Resistin

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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.