Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

Abstract

In obesity the cellular capacity to switch from using lipid to carbohydrate and vice versa as the energy substrate, known as 'metabolic flexibility', is impaired. Mitofusin 2 (MFN2), a mitochondrial membrane protein, seems to contribute to the maintenance and operation of the mitochondrial network, and its expression is reduced in obesity. The aim of this study was to verify whether MFN2 might be implicated in the metabolic inflexibility of obesity. Insulin sensitivity was measured in six morbidly obese women before and 2 years after malabsorptive bariatric surgery (BMI 53.3+/-10.5 vs 30.3+/-4.0 kg/m2). Skeletal muscle MFN2, SLC2A4 (formerly known as GLUT4), COX3 (encoding cytochrome c oxidase subunit III) and CS (encoding citrate synthase) mRNA levels were measured by real-time PCR. Following bilio-pancreatic surgery, significant increases in MFN2 mRNA (from 0.4+/-0.2 to 1.7+/-1.1 arbitrary units [AU], p=0.019) and SLC2A4 mRNA (0.38+/-0.12 to 0.76+/-0.24 AU, p=0.04) were observed, while increases in COX3 mRNA (from 14.2+/-6.4 to 20.2+/-12.5 AU) and CS mRNA (from 0.4+/-0.1 to 0.7+/-0.3 AU) failed to reach statistical significance. Insulin-mediated whole-body glucose uptake significantly (p<0.0001) increased from 21.2+/-4.1 to 52.8+/-5.9 micromol kg fat-free mass(-1) min(-1) and glucose oxidation rose from 11.1+/-2.1 to 37.7+/-4.7 micromol kg fat-free mass(-1) min(-1) (p<0.0001). Levels of MFN2 mRNA were strongly correlated with the absolute values for the glucose oxidation rate, both during fasting (glucose oxidation =3.55 MFN2 mRNA + 3.93; R2=0.92, p<0.0001) and during the clamp (glucose oxidation=18.8 MFN2 mRNA+34.7; R2=0.80, p<0.0001). The percentage changes in MFN2 mRNA were positively correlated with the percentage change in glucose oxidation during the clamp (glucose oxidation percent (%) change=0.3 MFN2 mRNA percent (%) change+153.2; R2=0.61, p<0.001). We propose that the significant increase in MFN2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity following bariatric surgery.