Adipocytes are highly specialized cells that are central to the control of energy balance and lipid homeostasis. Obesity, the excess accumulation of adipose tissue, is a risk factor for type 2 diabetes, cardiovascular disease, hypertension and cancer. With global rates of obesity on the rise, it is important to study adipocyte biology and function to gain insight to the molecular basis of these metabolic diseases. There have been many significant advances in the study of adipocyte biology with the discovery of transcription factors, coactivators and growth factors that are involved in adipocyte differentiation. PPAR gamma is considered to be the master regulator of the terminal differentiation phase of adipogenesis and functions in concert with members of the CCAT/enhancer binding protein (C/EBP) family and Kruppel like factor family in a transcriptional cascade. Although much is known about the molecular mechanisms regulating the late phase of adipocyte differentiation, little is known about the transcriptional regulation of the early phase (determination) of adipogenesis as well as intracellular signaling pathways that are involved in this regulatory process. In our studies, we demonstrated that ZNF638, a transcription factor involved in the early phase of adipogenesis, is essential for adipocyte differentiation in vivo. In this study, we generated mice with adipose specific knockdown of ZNF638 (Fat-ZNF638-KD) by cre-lox interference. Fat-ZNF638-KD mice were smaller, weighed less and had a significant reduction of adipose tissue in all depots. Furthermore, mice were resistant to diet induced obesity that was potentiated by a higher metabolic rate and greater lean mass when compared to controls. mRNA expression levels of key adipogenic genes were reduced in the visceral depot of Fat-ZNF638-KD mice. We also demonstrated that nuclear matrix coactivator 1 (NMC1), a novel isoform of ZNF638, interacts with Smad4-interacting factor 1 (SMIF). SMIF, an activator of TGF beta signaling, was found to be highly regulated during adipocyte differentiation and to physically interact and repress the transcriptional activity of PPAR gamma. Lastly, we demonstrated that fat specific ablation of Serum Glucocorticoid Inducible Kinase 1 (SGK1), an AKC kinase involved in the early phase of adipocyte differentiation, results in sexual dimorphism. Our study showed that female mice have an increased fat mass, a decrease lean mass, increased visceral and inguinal adiposity and a trend for insulin resistance. Male mice were indistinguishable from their wild type littermate controls. These data show that our laboratory has identified and confirmed in vitro two novel regulators. We have also identified one potential regulator of adipocyte differentiation.
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