Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure
Tanya Hansotia, Adriano Maida, Grace Flock, Yuichiro Yamada, Katsushi Tsukiyama, Yutaka Seino, Daniel. J. Drucker
Tanya Hansotia, Adriano Maida, Grace Flock, Yuichiro Yamada, Katsushi Tsukiyama, Yutaka Seino, Daniel. J. Drucker
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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 7

Chronic exposure of WT mice to incretin receptor agonists.

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Chronic exposure of WT mice to incretin receptor agonists. WT mice were ...
WT mice were maintained on HF diet starting from 6 weeks of age. After 4 weeks of HFF, mice were administered either PBS or 24 nmol/kg [D-Ala2]GIP or Ex-4 twice daily for 2 weeks, after which body fat composition was assessed by MRI. Mice were euthanized 1 hour after the last injection of PBS or peptide, and cardiac blood was collected. (A) Total body fat mass normalized to body weight (n = 8–19 per group). (B and C) Ambient levels of (B) plasma leptin and (C) plasma resistin in HF diet–fed WT mice treated twice daily with either [D-Ala2]GIP or Ex-4 (n = 8–19 per group). **P < 0.01 versus PBS; ΧP < 0.05, ΧΧΧP < 0.001 versus [D-Ala2]GIP; #P < 0.05 versus Ex-4.