Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity

Abstract

Jeong JK, Szabo G, Raso GM, Meli R, Diano S. Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity. Am J Physiol Endocrinol Metab 302: E1502-E1510, 2012. First published March 27, 2012 doi:10.1152/ajpendo.00544.2011.-␣-Melanocyte-stimulating hormone (␣-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCP gt/gt ) showed elevated levels of brain ␣-MSH, reduced food intake, and a leaner phenotype compared with wild-type controls. In addition, they were protected against diet-induced obesity. Here, we show that PRCP gt/gt animals have improved metabolic parameters compared with wild-type controls under a standard chow diet (SD) as well as on a high-fat diet (HFD). Similarly to when they are exposed to SD, PRCP gt/gt mice exposed to HFD for 13 wk showed a leaner phenotype due to decreased fat mass, increased energy expenditure, and locomotor activity. They also showed improved insulin sensitivity and glucose tolerance compared with WT controls and a significant reduction in fasting glucose levels. These improvements occured before changes in body weight and composition were evident, suggesting that the beneficial effect of PRCP ablation is independent of the adiposity levels. In support of a reduced gluconeogenesis, liver PEPCK and G-6-Pase mRNA levels were reduced significantly in PRCP gt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCP gt/gt compared with WT mice. Altogether, our data suggest that PRCP is an important regulator of energy and glucose homeostasis since its deletion significantly improves metabolic parameters in mice exposed to both SD and HFD.␣-melanocyte-stimulating hormone; energy metabolism; insulin sensitivity; glucose metabolism A PRECISE CONTROL OF CALORIC INTAKE and energy expenditure is fundamental for the balance of energy homeostasis. In the mammalian brain, a product of the proopiomelanocortin (POMC) gene, ␣-melanocyte-stimulating hormone (␣-MSH) plays a central role in detecting, integrating, and responding to a range of central and peripheral inputs relating to energy metabolism (1,4,13,14,20). The use of genetically altered mouse models has shown the importance of ␣-MSH in the regulation of a broad range of metabolic parameters (9, 17). Mice with ablation of the POMC gene are obese, whereas mice overexpressing ␣-MSH in the brain showed protection against diet-induced obesity with improved glucose homeostasis.We have reported recently a molecular mechanism that is responsible for the inactivation and degradation of ␣-MSH (21). Prolylcarboxypeptidase (PRCP) is a serine protease that cleaves the last amino acid at the COOH terminus of small peptides if proline is the penultimate amino acid. We have shown previously that PRCP is expressed in the lateral hypothalamus, where PRCP-expressing neurons target with their axons the paraventricular nucleus of the hypothalamus, a sit...

Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice

“…Adult male mice for Prep gt/gt and WT were acclimated in metabolic chambers (TSE System) for 4 d before the start of the recordings as previously published (27,28). For body composition, adult males were scanned in an EchoMRI machine (Echo Medical Systems), and their body composition was calculated according to body weight.…”

“…Glucose tolerance tests were performed in 16-h fasted animals as previously reported (27,28). Each animal received an i.p.…”

“…Blood glucose and insulin levels were measured after 15, 30, 60, and 120 min. An ITT was performed in ad-libitum-fed mice (27,28). Each animal received an i.p.…”

“…In situ hybridization was based on our previously published protocol (27,28). A 500-bp sequence between 1531 and 2030 was selected from the mouse PREP (GenBank accession no.…”

“…A 500-bp sequence between 1531 and 2030 was selected from the mouse PREP (GenBank accession no. NM_011156), synthesized (Biomatik), incorporated into pBluescript vector, and used as template (27,28). 35 S-labeled riboprobes were then purified using sephadex columns (ProbeQuant G-50 Micro Columns, Pharmacia Biotech) following the manufacturer's protocol, and 5 × 10 5 cpm per section was used for the hybridization (27,28).…”