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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, Scotland AB21 9SB, United Kingdom
3 University Clinic, Anatomy II, D-60590 Frankfurt
4 Clinical Research Group, Child and Adolescent Psychiatry at the Philipps-University of Marburg, D-35039 Marburg, Germany
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 to 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 neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (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 mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.
neuropeptide Y; pro-opiomelanocortin; genetic obesity; energy expenditure
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