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Oak Ridge National Labs, Functional Genomics Group, Oak Ridge, TN
U465 INSERM, Paris, France and CNRS UMR 6543, Nice, France.
Expression of angiotensinogen (agt), the only known precursor for ang II in adipocytes suggests its potential implication in obesity-associated hypertension. To understand mechanisms of ang II regulation of adiposity, we first performed in vitro studies in cultured adipocytes and demonstrated that ang II induced adipocyte lipogenic gene transcription in a glucose-dependent manner. We identified the adipocyte determination and differentiation factor 1 (ADD1) as an ang II-responsive transcription factor. To address the in vivo role of agt in regulating lipid metabolism and possibly blood pressure, we studied responsiveness of agt knockout mice (agt-/-) compared to wild type mice (wt) to high fat diets. Body weight, adiposity and insulinemia were significantly decreased (p<0.01) in agt-/- mice fed a chow diet compared to wt mice, circulating leptin levels were comparable. When fed a high fat diet, agt-/- mice exhibited significantly lower body weight (p< 0.01), lower adiposity (p<0.01) and lower leptin and insulin levels (p<0.01). These results demonstrate that agt deficiency plays an important role in regulating body fat mass. This differential responsiveness between the two genotypes was associated with alterations in receptor binding properties and adipocyte gene expression. Studies in transgenic mice where agt is limited or overexpressed specifically in adipose tissue demonstrated that adipose agt reaches the bloodstream and regulates blood pressure and kidney homeostasis (Massiera et al., 2001). Additionally, we demonstrated that overexpression of agt in adipose tissue induces adipocyte lipogenesis and hyperinsulinemia. The cellular and molecular mechanims linking adipocyte agt to obesity and hypertension are currently under investigation. In conclusion, ang II secreted from fat cells acts as a paracrine and endocrine factor that may link obesity to hypertension. Funded by the Am. Heart Assn, the TN Agr. Exp. Station and the PMERF.