REGULATION AND ACTIVATION OF STATS IN ADIPOCYTES

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Adipocytes are highly specialized cells which play a central role in lipid homeostasis and the maintenance of energy balance in vertebrate organisms. These cells store energy in the form of triglycerides during periods of nutritional abundance and release it in the form of free fatty acids at times of nutritional deprivation. Pathological conditions associated with altered adipocyte cell number or function include obesity and several lipodystrophy syndromes. Obesity, an excessive accumulation of adipose tissue, is a common disorder which affects over 30 percent of Americans. In humans, obesity is an independent risk factor for non-insulin dependent diabetes mellitus (NIDDM), hypertension, and coronary artery disease and is a major contributor to morbidity and mortality. Recent studies suggest that obesity and its related disorders may be linked to a breakdown in the regulatory mechanisms which control the expression of metabolic genes in adipocytes. Significant advances toward an understanding of these regulatory processes have been made by the identification of transcription factors which regulate adipocyte differentiation and gene expression. To date, members of two transcription factor families, C/EBP (C/AAAT Enhancer Binding Proteins) and PPAR (Peroxisome Proliferator Activated Receptors) have been shown to be induced during adipocyte differentiation and play a critical role in the regulation of fat-specific genes. Our recent investigations have demonstrated that an additional family of transcription factors are induced during adipocyte differentiation. The STATs (Signal Transducers and Activators of Transcription) comprise a family of transcription factors which reside in the cytoplasm of resting cells. Unlike either C/EBPs or PPARs, STATs can be rapidly activated to control gene expression. In a manner equivalent to both C/EBPalpha and PPARgamma, expression of three STAT family members correlates with lipid accumulation. Since STAT family members have unique tissue distributions and are highly expressed in adipocytes, we hypothesize that STATs play a key role in the regulation of adipocyte gene expression. To test this hypothesis, we will examine the regulation and activation of STATs in adipocytes. We have also designed a set of experiments to elucidate the function of these proteins in adipocytes. These studies may lead to insights into the molecular mechanisms regulating energy homeostasis and may have a profound impact on the defects underlying obesity and NIDDM.