 1723–1732, 2000.

40.) Heilbronn LK, Rood J, Janderova L, Albu JB, Kelley DE, Ravussin E, Smith SR, Relationship between serum resistin concentrations and insulin resistance in nonobese, obese, and obese diabetic subjects. J Clin Endocrinol Metab 2004;89(4):1844-8. PMID 15070954.

41.) Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. 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 2003;88(10):4848-56. PMID 14557464.

42.) Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001;409:307-312. PMID 11201732.


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