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1 Fachbereich Medizin, Dr Senckenbergische Anatomie, Institut fuer Anatomie II, Johann Wolfgang goethe-Universitaet, Frankfurt/Main, Germany; Arbeitsgruppe Energiebilanz und Adipositas, Max-Planck-Institut fuer Physiologische und Klinische Forschung, W.G. Kerckhoff-Institut, Bad Nauheim, Germany
2 Aberdeen Centre for Energy Balance and Obesity, Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen, Scotland, United Kingdom
3 Arbeitsgruppe Energiebilanz und Adipositas, Max-Planck-Institut fuer Physiologische und Klinische Forschung, W.G. Kerckhoff-Institut, Bad Nauheim, Germany
4 Fachbereich Medizin, Dr Senckenbergische Anatomie, Institut fuer Anatomie II, Johann Wolfgang goethe-Universitaet, Frankfurt/Main, Germany
* To whom correspondence should be addressed. E-mail: ingrid.schmidt{at}kerckhoff.mpg.de.
In young (35- to 56-day-old) and middle-aged (9-month-old) wildtype (+/+) and 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.
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