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 derived from adipose tissue that in humans is encoded by the RETNgene.
Resistin has been shown to cause "high levels of 'bad' cholesterol (low-density lipoprotein or LDL), increasing the risk of heart disease [...] resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in arteries, increasing the risk of heart disease. [...] resistin adversely impacts the effects of statins, the main cholesterol-reducing drug used in the treatment and prevention of cardiovascular disease."
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 (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion. It has also been demonstrated that resistin upregulates intercellular adhesion molecule-1 (ICAM1) vascular cell-adhesion molecule-1 (VCAM1) and chemokine (C-C motif) ligand 2 (CCL2), all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide, 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.
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, 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 lowered renal function and inflammation, but not with insulin resistance. 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
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 underlying belief among those in support of this theory is that serum resistin levels will increase with increased adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment. Specifically, central obesity (waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin. This fact takes on significant implications considering the well understood link between central obesity and insulin resistance, two marked peculiarities of T2DM.
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance that appears to be 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. This discovery is further supported by studies that confirm a direct correlation between resistin levels and subjects with T2DM. If resistin does contribute to the pathogenesis of insulin resistance in T2DM, then designing drugs to promote decreased serum resistin in T2DM subjects might deliver immense therapeutic benefits.
The amount of evidence supporting the resistin link theory between obesity and T2DM is vast. Nevertheless, this theory lacks support from the entire scientific community, as the number of studies presenting evidence against it continues to expand. Such studies have found significantly decreased serum concentrations of resistin with increased adiposity, suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between obesity and T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented; such studies instead report that weight loss is associated with marked increases in serum resistin. The idea that resistin links obesity to T2DM is now under even more scrutiny, as recent investigations have confirmed ubiquitous expression of resistin in many tissues, rather than those only characteristic of obesity, such as adipocytes.
Although nearly as many scientists oppose the theory as those who support it, there is sufficient evidence to support the idea that resistin does have some incompletely defined role in energy homeostasis, while also demonstrating properties that help to incite inflammatory responses to sites of infection.
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. 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 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 will be conserved.
The interchain disulfide bonds of resistin and resistin-like molecule β (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 is 9.9%, and 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.
A Cys6Ser resistin 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 a mandatory step toward activation. Other results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.
^Wang H, Chu WS, Hemphill C, Elbein SC (June 2002). "Human resistin gene: molecular scanning and evaluation of association with insulin sensitivity and type 2 diabetes in Caucasians". J. Clin. Endocrinol. Metab. 87 (6): 2520–4. doi:10.1210/jc.87.6.2520. PMID12050208.
^ abcSteppan 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. PMID11201732.
^ abDegawa-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. PMID14602788.
^ abGabriely 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. PMID12351432.
^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. PMID11832366.
^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. PMID17062773.
^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. PMID17175295.
^ abMilan 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. PMID12429872.
^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. PMID16039994.
^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. PMID12874180.
^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. PMID16395259.
^ abAsensio 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. PMID14962997.
^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. PMID15522996.
^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. PMID15045687.
^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. PMID14768774.
^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. PMID15220189.
^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. PMID14514348.
^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. PMID12829623.
^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. PMID14687894.
^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. PMID14671216.
^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. PMID17119268.
^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/S0006-291X(02)02864-4. PMID12507502.
^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. PMID14557464.
^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. PMID11444881.
^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. PMID15070954.
^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. PMID11574398.
^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. PMID11373275.