Retinoid-related orphan receptor γ regulates several genes that control metabolism in skeletal muscle cells: Links to modulation of reactive oxygen species production

Abstract

Retinoid-related orphan receptor γ (RORγ) is an orphan nuclear hormone receptor (NR) that is preferentially expressed in skeletal muscle and several other tissues, including pancreas, thymus, prostate, liver and testis. Surprisingly, the specific role of RORγ in skeletal muscle, a peripheral tissue, has not been examined. Muscle is one of the most energy demanding tissues which accounts for ∼40% of the total body mass and energy expenditure, > 75% of glucose disposal and relies heavily on β-oxidation of fatty acids. We hypothesize that RORγ regulates metabolism in this major mass lean tissue. This hypothesis was examined by gain and loss of function studies in an in vitro mouse skeletal muscle cell culture model. We show that RORγ mRNA and protein are dramatically induced during skeletal muscle cell differentiation. We utilize stable ectopic over-expression of VP16-RORγ (gain of function), native RORγ and RORγΔH12 (loss of function) vectors to modulate RORγ mRNA expression and function. Ectopic VP16 (herpes simplex vinis transcriptional activator)-RORγ and native RORγ expression increases RORα mRNA expression. Candidate-driven expression profiling of lines that ectopically express the native and variant forms of RORγ suggested that this orphan NR has a function in regulating the expression of genes that control lipid homeostasis (fatty acid-binding protein 4, CD36 (fatty acid translocase), lipoprotein lipase and uncoupling protein 3), carbohydrate metabolism (GLUT5 (fructose transporter), adiponectin receptor 2 and interleukin 15 (IL-15)) and muscle mass (including myostatin and IL-15). Surprisingly, the investigation revealed a function for RORγ in the pathway that regulates production of reactive oxygen species. © 2007 Society for Endocrinology.