ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 P515

Glucose-dependent insulinotropic polypeptide (GIP) receptor knock-out prevents ovariectomy-induced obesity in mice

Frank Isken1, Andreas FH Pfeiffer1, Rubén Nogueiras2, Martin A Osterhoff1, Michael Ristow3, Bernard Thorens4, Matthias H Tschöp2 & Martin O Weickert1


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


Objectives: Premature estrogen deficiency and menopause are associated with increases in body weight and fat mass. Ovariectomized (OVX) mice also show reduced locomotor activity. Because glucose-dependent-insulinotropic-polypeptide (GIP) is known to play an important role both in fat metabolism and locomotor activity, we hypothesized that effects of estrogen on the regulation of body weight, fat mass and spontaneous physical activity could be mediated in part by GIP signaling.

Methods: C57BL/6 mice and GIP-receptor knock-out mice (Gipr−/−) were exposed to OVX or sham-operation (n=10 per group). Effects on body composition, energy expenditure, locomotor activity, markers of insulin resistance, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26-weeks in all four groups of mice.

Results: 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 spontaneous locomotor activity levels and energy expenditure 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). Hypothalamic expression of cocaine and amphetamine related transcript (CART) or thyroid stimulating hormone releasing hormone (TRH) were not significantly different in OVX Gipr−/− vs OVX wild-type control mice.

Conclusions: GIP receptors appear to interact with estrogens in the hypothalamic regulation of food intake. Pharmacological inhibition of GIP receptors may carry promising potential for the prevention of obesity in estrogen deficient states.

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