White adipose tissue (VVAT) is a tissue specialized for the storage and mobilization of lipid energy. Chronic activation of WAT beta-adrenergic receptors by certain physiological and pharmacological conditions, however, transforms the tissue into one resembling brown fat, a thermogenic organ. Hallmarks of this tissue plasticity include the appearance of multilocular adipocytes and massive mitochondrial biogenesis within these cells. Although the multilocular cells resemble brown adipocytes, histological and biochemical evidence indicates they are not newly-recruited brown fat cells, but rather represent a novel phenotype. The novel multilocular adipocytes have a molecular profile suggesting a high capacity for lipid oxidation and futile substrate cycling. Furthermore, the multilocular adipocytes appear to derive from mature fat cells through a novel proliferative pathway. These observations raise numerous fundamental questions regarding how the cellular plasticity takes place in WAT, and the function of the novel adipocyte phenotype. Muitilocular adipocytes could represent a novel cellular target for anti-obesity and anti-diabetes therapeutics, and an understanding of the mechanisms controlling cellular plasticity in WAT could lead to novel points of therapeutic intervention for obesity and diabetes.
Our specific aims are: 1) To characterize the genesis and fate of novel multilocular white adipocytes. 2) To examine the function of novel multilocular white adipocytes in vivo and in vitro. 3) To test the involvement of PPAR-alpha and TLR4 in mediating adipocyte plasticity in vivo. ? ?
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