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 5

AGRP-B colocalizes with some markers for the pars tuberalis.

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AGRP-B colocalizes with some markers for the pars tuberalis. (A–C) We pe...
(A–C) We performed immunostaining for PITX1, CGA, and DAGLB from sections of the brains of Agrp-B-FLP Ai193 mice to determine colocalizations of these pars tuberalis markers with AGRP-B. There is perfect co-incidence between the PITX1 and AGRP-B tdTomato signals in A. In B, the AGRP-B tdTomato signal colocalizes with the CGA signal, although there are some CGA-positive cells that are not tdTomato labeled. Similarly, the DAGLB signal is co-incident with the AGRP-B signal, but there are some areas that are exclusively DAGLB-positive without AGRP-B. Orange arrows point to cells that show labeling for AGRP-B and CGA or DAGLB. (D) Native fluorescence from the brain of an Agrp-B-FLP Cck-IRES-Cre Ai193 mouse with Agrp-B-FLP activating tdTomato (red) and Cck-IRES-Cre activating GFP (green). There is no colocalization of the tdTomato signal with the GFP signal. (E and F) Colocalization of AGRP-ir with the tdTomato fluorescence induced by Agrp-B-FLP with an Agrp-B-FLP Ai193 male in E and an Agrp-B-FLP/Agrp-B-FLP Ai193 (Agrp-B–KO Ai193) male in F. There is extensive colocalization of AGRP-ir and tdTomato fluorescence in both genotypes. All images were taken of 50 μm sections at ×200. Scale bars: 20 μm in B, 50 μm in A, C, D, and E and 200 μm in F.