Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse.

Srisai D, Gillum MP, Panaro BL, Zhang XM, Kotchabhakdi N, Shulman GI, Ellacott KL, Cone RD
Endocrinology. 2011 152 (3): 890-902

PMID: 21239438 · PMCID: PMC3040060 · DOI:10.1210/en.2010-0716

Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R(-/-)). The human disease most commonly presents, however, as haploinsufficiency of the MC4R. This study validates the MC4R(+/-) mouse as a model of the human disease in that, like the MC4R(-/-), the MC4R(+/-) mouse also exhibits a sustained hyperphagic response to dietary fat. Furthermore, both saturated and monounsaturated fats elicit this response. N-acylphosphatidylethanolamine (NAPE) is a signaling lipid induced after several hours of high-fat feeding, that, if dysregulated, might explain the feeding behavior in melanocortin obesity syndrome. Remarkably, however, MC4R(-/-) mice produce elevated levels of NAPE and are fully responsive to the anorexigenic activity of NAPE and oleoylethanolamide. Interestingly, additional differences in N-acylethanolamine (NAE) biochemistry were seen in MC4R(-/-) animals, including reduced plasma NAE levels and elevated hypothalamic levels of fatty acid amide hydrolase expression. Thus, while reduced expression of NAPE or NAE does not explain the high-fat hyperphagia in the melanocortin obesity syndrome, alterations in this family of signaling lipids are evident. Analysis of the microstructure of feeding behavior in response to dietary fat in the MC4R(-/-) and MC4R(+/-) mice indicates that the high-fat hyperphagia involves defective satiation and an increased rate of food intake, suggesting defective satiety signaling and enhanced reward value of dietary fat.

MeSH Terms (15)

Amidohydrolases Animals Basic Helix-Loop-Helix Transcription Factors Dietary Fats Female Gene Expression Regulation Heterozygote Hyperphagia Male Mice Mice, Knockout Mutation Receptor, Melanocortin, Type 1 Receptor, Melanocortin, Type 4 Repressor Proteins

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