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 1

Structure of the Agrp gene and mRNA variants.

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Structure of the Agrp gene and mRNA variants. (A) The exon-intron struct...
(A) The exon-intron structure is shown schematically for the Agrp gene and its mRNA variants. Coding exons are shaded in gray. Each of the first exons (1A, 1B, and 1C) is presented in a different shade. The size of each intron is indicated below the intron. Each mRNA variant is presented with its included exons. Note that transcript C has an alternatively spliced exon (1C′). The number of spliced transcripts found from RNA-Seq studies, as reported in the NCBI Genome Data Viewer, is presented in italic text at the intron positions. Unfortunately, there are no data regarding the number of reads corresponding to intron-spanning reads that include exon A. (B) Results of mRNA variant–specific amplification from hypothalamic block RNA isolated from an adult male mouse. Total AGRP represents amplification for all AGRP mRNA variants, and each subsequent lane represents amplification for mRNA variants A–C.