Neuronal Inactivation of Peroxisome Proliferator-activated Receptor γ Coactivator 1α (PGC-1α) Protects Mice from Diet-induced Obesity and Leads to Degenerative Lesions

Peroxisome proliferator-activated receptor alpha coactivator 1 alpha (PGC-1 alpha) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1 alpha have elevated metabolic rate and are resistant to diet-induced obesity. However, it remains unknown whether this alteration in energy balance is due to the action of PGC-1 alpha in peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1 alpha knock-out mice (B alpha KO) using calcium/calmodulin-dependent protein kinase II alpha(CaMKII alpha)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1 alpha null mice, B alpha KO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, B alpha KO mice are hypermetabolic, and similar to whole body PGC-1 alpha null mice, are also resistant to diet-induced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1 alpha leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1 alpha null brain and impairs nutritional regulation of hypothalamic expression of genes that regulate systemic energy balance. Together, these studies have demonstrated a physiological role for neuronal PGC-1 alpha in the control of energy balance. Our results also implicate CaMKII alpha-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo.