RoleofPPARgammaCoactivatorsinObesityandThermogenesis

Nuclear hormone receptors are transcription factors that bind DNA and regulate transcription in a ligand-dependent manner. PPAR-gamma is a member of this gene family that is activated by fatty acids and thiazolidinedione drugs that plays a role in insulin sensitivity and adipogenesis (See Visceral Fat Deposits and the Metabolic Syndrome pathway). Like PPAR-alpha and other members of this gene family, PPAR-gamma activates transcription in concert with coactivators including Src-1 and Tif2 (see PPAR-alpha pathway). Although these coactivators act for multiple members of this gene family, coactivators may have specific functions in some settings. Deletion of the Src-1 gene or Tif2 gene in mice reduced the response to steroid hormones and development dependent on these hormones. Some PPAR-gamma ligands induce the specific recruitment of coactivators, and might evoke different functional responses based on the interactions they favor. The natural ligand 15-deoxy prostaglandin J2 stimulated PPAR-gamma interaction with SRC-1, TIF2, TRAP220, and p300, while the synthetic PPAR-gamma ligand troglitazone, an antidiabetic thiazolidinedione drug, did not promote these interactions, indicating that other distinct coactivators may mediate the response to PPAR-gamma when it binds this ligand. In normal rodents, a high-fat diet leads to high levels and free fatty acids and PPAR-gamma activation in white adipose tissue, stimulating fat uptake, adipogenesis and obesity. PPAR-gamma activation in brown adipose tissue depends mainly on Src-1 as a coactivator and Src-1 is essential for PGC-1 alpha to act as a coactivator to stimulate thermogenesis. Regulation of energy use by PGC-1 in other tissues such as muscle may contribute to weight loss associated with cancer and increased metabolism induced by exercise. High-fat feeding and high plasma free fatty acids reduce thermogenesis in brown fat due to the greater requirement of PPAR-gamma for Src-1 than Tif2 for activation in these cells. In white adipose cells, Tif2 predominates as the PPAR-gamma coactivator, stimulating fat uptake and adipogenesis in conditions of high-fat feeding. Trap220, a component of the TRAP coactivator complex, is also required for adipogenesis. Examining the metabolic consequences of coactivator deletion, Src-1 and Tif2 specifically alter PPAR-gamma signaling. Compared to normal rodents, Mice lacking the Tif2 coactivator are resistant to obesity when fed a high-fat diet, with increased lipolysis in adipocytes and decreased fatty acid uptake in adipose tissue. A high-fat diet increases the expression of Tif2 in both brown and white adipose cells, changing the Tif2 to Src-1 ratio. This change in the ratio of coactivators favors increased adipogenesis in white adipose while it blocks thermogenesis in brown adipose cells by opposing Src-1/PGC-1 alpha dependent signaling.

Contributor: Glenn Croston Ph.D.

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