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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/E350    most recent 00008.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Isken, F. Articles by Weickert, M. O. PubMed PubMed Citation Articles by Isken, F. Articles by Weickert, M. O.

Deficiency of glucose-dependent insulinotropic polypeptide receptor prevents ovariectomy-induced obesity in mice

¹Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nutheta; ²Department of Endocrinology, Diabetes and Nutrition, Charité-University-Medicine, Campus Benjamin Franklin, Berlin, Germany; ³Department of Psychiatry, University of Cincinnati Genome Research Institute, Cincinnati, Ohio; ⁴Department of Human Nutrition, Institute of Nutrition, University of Jena, Jena, Germany; and ⁵Department of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Submitted 4 January 2008 ; accepted in final form 14 May 2008

Menopause and premature gonadal steroid deficiency are associated with increases in fat mass and body weight. Ovariectomized (OVX) mice also show reduced locomotor activity. Glucose-dependent-insulinotropic-polypeptide (GIP) is known to play an important role both in fat metabolism and locomotor activity. Therefore, we hypothesized that the effects of estrogen on the regulation of body weight, fat mass, and spontaneous physical activity could be mediated in part by GIP signaling. To test this hypothesis, C57BL/6 mice and GIP-receptor knockout mice (Gipr^–/–) were exposed to OVX or sham operation (n = 10 per group). The effects on body composition, markers of insulin resistance, energy expenditure, locomotor activity, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26 wk in all four groups of mice. OVX wild-type mice developed obesity, increased fat mass, and elevated markers of insulin resistance as expected. This was completely prevented in OVX Gipr^–/– animals, even though their energy expenditure and spontaneous locomotor activity levels did not significantly differ from those of OVX wild-type mice. Cumulative food intake in OVX Gipr^–/– animals was significantly reduced and associated with significantly lower hypothalamic mRNA expression of the orexigenic neuropeptide Y (NPY) but not of cocaine-amphetamine-related transcript (CART), melanocortin receptors (MCR-3 and MCR-4), or thyrotropin-releasing hormone (TRH). GIP receptors thus interact with estrogens in the hypothalamic regulation of food intake in mice, and their blockade may carry promising potential for the prevention of obesity in gonadal steroid deficiency.

estrogen; energy expenditure; body fat