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Pro-Opiomelanocortin Modulates the Thermogenic and Physical Activity Responses to High-Fat Feeding and Markedly Influences Dietary Fat Preference

Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom

Address all correspondence and requests for reprints to: Anthony P. Coll, M.D., Ph.D., Laboratory 4.36, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom. E-mail: apc36{at}cam.ac.uk.

Complete proopiomelanocortin (POMC) deficiency causes a human syndrome of hypoadrenalism, altered skin and hair pigmentation, and severe hyperphagic obesity. Heterozygote carriers of nonsense mutations are strongly predisposed to obesity. Pomc^+/– mice have normal body weight on a chow diet but increase food intake and become more obese than wild-type littermates when placed on a high-fat diet. To further explore the mechanisms whereby dietary fat interacts with Pomc genotype to produce obesity, we examined Pomc-null, Pomc^+/–, and wild-type mice for changes in the components of energy balance in response to provision of a high-fat diet and macronutrient preference when presented with a selection of dietary choices. In contrast to wild-type mice, Pomc null mice did not increase their resting energy expenditure or their spontaneous physical activity when given a high-fat diet. Pomc^+/– mice increased resting energy expenditure similarly to wild types, but their increase in physical activity was significantly less than that seen in wild-type mice. In two independent experimental tests of macronutrient preference, Pomc genotype was a strong predictor of dietary fat preference with Pomc null animals choosing to eat approximately twice as much fat, but similar amounts of carbohydrate and protein, as wild-type animals. Pomc^+/– mice showed an intermediate response. In summary, POMC-derived peptides have influences on multiple aspects of the organism’s response to the presentation of high-fat diet. This includes a major influence, readily discernible even in heterozygote animals, on the dietary preference for fat.