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 4

An Agrp-B-FLP knockin/knockout allele is expressed in the pars tuberalis.

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An Agrp-B-FLP knockin/knockout allele is expressed in the pars tuberalis...
(A) Schematic representation of the Agrp-B-FLP knockin/knockout allele. The FLP recombinase coding sequence followed by a polyadenylation signal was introduced into exon 1B of Agrp. The polyadenylation signal acts as a transcription stop, preventing the production of AGRP-B mRNA that includes the Agrp coding exons. (B) Visualization of expression of Agrp-B with FLP-dependent expression of tdTomato (native fluorescence in red) from a female Agrp-B-FLP FSF-tdTomato mouse that is localized to the pars tuberalis (PT). A yellow arrow points to a cord of tdTomato cells that traverses the median eminence (ME) to end in the zone directly below the floor of the third ventricle (3V). Scale bars: 100 μm and 20 μm. (C) Imaging of a male Agrp-B-FLP FSF-tdTomato Npy-GFP mouse with GFP native fluorescence in green and tdTomato fluorescence in red. Note that the AGRP tdTomato signal is localized to the pars tuberalis while the Npy-GFP signal is localized to the arcuate nucleus (ARC). (D) Native fluorescence imaging from a male Agrp-B-FLP Agrp-IRES-Cre Ai193 mouse with FLP activating tdTomato in red and Cre activating GFP in green. The AGRP-B tdTomato red signal is localized to the pars tuberalis, while the AGRP-GFP green signal is apparent in both the pars tuberalis and the ARC. The tdTomato and GFP signals in the pars tuberalis are co-incident. The GFP signal of the pars tuberalis is above the background signal but is much weaker than in the ARC. All sections were imaged at ×200 and mounted in DAPI-containing medium.