17β-estradiol inhibits PPARα of skeletal muscle

Abstract

To determine whether 17β-estradiol regulates peroxisome proliferator-activated receptor α (PPARα)-mediated lipid reduction in skeletal muscle cells and tissues and to investigate the molecular mechanism involved in this process, C2C12 myotubes and female ovariectomized C57BL/6J mice were treated with combinations of the PPARα agonist fenofibrate or 17β-estradiol. Both differentiated C2C12 myotubes and skeletal muscle of high-fat diet-fed obese mice showed lipid accumulation. However, either fenofibrate or 17β-estradiol decreased lipid droplets and increased mRNA levels of PPARα target enzymes responsible for fatty acid oxidation. When mice and myotubes were concomitantly treated with fenofibrate and 17β-estradiol, 17β-estradiol reversed the effects of fenofibrate on lipid accumulation and mRNA expression of PPARα target genes. In addition, 17β-estradiol not only decreased basal levels of PPARα reporter gene activation but also reduced fenofibrate-induced luciferase reporter activity in C2C12 myoblasts. Moreover, 17β-estradiol inhibited the recruitment of the PPARα coactivator CREB-binding protein. These results demonstrate that 17β-estradiol inhibits the actions of PPARα on skeletal muscle lipid metabolism by down-regulating the expression of PPARα target genes for fatty acid catabolism, which may be mediated through the inhibition of PPARα-dependent coactivator recruitment.