Prolyl carboxypeptidase regulates energy expenditure and the thyroid axis.
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 1 mRNA 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.
Department of Obstetrics and Gynecology and Reproductive Sciences, Yale University School of Medicine, P.O. Box 208063, New Haven, Connecticut 06520-208063, USA.
Jin Kwon
JK
Jeong
Gyorgyi
G
Szabo
Kaitlin
K
Kelly
Sabrina
S
Diano
D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002268:Carboxypeptidases / Q000235:genetics / Q000378:metabolism*; D004734:Energy Metabolism / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D007031:Hypothalamus / Q000201:enzymology; D007037:Hypothyroidism / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000235:genetics / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism; D000071256:Uncoupling Protein 1
D007473:Ion Channels; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D014284:Triiodothyronine; D013972:Thyrotropin; D002268:Carboxypeptidases; C022448:lysosomal Pro-X carboxypeptidase