Resistin

Resistin or “resistance to insulin”, is a 12 kDa cysteine-rich polypeptide hormone protein secreted by macrophages in humans and adipocytes in mice ¹. Resistin is a proinflammatory adipokine originally discovered in mice and was named for its ability to resist insulin action ². Resistin is the founding member of the resistin-like molecule hormone family, and it consists of 108 amino acid peptides; in human blood, resistin circulates as a dimeric protein consisting of two 92-amino acid polypeptides ³. Resistin is produced by white and brown adipose tissues, but it also has been identified in several other peripheral tissues. The site of resistin production is species dependent. In mice, resistin is produced by adipocytes, whereas in humans, it is predominantly expressed in macrophages ⁴. Mice resistin is mainly implicated in the pathogenesis of obesity-mediated insulin resistance and type 2 diabetes, but the concrete target cells remain inconclusive ⁵. However, some authors believe that in humans, immune cells are found to be recruited by resistin and participate in inflammatory processes ⁶.

Resistin hormone function

Resistin suppresses the ability of insulin to stimulate cellular glucose uptake and plays a role in obesity, insulin resistance, diabetes ⁷, rheumatoid arthritis (RA), and osteoarthritis (OA) ⁸. Some authors believe that in humans, resistin plays a more important role in inflammatory processes than in insulin resistance, as serum resistin levels correlate better with subclinical inflammation than with insulin resistance ⁹. In addition, it has been proven in studies that human resistin alone can promote inflammation ¹⁰, while other studies have also shown that human resistin may exert anti-inflammation in response to a fatal endotoxin challenge ¹¹. These conflicting findings point towards the idea that the pro-inflammatory or anti-inflammatory function of resistin is context related and disease specific ¹. The general consensus is that resistin in metabolism plays a pathologic role in promoting insulin resistance, atherosclerosis, and hypertension, whether in mouse or human studies ¹². In humans, resistin levels have been positively associated with central/visceral obesity (but not body mass index [BMI]) and play a role in proinflammatory processes ¹³. In healthy subjects, resistin expression was also detected. The findings from a cross-sectional study of 6636 adults recruited randomly indicated that mean resistin level was slightly higher in women (6.06 ± 2.41 ng/mL vs. 5.63 ± 2.18 ng/mL) for these healthy people ¹⁴.

Recently, some authors have suggested that resistin is expressed in the synovial joints of rheumatoid arthritis (RA), and osteoarthritis (OA) patients ¹⁵. Resistin upregulates the expression of inflammatory cytokines and chemokines in chondrocytes, and intra-articular resistin injection induces arthritis in healthy mouse joints ¹⁶. Other studies have shown that serum resistin levels are higher in patients with severe osteoarthritis than in controls without osteoarthritis , and that resistin is present in both serum and synovial fluid, suggesting its systemic and local involvement in the inflammatory changes of osteoarthritis ¹⁷. The role of resistin in osteoarthritis could be explained by its action as an inducer of proinflammatory cytokines, such as tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, and IL-12, via the nuclear factor- (NF-) κB signaling pathway in diverse inflammatory conditions ¹⁸.

Adiponectin

Adiponectin is an insulin sensitizing hormone that also plays a role in inflammation ³. Adiponectin inhibits effects of proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-6 (IL-6), on endothelial and other cell types ¹⁹ and also induces expression of anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) ²⁰. However, adiponectin also has proinflammatory effects that become manifest under selected conditions. For example, adiponectin induces IL-6 and matrix metalloproteinase-1 secretion in the synovial tissue of patients with arthritis ²¹. Adiponectin can also induce activation of the proinflammatory transcription factor, nuclear factor (NF)-κB in monocytic cell lines ²², while inhibiting the same in endothelial cells ²³.

Leptin

The hormone leptin, which derives its name from the Greek word leptos, meaning thin, is a 16 kD protein derived from the obese (OB) gene and is expressed predominantly in adipocytes ²⁴. Consequently, leptin is produced in proportion to adipocyte mass, and leptin concentrations are 4–6 times greater in severely obese compared to lean human subjects ²⁵. Serum leptin concentrations increase with feeding and in infectious and inflammatory states ²⁶. Serum leptin concentrations also display a circadian rhythm, with a nadir around 8 in the morning ²⁷. Women and postpubertal girls have 40–200% higher concentrations of circulating leptin than their male counterparts, after adjustment for percent body fat ²⁸. The rate of increase of circulating leptin concentrations with BMI is about three-fold more rapid in women as in men ²⁹. Although estrogen supplementation increases and testosterone supplementation decreases leptin concentrations ³⁰, sex differences in circulating leptin are not entirely explained by either sex hormones or body fat distribution ³¹. Instead, these sex differences may involve greater leptin gene expression in subcutaneous than visceral adipose tissue ³² (subcutaneous adipose tissue is more abundant in women) and/or greater release of leptin from nonadipose sources ³³. Leptin can be expressed by various cell types in the human lung, including bronchial epithelial cells and alveolar type II pneumocytes and macrophages ³⁴. Whether these cells result in leptin production that is significant compared with that provided through the blood remains to be established. However, the observations that airway leptin concentrations (measured in either sputum or bronchoalveolar lavage fluid) are strongly correlated with serum leptin concentrations ³⁵, suggest that pulmonary sources may be of limited physiological importance. Such correlations also suggest that, in contrast to adiponectin, leptin is readily transported from the blood to the lung.

Leptin plays a key role in the regulation of appetite, metabolism, and body weight, and both leptin deficient and OB-Rb deficient mice are massively obese ³⁶. Leptin also has profound effects on both innate and adaptive immune system that may impact asthma. Leptin promotes neutrophil chemotaxis and generation of reactive oxygen species, induces activation of NK cells, and also promotes macrophage activation, phagocytosis, and cytokine release ³⁷. The ability of leptin to upregulate leukotriene biosynthesis in alveolar macrophages ³⁸ may be particularly relevant to asthma given the potency of cysteinyl leukotrienes as bronchoconstrictors. The observation that leptin deficient mice have thymic atrophy ³⁹ emphasizes the role of leptin in adaptive immunity. CD4+ T cells express OB-Rb, and leptin induces proliferation of naïve but not memory T cells ³⁹. Leptin also differentially affects cytokine production in Th1 and Th2 cells; leptin increases production of Th1 cytokines including interferon-γ but suppresses production of Th2 cytokines including IL-4 ³⁹. It is increasingly appreciated that IL-17 may contribute to severe asthma. It is interesting, in this context, that when purified naïve splenic CD4+ T cells are grown under Th17 biasing conditions, leptin administration augments Th17 cell generation ⁴⁰. Leptin also inhibits the function of regulatory T cells (Tregs) ⁴¹, which would be expected to augment allergen induced T cell activation.

References

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