PPARdelta and its co-regulators in energy metabolism

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DESCRIPTION (provided by applicant): Our long-term goal is to understand the transcription basis of energy metabolism and how the involved transcriptional pathways contribute to metabolic diseases. We have recently demonstrated that nuclear receptor PPAR??is a key regulator for fat burning by activating multiple, coordinated metabolic programs involved in energy expenditure. Importantly, we and others have shown that treatment of wild-type mice with the PPAR??agonist prevents high-fat diet induced obesity and insulin resistance, indicating potential therapeutic values of the agonist for the treatment of metabolic diseases. Our current focus is to determine in detail the physiological role of PPAR??in brown fat metabolism and identify the key molecular regulatory mechanisms that are used to regulate its function. In the first aim, we will use both PPAR?-deficient brown fat cells and fat-specific PPAR??knockout mice to determine whether PPAR??is required for both basal oxidative metabolism and energy uncoupling in brown fat cells, whether PPAR??is required for ?-adrenergic receptor-stimulated thermogenesis, and whether fat-specific PPAR??is important to obesity resistance. In the second aim, we will determine the genetic and biochemical interactions of PPAR??and co-activator PGC-1??in brown fat. We will examine whether in brown fat cells PPAR??employs PGC-1??as its major coactivator and whether the metabolic function of PGC-1??is mediated, at least in part, by PPAR?. In the third aim, we will characterize the metabolic function of a transcriptional co-factor that we have recently identified as a bona fide modulator for PGC-1?/PPAR?- regulated oxidative metabolism pathway. We will examine the physical and functional interactions of this factor with PGC-1??and PPAR?. We will generate transgenic mice expressing this factor in adipose tissue to analyze its in vivo role in energy metabolism.