PPARdelta and its co-regulators in energy metabolism

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Our long-term goal is to understand the transcriptional basis of energy metabolism and how the involved transcriptional pathways contribute to metabolic diseases. We have recently demonstrated that the nuclear receptor PPAR6 is a key regulator for fat burning by activating multiple, coordinated metabolic programs. Importantly, we and others have shown that the PPAR5 agonist prevents high-fat diet induced obesity and insulin resistance in mice, 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 PPAR6 in brown fat metabolism and identify key molecular regulatory mechanisms that are used to regulate its function. In the first aim, we will use both PPAR6-deficient brown fat cells and fat-specific PPAR8 knockout mice to determine whether PPAR6 is required for both basal oxidative metabolism and energy uncoupling in brown fat cells, whether PPAR6 is required for p-adrenergic receptor-stimulated thermogenesis, and whether fat-specific PPAR5 is important for obesity resistance. In the second aim, we will determine the genetic and biochemical interactions between PPAR5 and co-activator PGC-1a in brown fat. We will examine whether PPAR5 employs PGC-1a as its major co-activator and whether the metabolic function of PGC-1a is mediated, at least in part, by PPAR5. In the third aim, we will characterize the metabolic function of a transcriptional cofactor that we recently identified as a bona fide modulator for PGC-1cc/PPAR6-regulated oxidative metabolism pathway. We will examine the physical and functional interactions of this co-factor with PGC-1a and PPAR8. We will generate transgenic mice expressing this co-factor in adipose tissue to analyze its in vivo role in energy metabolism. Obesity and associated type 2 diabetes and cardiovascular diseases are serious medical problems in the industrial world. Disregulation of energy metabolism is largely responsible for these diseases. Our studies should provide us novel molecular insights into PPAR6 and its co-regulators in control of energy metabolism, which will clearly be very useful for the development of new therapies.