CHEMERIN REGULATES ADIPOSITY AND ENERGY HOMEOSTASIS

Abstract

Obesity, characterized by an excess of adipose tissue, is an established risk factor for cardiovascular disease and type II diabetes. Different mechanisms linking obesity with these comorbidities have been postulated but remain poorly understood. Adipose tissue secretes bioactive signaling molecules, termed adipokines, which regulate various biological functions including appetite, energy balance, glucose homeostasis, and inflammation. Chemerin is a novel adipokine that regulates adipocyte differentiation and metabolism by binding to and activating the G protein-coupled receptor chemokine like receptor-1 (CMKLR1). Herein, we have shown that serum levels of the novel adipokine chemerin are significantly elevated in mouse models of obesity/diabetes. Administration of exogenous chemerin exacerbates glucose intolerance, lowers serum insulin levels, and decreases tissue glucose uptake in obese/diabetic but not normoglycemic mice. In CMKLR1-deficient mice food consumption, total body mass, and percent body fat are lower compared to wildtype controls, regardless of diet (low or high fat). CMKLR1-/- mice also exhibited decreased hepatic and white adipose tissue TNF? and IL-6 mRNA levels coincident with decreased hepatic dendritic cell infiltration, decreased adipose CD3+ T cells and increased adipose natural killer cells. CMKLR1-/- mice were also glucose intolerant compared to wildtype mice, and this was associated with decreased glucose stimulated insulin secretion as well as decreased skeletal muscle and white adipose tissue glucose uptake. Collectively, these data provide compelling evidence that chemerin/CMKLR1 signaling influences adipose tissue development, inflammation, and glucose homeostasis and may contribute to the metabolic derangements characteristic of obesity and obesity-related diseases.