Prolyl Carboxypeptidase Regulates Energy Expenditure and the Thyroid Axis

Hypothalamic alpha-melanocyte-stimulating hormone (alpha-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 alpha-MSH. PRCP null animals (PRCPgt/gt mice) display elevated alpha-MSH in the hypothalamus, lower body weight, and are protected from diet induced obesity. Here, we report that PRCPgt/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 alpha-MSH on energy metabolism, PRCPgt/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 PRCPgt/gt animals compared with fed wild-type controls. Fasting significantly decreased TRH mRNA levels in both PRCPgt/gt and wild-type (WT) mice. However, TRH mRNA levels in fasted PRCPgt/gt animals were significantly higher than those of fasted WT mice. Refeeding analysis after fasting showed a reduced food intake in PRCPgt/gt compared with WT mice. Finally, TRH mRNA levels in T-3-treated hypothyroid PRCPgt/gt mice showed a non significant reduction compared with those of hypothyroid PRCPgt/gt mice, supporting the impairment of the hypothalamo-pituitary-thyroid axis in PRCPgt/gt mice. All together, these data confirm that PRCP plays a role in the regulation of energy metabolism. (Endocrinology 153: 683-689, 2012)