Submitted on January 4, 2008
Accepted on May 14, 2008
Deficiency of Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Prevents Ovariectomy-Induced Obesity in Mice
Frank Isken1*, Andreas FH Pfeiffer1, Ruben Nogueiras2, Martin A Osterhoff1, Michael Ristow3, Bernard Thorens4, Mathias H. Tschop5, and Martin O. Weickert1
1 Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrucke, Germany
2 Obesity Research Center, University of Cincinnati, Cincinnati, Ohio, United States
3 Department of Human Nutrition, University of Jena, Jena, Germany; Department of Clinical Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrucke, Germany
4 Department of Physiology, CH-1005 Lausanne, Switzerland., University of Lausanne, Lausanne, Switzerland
5 Genome Research Institute, University of Cincinnati, Cincinnatti, Ohio, United States
* To whom correspondence should be addressed. E-mail: isken{at}dife.de.
Menopause and premature gonadal steroid deficiency 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 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 knock-out mice (Gipr-/-) were exposed to OVX or sham-operation (n = 10 per group). Effects on body composition, markers of insulin resistance, energy expenditure, locomotor activity, and expression of hypothalamic anorexigenic and orexigenic factors were investigated over 26-weeks 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 and amphetamine related transcript (CART), melanocortin receptors (MCR-3 and MCR-4), or thyroid stimulating hormone 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.
