title: Deletion of prolyl carboxypeptidase attenuates the metabolic effects of diet-induced obesity.
abstract: α-Melanocyte-stimulating hormone (α-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 α-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.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520-208063, USA.
authors.forename: Jin Kwon
authors.initials: JK
authors.lastname: Jeong
authors.forename: Gyorgyi
authors.initials: G
authors.lastname: Szabo
authors.forename: Giuseppina Mattace
authors.initials: GM
authors.lastname: Raso
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
mesh_terms: D000818:Animals; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002268:Carboxypeptidases / Q000235:genetics* / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004734:Energy Metabolism / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D005943:Gluconeogenesis / Q000235:genetics / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000502:physiology; D006728:Hormones / Q000097:blood; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism*; D009929:Organ Size / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005227:Fatty Acids; D006728:Hormones; D020738:Leptin; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase; D005947:Glucose