Positive association between musclin and insulin resistance in obesity: evidence of a human study and an animal experiment

Musclin is a novel skeletal muscle-derived secretory factor considered to be a potent regulator of the glucose metabolism and therefore may contribute to the pathogenesis of obesity and insulin resistance (IR). To test this hypothesis, we examined the plasma musclin levels in overweight/obese subjects and lean controls. Rats on a high fat diet (HFD) were used as the annimal model of obesity. Radioimmunoassay and western blot were used to determine musclin levels in plasma and skeletal muscle. According to radioimmunoassays,the overweight/obese subjects exhibited elevated musclin plasma levels compared with the lean controls (89.49 ± 19.00 ng/L vs 80.39 ± 16.35 ng/L, P < 0.01). The musclin levels were positively correlated with triglyceride, fasting plasma glucose, and homeostasis model assessment of IR levels. These observations were confirmed with a high-fat diet(HFD) rat model. HFD rats also exhibited increased musclin immunoreactivity in plasma ( P < 0.01) and in skeletal muscle ( P < 0.05), as well as increased musclin mRNA levels in skeletal muscle ( P < 0.01). Musclin incubation significantly inhibited muscles 3 H-2-DG uptake in the normal diet(ND) group ( P < 0.01). The protein expression of glucose transporter type 4 was significantly down regulated by 30% ( P < 0.05) in the ND group after soleusmuscle was incubated with musclin compared with the control. Musclin incubation also increased the protein levels of glucose-regulated protein (GRP)78 and GRP94 by 146.8 and 54% (both P < 0.05), respectively, in ND rats. Our data support the hypothesis that musclin has a strong relationship with obesity-associated IR by impairing the glucose metabolism and, at least in part, through causing endoplasmic reticulum stress.