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

被引:286
作者
Challis, BG
Coll, AP
Yeo, GSH
Pinnock, SB
Dickson, SL
Thresher, RR
Dixon, J
Zahn, D
Rochford, JJ
White, A
Oliver, RL
Millington, G
Aparicio, SA
Colledge, WH
Russ, AP
Carlton, MB
O'Rahilly, S
机构
[1] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 2XY, England
[2] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med, Cambridge CB2 2XY, England
[3] Univ Cambridge, Dept Physiol, Cambridge CB2 3EG, England
[4] Paradigm Therapeut, Cambridge CB4 0WA, England
[5] Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England
[6] Univ Manchester, Fac Med, Manchester M13 9PT, Lancs, England
[7] Univ Cambridge, Hutchinson Med Res Council Res Ctr, Dept Oncol, Cambridge CB2 2XZ, England
[8] Univ Oxford, Dept Biochem, Genet Unit, Oxford OX1 3QU, England
关键词
D O I
10.1073/pnas.0306931101
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
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页码:4695 / 4700
页数:6
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