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-1α in 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, BαKO mice have normal adaptive metabolic response to starvation and cold exposure in peripheral tissues. In contrast, BαKO mice are hypermetabolic, and similar to whole body PGC-1α null mice, are also resistant to diet-induced 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.