Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY3-36

BG Challis, AP Coll, GSH Yeo… - Proceedings of the …, 2004 - National Acad Sciences
BG Challis, AP Coll, GSH Yeo, SB Pinnock, SL Dickson, RR Thresher, J Dixon, D Zahn…
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans
leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-
deficiency leads to disordered energy homeostasis, we have generated mice lacking all
POMC-derived peptides. Consistent with a previously reported model, Pomc-/-mice were
obese and hyperphagic. They also showed reduced resting oxygen consumption associated
with lowered serum levels of thyroxine. Hypothalami from Pomc-/-mice showed markedly …
Inactivating mutations of the pro-opiomelanocortin (POMC) gene in both mice and humans leads to hyperphagia and obesity. To further examine the mechanisms whereby POMC-deficiency leads to disordered energy homeostasis, we have generated mice lacking all POMC-derived peptides. Consistent with a previously reported model, Pomc-/- mice were obese and hyperphagic. They also showed reduced resting oxygen consumption associated with lowered serum levels of thyroxine. Hypothalami from Pomc-/- mice showed markedly increased expression of melanin-concentrating hormone mRNA in the lateral hypothalamus, but expression of neuropeptide Y mRNA in the arcuate nucleus was not altered. Provision of a 45% fat diet increased energy intake and body weight in both Pomc-/- and Pomc+/- mice. The effects of leptin on food intake and body weight were blunted in obese Pomc-/- mice whereas nonobese Pomc-/- mice were sensitive to leptin. Surprisingly, we found that Pomc-/- mice maintained their acute anorectic response to peptide-YY3-36 (PYY3-36). However, 7 days of PYY3-36 administration had no effect on cumulative food intake or body weight in wild-type or Pomc-/- mice. Thus, POMC peptides seem to be necessary for the normal response of energy balance to high-fat feeding, but not for the acute anorectic effect of PYY3-36 or full effects of leptin on feeding. The finding that the loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding emphasizes the potential importance of this locus as a site for gene-environment interactions predisposing to obesity.
National Acad Sciences