Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis

Abstract

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 1mRNA 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 T 3-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. Copyright © 2012 by The Endocrine Society.