Regulation of adipose tissue development and function by nuclear receptors PPARγ and Rev-erbα

Adipose tissue is an important fat-storage and endocrine organ, whose dysfunction is closely associated with the development of obesity, diabetes mellitus and cardiovascular disease. Nuclear receptors are DNA-binding proteins which directly regulate gene expression in response to ligands derived from endocrine glands, metabolism, diet and the environment. They are widely believed to act as key regulators in various physiological processes, such as circadian rhythm, metabolism, development, reproduction and energy homeostasis. Specifically, our studies mainly focused on the roles of nuclear receptor, PPARγ and Rev-erbα, in adipose tissue development and function. PPARγ is considered the master regulator of adipocyte biology. Although its cell-autonomous role in adipogenesis has been clearly demonstrated in vitro, modest phenotypes and contradictory results of insulin sensitivity in the previously generated fat-specific PPARγ knockout mice makes it of great interest to re-evaluate the effects of PPARγ ablation in fat. By taking advantage of Adipoq-Cre mice, we report a novel fat-specific PPARγ knockout (PPARγ FKO) mouse model without visible brown and white adipose tissue at the age of 3 months, accompanied with massive fatty liver, hugely enlarged pancreatic islets, and extreme insulin resistance and diabetes. Delayed hair coat formation, arrested mammary gland development and high bone mass were also observed in PPARγ FKO animals. These data together demonstrated the necessity of fat PPARγ in adipose formation in vivo, whole-body metabolic homeostasis and normal development of fat-associated tissues. In another study, we examined the functions of Rev-erbα in mouse adipose tissues by performing genome-wide studies. It was found that Rev-erbα bound to more than 5000 sites in adipose genome, recruiting its corepressor complex NCoR/HDAC3 to the majority of these regions in a circadian manner. Rev-erbα ablation in mouse adipose tissue caused the altered expression of hundreds of genes with strong association of nearby Rev-erbα binding and rhythmic expression. The integrated analysis of these genome-wide data enabled us to find that betaKlotho, an essential coreceptor for FGF21, was repressed by Rev-erbα in fat via the direct binding of Rev-erbα in its first intron. Loss of fat Rev-erbα abolished the daily oscillation of betaKlotho and caused the robust elevation of its expression level which translated into enhanced FGF21 response in mouse adipose tissue. These findings showed Rev-erbα acted as a key modulator of FGF21 signal in fat. Collectively, our studies established the vital roles of two nuclear receptors in the normal development and function of adipose tissues