Transgenic Rescue of Adipocyte Glucose-dependent Insulinotropic Polypeptide Receptor Expression Restores High Fat Diet-induced Body Weight Gain

Randi Ugleholdt; Jens Pedersen; Maria Rosaria Bassi; Ernst-Martin Füchtbauer; Signe Marie Jørgensen; Hanne-Louise Kissow; Nikolaj Nytofte; Steen Seier Poulsen; Mette Marie Rosenkilde; Yutaka Seino; Peter Thams; Peter Johannes Holst; Jens Juul Holst

doi:10.1074/jbc.M111.311779

Transgenic Rescue of Adipocyte Glucose-dependent Insulinotropic Polypeptide Receptor Expression Restores High Fat Diet-induced Body Weight Gain*

From the ^‡Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark,
the ^§Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark,
the ^¶Department of International Health Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, DK-1014 Copenhagen, Denmark,
the ^‖Department of Molecular Biology and Genetics, University of Aarhus, DK-8000 Aarhus, Denmark,
the ^**Department of Neuroscience and Pharmacology, University of Copenhagen, DK-2200 Copenhagen, Denmark, and
the ^‡‡Department of Diabetes and Clinical Nutrition, Kyoto University, Kyoto 606-8507, Japan

↵1 To whom correspondence should be addressed: Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen N, Denmark. Tel.: 45-3532-7518; Fax: 45-3532-7537; E-mail: jjholst{at}sund.ku.dk.

Background: Glucose-dependent insulinotropic polypeptide (GIP) is pursued as an anti-obesity target.

Results: The adipocyte GIP receptor (GIPr) promotes high fat diet (HFD)-induced body weight gain by an increase in lean mass rather than fat mass in mice.

Conclusion: The adipocyte GIPr regulates both body weight and body composition.

Significance: Targeting the GIPr may have effects beyond lipid storage and acute glucose metabolism.

Abstract

The glucose-dependent insulinotropic polypeptide receptor (GIPr) has been implicated in high fat diet-induced obesity and is proposed as an anti-obesity target despite an uncertainty regarding the mechanism of action. To independently investigate the contribution of the insulinotropic effects and the direct effects on adipose tissue, we generated transgenic mice with targeted expression of the human GIPr to white adipose tissue or beta-cells, respectively. These mice were then cross-bred with the GIPr knock-out strain. The central findings of the study are that mice with GIPr expression targeted to adipose tissue have a similar high fat diet -induced body weight gain as control mice, significantly greater than the weight gain in mice with a general ablation of the receptor. Surprisingly, this difference was due to an increase in total lean body mass rather than a gain in total fat mass that was similar between the groups. In contrast, glucose-dependent insulinotropic polypeptide-mediated insulin secretion does not seem to be important for regulation of body weight after high fat feeding. The study supports a role of the adipocyte GIPr in nutrient-dependent regulation of body weight and lean mass, but it does not support a direct and independent role for the adipocyte or beta-cell GIPr in promoting adipogenesis.

Footnotes

↵* This work was supported by the Danish Medical Research Council, the Novo Nordisk Foundation, Fabrikant Vilhelm Pedersen og Hustrus Mindelegat, the Aase and Ejnar Danielsens Foundation, the Augustinus Foundation, the Becket Foundation, and Fonden til Laegevidenskabens Fremme.