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

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

SUBMITTER: Meissburger B

PROVIDER: S-EPMC3377107 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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

Meissburger Bettina B Ukropec Jozef J Roeder Eva E Beaton Nigel N Geiger Matthias M Teupser Daniel D Civan Burcak B Langhans Wolfgang W Nawroth Peter P PP Gasperikova Daniela D Rudofsky Gottfried G Wolfrum Christian C

EMBO molecular medicine 20110819 11

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 ...[more]

PMID: 21853531

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Project description:With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor ? activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.

Dataset Information

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

Publications

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

Similar Datasets

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