Resistin

Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a is_associated_with::cysteine-rich adipose-derived is_associated_with::peptide hormone that in humans is encoded by the RETN is_associated_with::gene.

In is_associated_with::primates, pigs, and dogs, resistin is secreted by is_associated_with::immune and is_associated_with::epithelial cells, while, in rodents, it is secreted by is_associated_with::adipose tissue. The length of the resistin pre-peptide in human is 108 is_associated_with::amino acid residues and in the mouse and rat it is 114 aa; the is_associated_with::molecular weight is ~12.5 is_associated_with::kDa. Resistin is an is_associated_with::adipose-derived hormone (similar to a is_associated_with::cytokine) whose physiologic role has been the subject of much controversy regarding its involvement with is_associated_with::obesity and type II diabetes mellitus (T2DM).

Resistin has been shown to cause "high levels of 'bad' is_associated_with::cholesterol (is_associated_with::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 is_associated_with::liver.  As a result, the liver is less able to clear 'bad' cholesterol from the body. Resistin accelerates the accumulation of LDL in is_associated_with::arteries, increasing the risk of heart disease.  [...] resistin adversely impacts the effects of is_associated_with::statins, the main cholesterol-reducing drug used in the treatment and prevention of is_associated_with::cardiovascular disease."

Discovery
Resistin was discovered in 2001 by the group of Dr Mitchell A. Lazar from the is_associated_with::University of Pennsylvania School of Medicine. It was called "resistin" because of the observed is_associated_with::insulin resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve is_associated_with::endocrine functions likely involved in is_associated_with::insulin resistance. This idea primarily stems from studies demonstrating that serum resistin levels increase with obesity in several model systems (humans, is_associated_with::rats, and is_associated_with::mice). Since these observations, further research has linked resistin to other physiological systems such as is_associated_with::inflammation and energy is_associated_with::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
Inflammation is the first is_associated_with::innate immune response to is_associated_with::infection or is_associated_with::irritation resulting from is_associated_with::leukocyte (is_associated_with::neutrophils, is_associated_with::mast cells, etc.) accumulation and their secretion of inflammatory, is_associated_with::biogenic chemicals such as is_associated_with::histamine, is_associated_with::prostaglandin, and pro-inflammatory is_associated_with::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) is_associated_with::interleukin-1 (IL-1), is_associated_with::interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (is_associated_with::TNF-α) in an is_associated_with::NF-κB-mediated (nuclear factor kappa-light-chain-enhancer of activated B cells-mediated) fashion. It has also been demonstrated that resistin upregulates intercellular is_associated_with::adhesion molecule-1 (is_associated_with::ICAM1) vascular cell-adhesion molecule-1 (is_associated_with::VCAM1) and chemokine (C-C motif) ligand 2 (is_associated_with::CCL2), all of which are occupied in is_associated_with::chemotactic pathways involved in is_associated_with::leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by is_associated_with::microbial antigens such as is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::diseases with or without associated insulin resistance.

Arguments for
Much of what is is_associated_with::hypothesized about a resistin role in energy is_associated_with::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 is_associated_with::adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following is_associated_with::medical treatment. Specifically, is_associated_with::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 is_associated_with::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 is_associated_with::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.

Arguments against
The amount of is_associated_with::evidence supporting the resistin link theory between obesity and T2DM is vast. Nevertheless, this is_associated_with::theory lacks support from the entire is_associated_with::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 is_associated_with::adiposity,  suggesting not only that resistin is downregulated in obese subjects, but also that decreased resistin levels may contribute to the links between is_associated_with::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 is_associated_with::infection.

Structure
Crystal structures of resistin reveal an unusual composition of several subunits that are held together by is_associated_with::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 is_associated_with::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.