Hypothalamic α-melanocyte-stimulating hormone (α-MSH) plays a central role in regulating energy uptake and expenditure. Prolyl carboxypeptidase (PRCP), a protease expressed in the hypothalamus, is responsible for the degradation of α-MSH. PRCP null animals (PRCP^gt/gt mice) display elevated α-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCP^gt/gt mice have a significant decrease in fat mass, although an increase in lean mass was also observed. In agreement with low fat accumulation, reduced leptin levels were found. Consistent with the effect of α-MSH on energy metabolism, PRCP^gt/gt mice had increased energy expenditure with elevated circulating thyroid hormone levels and brown adipose tissue uncoupling protein 1 mRNA levels compared with control mice when exposed to regular diet. TRH mRNA levels in the PVN were significantly higher in fed PRCP^gt/gt animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCP^gt/gt and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCP^gt/gt animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCP^gt/gt compared with WT mice. Finally, TRH mRNA levels in T₃-treated hypothyroid PRCP^gt/gt mice showed a non significant reduction compared with those of hypothyroid PRCP^gt/gt mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCP^gt/gt mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism.