Proopiomelanocortin-deficient mice are hypersensitive to the adverse metabolic effects of glucocorticoids.
Congenital lack of proopiomelanocortin (POMC) causes obesity and glucocorticoid deficiency. The responses of Pomc-/- and wild-type mice to the administration of corticosterone were compared. In study 1, mice were given corticosterone-supplemented water (CORT) for 10 days, resulting in plasma CORT levels within the physiological range, with partial suppression of hypothalamic corticotropin-releasing hormone expression to a similar degree between genotypes. Body weight, fat mass, and food intake increased in CORT-treated Pomc-/- but not wild-type mice. CORT increased plasma insulin levels 50-fold in Pomc-/- versus 14-fold in wild-type mice (P < 0.01) and increased hypothalamic agouti-related protein (AgRP) expression by more than 200% in Pomc-/- versus 40% in wild type (P < 0.05). In study 2, mice were given CORT from weaning, and Pomc-/- but not wild-type mice developed hyperglycemia, ketonuria, and hepatic steatosis by 8-12 weeks. Thus, Pomc-/- mice are hypersensitive to the adverse metabolic effects of glucocorticoids. Additionally, as the levels of plasma CORT achieved, especially in study 1, were not grossly supraphysiological, we conclude that glucocorticoid deficiency may afford Pomc-/- mice some protection from the full adverse consequences of melanocortin deficiency. This may occur through a mechanism involving the suppression of AgRP by the hypoadrenal state.
Coll
Anthony P
AP
University Department of Medicine,Addenbrooke's Hospital, Cambridge CB2 2QR, UK.
Challis
Benjamin G
BG
López
Miguel
M
Piper
Sarah
S
Yeo
Giles S H
GS
O'Rahilly
Stephen
S
D000273:Adipose Tissue; D054369:Agouti-Related Protein; D000818:Animals; D001823:Body Composition; D003345:Corticosterone / Q000008:administration & dosage / Q000097:blood; D004326:Drinking; D004435:Eating; D005938:Glucocorticoids / Q000009:adverse effects*; D006943:Hyperglycemia / Q000139:chemically induced; D006963:Hyperphagia / Q000139:chemically induced; D007328:Insulin / Q000097:blood; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption; D011333:Pro-Opiomelanocortin / Q000172:deficiency*; D011506:Proteins / Q000235:genetics; D014886:Weaning; D015430:Weight Gain
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D005938:Glucocorticoids; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011333:Pro-Opiomelanocortin; D003345:Corticosterone