The gut signals to AGRP-expressing cells of the pituitary to control glucose homeostasis
Shun-Mei Liu, Bruno Ifebi, Fred Johnson, Alison Xu, Jacquelin Ho, Yunlei Yang, Gary Schwartz, Young Hwan Jo, Streamson Chua Jr.
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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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 6

AGRP-B expression in the anterior lobe of the pituitary.

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AGRP-B expression in the anterior lobe of the pituitary. (A) Cells expre...
(A) Cells expressing Agrp-B induced tdTomato fluorescence in the anterior pituitary of a female Agrp-B-FLP Ai193 mouse (original magnification, ×400). There is extensive tdTomato fluorescence in star-shaped cells that are distinctly separate from discrete, rounded CGA-ir hormone-expressing cells. An orange arrow in the merged image points to a double-labeled cell (AGRP-B+CGA+). The pars nervosa has very weak, if any, tdTomato fluorescence. Scale bars: 50 μm. (B and C) Immunoreactivity for S100b (B) and SOX2 (C) in star-shaped cells of the anterior lobe that show extensive codistribution with the tdTomato label of a female Agrp-B-FLP Ai193 mouse. Scale bars: 100 μm. (D) Extensive labeling of FGFR1-ir with tdTomato-labeled star-shaped cells in the anterior lobe of a male Agrp-B-FLP Ai193 mouse. Scale bars: 50 μm. (E) A 5-day taurocholate (TC) treatment could significantly reduce AGRP-B mRNA in the pituitary of 2- to 3-month-old male mice (P < 0.02, n = 6 per group). #P < 0.05, 1-tailed t test.