Abstract P074: Role of Peroxisome Proliferator-Activated Receptor-γ (PPAR) in the Pro-opiomelanocortin (POMC) Neuron-Mediated Regulation of Energy Balance

Abstract

PPARγ, a master regulator of adipogenesis, was recently shown to affect energy homeostasis through its actions in the brain. Deletion of PPARγ in mouse brain, and specifically in the POMC neurons, results in resistance to diet-induced obesity. To study the mechanisms by which PPARγ in POMC neurons controls energy balance, we generated a transgenic mouse model in which a dominant-negative mutant (P467L) form of PPARγ is conditionally expressed in POMC neurons. The transgene will express both human PPARγ-P467L and the tdTomato reporter gene after it is selectively activated by a Cre-recombinase driver. Here, POMC-Cre was used to direct POMC neuron-specific expression of the transgene. Co-localization of tdTomato and ACTH staining in the Arcuate nucleus of POMC-Cre X PPARγ-P467L double transgenic (DTg) mice demonstrates successful transgene activation in POMC neurons. Interestingly, 25 week treatment with 60% high fat diet resulted in no difference in body weight in DTg mice compared to littermate controls (55.7±1.0 g vs 57.1±1.2 g, n>11). However, feeding these mice a 10% fat isocaloric-matched control diet led to a significant increase in the body weight of DTg mice compared to littermate controls (36.0±0.9g vs. 31.7±0.5g, p<0.0001, n=10). The increased body weight in DTg was due to increased adipose mass (DTg: 23.9±2.4% vs. control: 16.8±2.2%, p=0.04, n=10) and decreased lean mass (DTg: 60.5±2.0% vs. control: 66.5±1.7%, p=0.04) respectively, as demonstrated by nuclear magnetic resonance spectroscopy. We observed no difference between genotypes in food intake (DTg: 2.1±0.1g vs. controls: 2.2±0.1g, n>9) and cumulative body weight change (DTg: -4.5±0.7% vs. controls: -4.4±1.0%, n>9) in response to 1mg/kg (i.p.) leptin. Since interference with PPARγ in POMC neurons does not impede sensitivity to leptin, we speculate that increased weight gain in DTg mice on low fat diet may be due to differences in food intake, decreased sympathetic drive to adipose tissues, and/or decreased energy expenditure, mechanisms which are currently under investigation. We conclude that PPARγ in POMC neurons may play a role in energy balance under certain dietary conditions.