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Manipulating Hypoxia Inducible Factor (HIF) activity in the adipose cell. A means of altering cell differentiation and metabolism ?


In most individuals, the adipose tissue, like other adult tissues, maintains a stable mass. Nevertheless, this tissue displays a unique capacity to grow or regress during adulthood, when energy balance shifts positively or negatively. In humans, phenotypes of adipose dystrophy range from massive obesity, where adipose mass represents 60 to 70% of body weight, to lipoatrophy, with less than 2% of fat. Starting during the past 10-20 years, the number of obese individuals is increasing on an epidemic scale wor ld-wide. The clinical problem of excessive adipose tissue mass resides in its strong association with a number of life-threatening conditions: hyperlipidemia, high blood pressure, glucose intolerance and diabetes, coronary heart disease and some types of c ancers.The main cellular components of adipose tissue are adipocytes. It is now recognised that these cells are at the heart of a complex endocrine and paracrine network, which substantially influences the whole organism. Dysregulation of adipose cell mass induces profound alterations of the cell\'s metabolic properties and hormonal responsiveness, leading to alteration in adipose-derived circulating factors. These defects have been causally implicated in several obesity-related co-morbidities.We and others have recently revealed that adipose differentiation, metabolism and secretory function are sensitive to hypoxia and that Hypoxia Inducible Factor (HIF) activation underlies several ol these responses. Here, we propose to investigate the genomic and phenot ypic effects of modulation of HIF activity in the adipose cell. At the cellular level, the effect of genetic and pharmacological activation of the HIF system on adipose gene expression and metabolic activity will be studied in the mouse 3T3-L1 pre-adipose cell line. The physiological effects of manipulating HIF will also be investigated in transgenic mice with enhanced HIF activity specifically in the adipose tissue.

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