Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that regulates diverse aspects of energy metabolism in peripheral tissues. Mice deficient in PGC-1α 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-1αin peripheral tissues or the central nervous system. In this study, we generated neuronal PGC-1α knock-out mice (BαKO) using calcium/calmodulin-dependent protein kinase IIα (CaMKIIα)-Cre to address its role in the regulation of energy balance and neuronal function. Unlike whole body PGC-1α null mice, Bα KO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, Bα KO mice are hypermetabolic, and similar to whole body PGC-1α null mice, are also resistant to dietinduced obesity, resulting in significantly improved metabolic profiles. Neuronal inactivation of PGC-1α leads to striatal lesions that are reminiscent of neurodegeneration in whole body PGC-1α 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-1α in the control of energy balance. Our results also implicate CaMKIIα-positive neurons as an important part of the neural circuitry that governs energy expenditure in vivo. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.