Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 302, Issue 12, Pages E1502-E1510Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00544.2011
Keywords
alpha-melanocyte-stimulating hormone; energy metabolism; insulin sensitivity; glucose metabolism
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Funding
- National Institute of Diabetes and Digestive and Kidney Diseases [R01-DK-084065]
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alpha-Melanocyte-stimulating hormone (alpha-MSH) is a critical regulator of energy metabolism. Prolyl carboxypeptidase (PRCP) is an enzyme responsible for its degradation and inactivation. PRCP-null mice (PRCPgt/gt) showed elevated levels of brain alpha-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 PRCPgt/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, PRCPgt/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 PRCPgt/gt compared with WT mice. A significant decrease in liver weight and hepatic triglycerides were also observed in PRCPgt/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.
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