Chemerin Is a Novel Adipocyte-Derived Factor Inducing Insulin Resistance in Primary Human Skeletal Muscle Cells

Abstract

OBJECTIVEChemerin is an adipokine that affects adipogenesis and glucose homeostasis in adipocytes and increases with BMI in humans. This study was aimed at investigating the regulation of chemerin release and its effects on glucose metabolism in skeletal muscle cells.RESEARCH DESIGN AND METHODSHuman skeletal muscle cells were treated with chemerin to study insulin signaling, glucose uptake, and activation of stress kinases. The release of chemerin was analyzed from in vitro differentiated human adipocytes and adipose tissue explants from 27 lean and 26 obese patients.RESULTSHuman adipocytes express chemerin and chemokine-like receptor 1 (CMKLR1) differentiation dependently and secrete chemerin (15 ng/ml from 106 cells). This process is slightly but significantly increased by tumor necrosis factor-α and markedly inhibited by >80% by peroxisome proliferator–activated receptor-γ activation. Adipose tissue explants from obese patients are characterized by significantly higher chemerin secretion compared with lean control subjects (21 and 8 ng from 107 cells, respectively). Chemerin release is correlated with BMI, waist-to-hip ratio, and adipocyte volume. Furthermore, higher chemerin release is associated with insulin resistance at the level of lipogenesis and insulin-induced antilipolysis in adipocytes. Chemerin induces insulin resistance in human skeletal muscle cells at the level of insulin receptor substrate 1, Akt and glycogen synthase kinase 3 phosphorylation, and glucose uptake. Furthermore, chemerin activates p38 mitogen-activated protein kinase, nuclear factor-κB, and extracellular signal–regulated kinase (ERK)-1/2. Inhibition of ERK prevents chemerin-induced insulin resistance, pointing to participation of this pathway in chemerin action.CONCLUSIONSAdipocyte-derived secretion of chemerin may be involved in the negative cross talk between adipose tissue and skeletal muscle contributing to the negative relationship between obesity and insulin sensitivity.

Differential Patterns of Serum Concentration and Adipose Tissue Expression of Chemerin in Obesity: Adipose Depot Specificity and Gender Dimorphism

“…metabolic diseases. Several recent studies have demonstrated that circulating chemerin levels are elevated in both obese humans and obese/diabetic experimental animals and are positively correlated with various aspects of metabolic syndrome (Bozaoglu et al, 2007;Sell et al, 2009). The administration of exogenous chemerin to obese/diabetic (but not normoglycemic) mice resulted in exacerbated glucose intolerance, lower serum insulin levels, and decreased tissue glucose uptake .…”

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

“…Therefore, PRAS40 (also known as AKT1S1) was silenced in hSkMC and the effects on insulin action were determined. In addition, we examined whether the chemokines chemerin and monocyte chemotactic protein 1 (MCP-1), which have been implicated in the induction of insulin resistance in hSkMC [25,26], exert an additive effect in hSKMC in which PRAS40 was silenced.…”

ChemR23, the Receptor for Chemerin and Resolvin E1, Is Expressed and Functional on M1 but Not on M2 Macrophages

“…Increased serum levels of chemerin have been associated with chronic inflammatory diseases (19,20), coronary artery disease (21), the metabolic syndrome, and obesity (22). There is indication that high chemerin production in obese adipose tissue (23) might contribute to the increased infiltration of macrophages observed in obese adipose tissue leading to low-level inflammation (24).…”