Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma

Obesity is a well-known risk factor for the development of secondary complications such as type 2 diabetes. However, only a part of the obese population develops secondary metabolic disorders. Here, we identify the transcription factor retinoid-related orphan receptor gamma (ROR gamma) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3. In vivo differentiation of adipocyte progenitor cells from Rorg-deficient mice is enhanced and obese Ror gamma(-/-) mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Ror gamma(-/-) mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Ror gamma expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify ROR gamma as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. ROR gamma might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.