Transgenic rescue of adipocyte glucose-dependent insulinotropic polypeptide receptor expression restores high fat diet-induced body weight gain

TY - JOUR

T1 - Transgenic rescue of adipocyte glucose-dependent insulinotropic polypeptide receptor expression restores high fat diet-induced body weight gain

AU - Ugleholdt, Randi

AU - Pedersen, Jens

AU - Bassi, Maria Rosaria

AU - Füchtbauer, Ernst-Martin

AU - Jørgensen, Signe Marie

AU - Kissow, Hannelouise

AU - Nytofte, Nikolaj

AU - Poulsen, Steen Seier

AU - Rosenkilde, Mette Marie

AU - Seino, Yutaka

AU - Thams, Peter

AU - Holst, Peter Johannes

AU - Holst, Jens Juul

PY - 2011/12/30

Y1 - 2011/12/30

N2 - 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.

AB - 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.

KW - Adipocytes

KW - Adipogenesis

KW - Animals

KW - Dietary Fats

KW - Gastric Inhibitory Polypeptide

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Mice

KW - Mice, Knockout

KW - Obesity

KW - Receptors, Gastrointestinal Hormone

KW - Receptors, Peptide

KW - Transgenes

KW - Weight Gain

U2 - 10.1074/jbc.M111.311779

DO - 10.1074/jbc.M111.311779

M3 - Journal article

C2 - 22027838

SN - 0021-9258

VL - 286

SP - 44632

EP - 44645

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 52

ER -