Deficiency of glucose-dependent insulinotropic polypeptide receptor prevents ovariectomy-induced obesity in mice.
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.
Isken
Frank
F
Department of Endocrinology, Diabetes and Nutrition, Charité-University-Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, Berlin, Germany. isken@dife.de
Pfeiffer
Andreas F H
AF
Nogueiras
Rubén
R
Osterhoff
Martin A
MA
Ristow
Michael
M
Thorens
Bernard
B
Tschöp
Matthias H
MH
Weickert
Martin O
MO
D000818:Animals; D001823:Body Composition / Q000502:physiology; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009478:Neuropeptide Y / Q000096:biosynthesis / Q000235:genetics; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D010052:Ovariectomy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011964:Receptors, Gastrointestinal Hormone / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D044101:Receptors, Melanocortin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013973:Thyrotropin-Releasing Hormone / Q000096:biosynthesis / Q000235:genetics; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D012333:RNA, Messenger; D011964:Receptors, Gastrointestinal Hormone; D044101:Receptors, Melanocortin; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D005749:Gastric Inhibitory Polypeptide; D013973:Thyrotropin-Releasing Hormone; C041086:gastric inhibitory polypeptide receptor