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

Bettina Meissburger,Wolfgang Langhans,Jozef Ukropec,Daniela Gasperikova,Christian Wolfrum,Peter P Nawroth,Gottfried Rudofsky,Daniel Teupser,Matthias Geiger,Nigel Beaton,Burcak Civan,Eva Roeder

doi:10.1002/emmm.201100172

Abstract

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 (RORγ) 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 Rorγ-deficient mice is enhanced and obese Rorγ−/− mice show decreased adipocyte sizes. These small adipocytes are highly insulin sensitive, leading to an improved control of circulating free fatty acids. Ultimately, Rorγ−/− mice are protected from hyperglycemia and insulin resistance in the state of obesity. In adipose stromal-vascular fraction from obese human subjects, Rorγ expression is correlated with adipocyte size and negatively correlated with adipogenesis and insulin sensitivity. Taken together, our findings identify RORγ as a factor, which controls adipogenesis as well as adipocyte size and modulates insulin sensitivity in obesity. RORγ might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance.

Highlights

Obesity is a major risk factor for the development of type 2 diabetes and the metabolic syndrome
As this factor is highly expressed in the preadipocytecontaining stromal-vascular fraction (SVF), we analysed whether receptor gamma (RORg) plays a role in regulating adipose tissue plasticity
During high-fat diet feeding of mice, adipocyte size is only mildly affected in the early phase of weight gain, whereas adipocyte hypertrophy mainly occurs in late adiposity

Summary

Introduction

Obesity is a major risk factor for the development of type 2 diabetes and the metabolic syndrome. Adipose tissue mass increases during obesity via two distinct mechanisms, increasing cell number (hyperplasia) and/or increasing (1) ETH Zurich, Institute of Food Nutrition and Health, Schwerzenbach, Switzerland (2) Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia (3) Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany (4) Institut fur Laboratoriumsmedizin Klinische Chemie und Molekulare Diagnostik, Universitatsklinikum Leipzig, Leipzig, Germany www.embomolmed.org. An important regulator of the adipogenic process is the proteolytic remodelling of the extracellular matrix, as preadipocytes have to undergo cell shape transition during differentiation (Kubo et al, 2000). Global inhibition of MMP activity inhibits differentiation of preadipocytes and adipose tissue development (Bouloumie et al, 2001; Lijnen et al, 2002). Mmp3-deficient mice show accelerated adipogenesis during mammary gland involution, suggesting a negative regulatory role for MMP3 in adipocyte differentiation (Alexander et al, 2001)

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