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1 Dr Senckenbergische Anatomie, Institut fuer Anatomie II, Fachbereich Medizin, Johann Wolfgang Goethe-Universitaet, D-60590 Frankfurt/Main
2 Max-Planck-Institut fuer Physiologische und Klinische Forschung, W. G. Kerckhoff-Institut, Arbeitsgruppe Energiebilanz und Adipositas, D-61231 Bad Nauheim, Germany
3 Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen Centre for Energy Balance and Obesity, Aberdeen, Scotland AB21 9SB, United Kingdom
In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and cocaine-and-amphetamine-regulated transcript (CART) were analyzed in the arcuate nucleus (ARC) and adjacent regions comprising the dorsomedial (DMN) and ventromedial (VMN) nucleus. In the ARC of young mice, NPY and AGRP expression increased and POMC and CART expression decreased with body fat content. Adjusting for the influence of body fat content by ANCOVA showed that the levels of NPY, POMC, and CART were highest and of AGRP lowest in young -/- mice. In the middle-aged mice, feedback from body fat content was weakened. For -/- mice ANCOVA revealed higher NPY and AGRP, lower POMC, and unchanged CART expression levels relative to young -/- mice. In the DMN and VMN, POMC and AGRP signals were absent at each age. CART was expressed in the DMN independent of age, fat content, and genotype. For NPY expression, an age-dependent induction was found in the DMN and VMN; it was absent in the young but present in the middle-aged mice, showing close positive correlations between body fat content and the numbers of NPY-labeled cells which were further enhanced in -/- mice. Thus MC4R deficiency augments age-induced NPY expression in the DMN and VMN with no feedback from body fat content. Negative feedback control by body fat content on ARC neuropeptide expression is present in young animals but vanishes with age and is modulated by MC4R deficiency.
orexigenic and anorexigenic neuropeptides; arcuate hypothalamic nuclei; ventromedial hypothalamic nuclei; dorsomedial hypothalamic nuclei; central leptin signaling; in situ hybridization