Crystallographic structure of a hexamer of mouse resistin (rainbow colored, N-terminus = blue, C-terminus = red).
|RNA expression pattern|
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 adipose-derived peptide hormone that in humans is encoded by the RETN gene.
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue. The length of the resistin pre-peptide in human is 108 amino acid residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa. 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 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."
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the University of Pennsylvania School of Medicine. 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). Since these observations, further research has linked resistin to other physiological systems such as inflammation and energy homeostasis.
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.
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. It has also been demonstrated that resistin upregulates intercellular 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. 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 declined 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 resasdasdistance.
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; 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 and may continue to grow. Nevertheless, this theory lacks support from the entire scientific community, as the number of studies presenting evidence against this theory 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. In reality, almost all findings (many times elucidated under the same experimental conditions) reported by groups opposing the resistin link theory are the exact opposite from those observed by groups that support the theory. 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 whom 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 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 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. 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 crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. 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. The results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.
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