OBJECTIVE Receptor activity–modifying proteins (RAMPs) 1, 2, and 3 are unusual accessory proteins that dictate the binding specificity of two G protein–coupled receptors involved in energy homeostasis: calcitonin gene–related peptide (CGRP) and amylin receptors. These proteins are expressed throughout the central nervous system (CNS), including in the brain regions involved in the regulation of energy homeostasis, but the significance of CNS RAMPs in the control of energy balance remains unknown. RESEARCH DESIGN AND METHODS To examine the functional significance of modulating neuronal RAMP1, we assessed the effect of overexpressing human RAMP1 (hRAMP1) in the CNS on body energy balance. RESULTS Nestin/hRAMP1 transgenic mice have a remarkably decreased body weight associated with reduced fat mass and circulating leptin levels. The transgenic mice exhibited higher energy expenditure as indicated by increased oxygen consumption, body temperature, and sympathetic tone subserving brown adipose tissue (BAT). Consistent with this, the nestin/hRAMP1 transgenic mice had elevated BAT mRNA levels of peroxisome proliferator–activated receptor γ coactivator 1α and uncoupling protein 1 and 3, and these changes can be reversed by chronic blockade of sympathetic nervous system signaling. Furthermore, metabolic response to amylin was enhanced in the nestin/hRAMP1 mice whereas the response to CGRP was blunted, possibly the result of higher expression of CGRP in the CNS. CONCLUSIONS These data demonstrate that CNS RAMP1 plays a pivotal role in the regulation of energy homeostasis by promoting energy expenditure.