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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.
Background adaptation is used by teleosts as one of a variety of camouflage mechanisms for avoidance of predation. Background adaptation is known to involve light sensing by the retina and subsequent regulation of melanophore dispersion or contraction in melanocytes, mediated by α-melanocyte-stimulating hormone and melanin-concentrating hormone, respectively. Here, we demonstrate that an agouti gene unique to teleosts, agrp2, is specifically expressed in the pineal and is required for up-regulation of hypothalamic pmch and pmchl mRNA and melanosome contraction in dermal melanocytes in response to a white background. floating head, a mutant with defective pineal development, exhibits defective up-regulation of mch mRNAs by white background, whereas nrc, a blind mutant, exhibits a normal response. These studies identify a role for the pineal in background adaptation in teleosts, a unique physiological function for the agouti family of proteins, and define a neuroendocrine axis by which environmental background regulates pigmentation.