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Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat

Nature Neuroscience volume 4, pages 605–611 (2001)Cite this article

Abstract

In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R−/−) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain. We report two specific defects in coordinating energy expenditure with food intake in MC4R−/− mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R−/− mice. Leptin-deficient and MC3R−/− mice regulate metabolic rate similarly to wild-type mice in this protocol. Melanocortinergic pathways involving MC4-R-regulated neurons, which rapidly respond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.

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Figure 1: Response of MC4R−/− and wild-type mice to restricted food intake and cold.
Figure 2: Marked increase in weight observed in MC4R−/− mice associated with a change from low-fat to moderate-fat diet is not observed in wild-type or Lepob/Lepob mice.
Figure 3: Abnormal feeding response of MC4R−/− mice to increasing fat content of the diet.
Figure 4: Male MC4R−/− mice fail to increase energy expenditure and regulate the ratio of fatty acid/carbohydrate oxidation in response to switching from low-fat to moderate-fat diet.
Figure 5: Increase in dietary fat content does not affect catecholamine turnover in wild-type mice during the period used to record VO2.
Figure 6: Wild-type mice, but not MC4R−/− mice, respond to the increased caloric content of the moderate-fat diet by increasing wheel running behavior (wheel turns per minute) during the lights-off period.

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Acknowledgements

This work was supported by NIH grant PPGDK55819 to R.D.C. We thank K. Khong, E. Douthit and K.E. Miles for their help.

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Authors and Affiliations

  1. Vollum Institute, Oregon Health Sciences University, 3181 SW Sam Jackson Park Road, Portland, 97201, Oregon, USA

    Andrew A. Butler, Wei Fan & Roger D. Cone

  2. Department of Pediatric Endocrinology, Oregon Health Sciences University CDRCP, Portland, 97201, Oregon, USA

    Daniel L. Marks

  3. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    Cynthia M. Kuhn & Maria Bartolome

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Correspondence to Roger D. Cone.

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Butler, A., Marks, D., Fan, W. et al. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci 4, 605–611 (2001). https://doi.org/10.1038/88423

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