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1 Max-Planck-Institut fuer physiologische und klinische Forschung, W.G.Kerckhoff-Institut, D-61231 Bad Nauheim, Germany
2 Molecular Neuroendocrinology Group, Aberdeen Centre for Energy Regulation and Obesity, Rowett Research Institute, Aberdeen AB21 9SB, United Kingdom
3 University Clinic, Anatomy II, D-60590 Frankfurt a.M., Germany
4 Clinical Research Group, Child and Adolescent Psychiatry at the Philipps-University of Marburg, D-35039 Marburg, Germany
* To whom correspondence should be addressed. E-mail: I.Schmidt{at}kerckhoff.mpg.de.
Previous studies on mice with melanocortin-4-receptor-gene (MC4r) knockout have focused on obese adults. Because humans with functional MC4r-mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r-/- on day 35 and MC4r+/- on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21-35, onset of excessive fat deposition in MC4r-/- is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus NPY-mRNA decreases and POMC-mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY- and POMC-mRNA due to melanocortin-4-receptor deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in melanocortin-4-receptor-deficient mice at weaning, and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.
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