The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis
Shun-Mei Liu, … , Young Hwan Jo, Streamson Chua Jr.
Shun-Mei Liu, … , Young Hwan Jo, Streamson Chua Jr.
Published February 14, 2023
Citation Information: J Clin Invest. 2023;133(7):e164185. https://doi.org/10.1172/JCI164185.
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Research Article Endocrinology Metabolism

The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis

Abstract

Glucose homeostasis can be improved after bariatric surgery, which alters bile flow and stimulates gut hormone secretion, particularly FGF15/19. FGFR1 expression in AGRP-expressing cells is required for bile acids’ ability to improve glucose control. We show that the mouse Agrp gene has 3 promoter/enhancer regions that direct transcription of each of their own AGRP transcripts. One of these Agrp promoters/enhancers, Agrp-B, is regulated by bile acids. We generated an Agrp-B knockin FLP/knockout allele. AGRP-B–expressing cells are found in endocrine cells of the pars tuberalis and coexpress diacylglycerol lipase B — an endocannabinoid biosynthetic enzyme — distinct from pars tuberalis thyrotropes. AGRP-B expression is also found in the folliculostellate cells of the pituitary’s anterior lobe. Mice without AGRP-B were protected from glucose intolerance induced by high-fat feeding but not from excess weight gain. Chemogenetic inhibition of AGRP-B cells improved glucose tolerance by enhancing glucose-stimulated insulin secretion. Inhibition of the AGRP-B cells also caused weight loss. The improved glucose tolerance and reduced body weight persisted up to 6 weeks after cessation of the DREADD-mediated inhibition, suggesting the presence of a biological switch for glucose homeostasis that is regulated by long-term stability of food availability.

Authors

Shun-Mei Liu, Bruno Ifebi, Fred Johnson, Alison Xu, Jacquelin Ho, Yunlei Yang, Gary Schwartz, Young Hwan Jo, Streamson Chua Jr.

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Figure 7

AGRP-B is involved in developing glucose intolerance during high-fat feeding.

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AGRP-B is involved in developing glucose intolerance during high-fat fee...
(A) Oral glucose tolerance tests (oGTTs) of Agrp-B–KO (Agrp-B-FLP/Agrp-B-FLP) male mice and control littermates on normal chow and a 60% fat by calorie diet (n = 5, 2–3 months old at the start of the study, 28 days on high-fat diet [HFD]). Mice were tested on chow at 2 months of age, placed on HFD for 4 weeks, and retested at 3 months of age. Note that mice of the 2 genotypes were not different when fed chow whereas only the control mice became glucose intolerant when fed the HFD. (B) Body weights at the start and conclusion of the study, with both groups of mice gaining equivalent body masses on HFD. Also shown are the areas under the curve (AUCs) for the 2 genotypes on chow and HFD, with only the control siblings increasing their AUCs during the GTT while the AGRP-B–deficient mice showed no alteration despite gaining weight. (C) The effect of taurocholate (TC) on Agrp-B–KO (Agrp-B-FLP/FLP) mice on HFD (n = 6 males, 50 days on HFD, 5 days of taurocholate treatment). There is a small but significant improvement in glucose tolerance after taurocholate gavage of Agrp-B–KO mice, based on an analysis of the AUCs. #P < 0.05, 1-tailed paired t test.