Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure
Tanya Hansotia, … , Yutaka Seino, Daniel. J. Drucker
Tanya Hansotia, … , Yutaka Seino, Daniel. J. Drucker
Published January 2, 2007
Citation Information: J Clin Invest. 2007;117(1):143-152. https://doi.org/10.1172/JCI25483.
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Research Article Metabolism

Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure

Abstract

The incretin hormones glucagon-like peptide–1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) control glucose homeostasis through well-defined actions on the islet β cell via stimulation of insulin secretion and preservation and expansion of β cell mass. We examined the importance of endogenous incretin receptors for control of glucose homeostasis through analysis of Glp1r–/–, Gipr–/–, and double incretin receptor knockout (DIRKO) mice fed a high-fat (HF) diet. DIRKO mice failed to upregulate levels of plasma insulin, pancreatic insulin mRNA transcripts, and insulin content following several months of HF feeding. Both single incretin receptor knockout and DIRKO mice exhibited resistance to diet-induced obesity, preservation of insulin sensitivity, and increased energy expenditure associated with increased locomotor activity. Moreover, plasma levels of plasminogen activator inhibitor–1 and resistin failed to increase significantly in DIRKO mice after HF feeding, and the GIP receptor agonist [D-Ala2]GIP, but not the GLP-1 receptor agonist exendin-4, increased the levels of plasma resistin in studies of both acute and chronic administration. These findings extend our understanding of how endogenous incretin circuits regulate glucose homeostasis independent of the β cell via control of adipokine secretion and energy expenditure.

Authors

Tanya Hansotia, Adriano Maida, Grace Flock, Yuichiro Yamada, Katsushi Tsukiyama, Yutaka Seino, Daniel. J. Drucker

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Figure 3

DIRKO mice are protected from HF diet–induced insulin resistance.

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DIRKO mice are protected from HF diet–induced insulin resistance. (A) Gl...
(A) Glucose levels during an insulin tolerance test in RC- and HF diet–fed WT and DIRKO mice (n = 8–9 per group). After 19 weeks of HFF, WT and DIRKO mice were fasted for 5 hours and subsequently injected with 1.2 U/kg insulin. Blood glucose levels were monitored for 4 hours following insulin administration. (B) Glucose levels during an insulin tolerance test expressed as percentage of baseline blood glucose values in WT and DIRKO mice. (C) Quantification of AUC for the total glycemic excursions in A and AUC normalized to fat mass. (D) Weights of total body fat and lean mass normalized to body weight (n = 8–9 per group) in WT and DIRKO mice fed RC or HF diet for 19 weeks as assessed by MRI. (E) Weights of perirenal, epididymal, and inguinal fat pads normalized to body weight (n = 8–12 per group). (F) Weight of brown adipose tissue (BAT) normalized to body weight (n = 8–12 per group). (G–I) Histological analyses of (G) liver, (H) epididymal white adipose tissue (WAT), and (I) brown adipose tissue from WT and DIRKO mice fed RC or HF diet. Sections were stained with H&E. Original magnification, ×200. *P < 0.05, **P < 0.01, ***P < 0.001 versus WT-RC; ###P < 0.001 versus WT-HF; ΧΧP < 0.01, ΧΧΧP < 0.001 versus DIRKO-RC.