Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma.
Bottom Line: Here, we identify the transcription factor retinoid-related orphan receptor gamma (RORγ) as a negative regulator of adipocyte differentiation through expression of its newly identified target gene matrix metalloproteinase 3.In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity.RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.
Affiliation: ETH Zürich, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.Show MeSH
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Mentions: As Rorγ−/− mice show alterations in adipocyte size distribution, we examined the metabolic consequences of altered fat cell size in obese mouse models. Mean body weight was slightly reduced for male and female knockout animals on a high-fat diet (Fig 5A and Fig S4A of Supporting information), whereas chow fed animals did not show any changes in body weight (Fig S4B of Supporting information). In all models, Rorγ−/− mice were protected from obesity-induced hyperglycemia (Fig 5B), whereas no effect on glucose levels was observed in chow diet fed animals (Fig S4C of Supporting information). Decreased blood glucose levels in obese Rorγ−/− mice were accompanied by lower insulin levels in the fasted and in the fed state (Fig 5C and Fig S4D of Supporting information). In an insulin tolerance test, male Rorγ−/− animals showed improved insulin sensitivity compared to control mice after 8 weeks of high-fat diet (Fig 5D). Besides whole body insulin sensitivity, we also tested insulin sensitivity of isolated primary adipocytes from obese Rorγ−/− mice and control littermates. As expected from the observed differences in adipocyte size, insulin-mediated repression of lipolysis in obese Rorγ−/− animals was similar to wild-type chow fed animals. In contrast, adipocytes from obese wild-type mice were completely insulin-resistant (Fig 5E). In line with this, concentrations of circulating free fatty acids were significantly decreased in obese Rorγ−/− mice both in fasted and fed state (Fig 5F and Fig S4E of Supporting information). Triglyceride concentrations were mildly altered only in male high-fat diet animals (Fig S4F of Supporting information).
Affiliation: ETH Zürich, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland.