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.
View: Text | PDF
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.

×

Figure 8

Acute inhibition of AGRP-B–expressing cells results in long-lasting improvement in glucose tolerance by restoring glucose-stimulated insulin secretion.

Options: View larger image (or click on image) Download as PowerPoint
Acute inhibition of AGRP-B–expressing cells results in long-lasting impr...
(A) oGTTs after chemogenetic inhibition of AGRP-B cells with Compound 21 activation of hM4Di in Agrp-B-FLP Agrp-IRES-Cre RC:FPDi mice. Male mice (n = 5, 8–10 months old) on chow were tested before and after Compound 21 treatment for 5 days. Chemogenetic inhibition of AGRP-B cells caused reduction in glucose concentrations at all time points after glucose load. (B) FPDi-negative control littermate males were similarly tested before and during Compound 21 treatment (n = 3, 8–10 months old, on chow). Compound 21 had no effect on glucose tolerance. (C) Insulin concentrations during GTT at times 0 and 15 minutes after glucose load. Before Compound 21 treatment, mice had no apparent increase in insulin secretion, whereas Compound 21 treatment produced an excellent increase in insulin secretion upon glucose loading. (D) Results of an extended testing period for the same mice with an additional 5-day period of Compound 21 treatment followed by a washout of 6 weeks. In B and C, each mouse is represented by its own colored line and/or symbol. oGTTs and body weights were followed over the course of the extended testing. The additional Compound 21 treatment did not result in any additional improvement in glucose tolerance. At 2 weeks and 6 weeks after cessation of Compound 21, mice retained their improved glucose tolerance. Similarly, body weights remained below starting weights after Compound 21 treatment and remained at this reduced level after cessation of Compound 21. We also examined the impact of inhibiting AGRP-B cells in young male mice (on high-fat diet) (n = 5, 3 months old). (E) Younger male Agrp-B-FLP Agrp-IRES-Cre RC:FPDi mice also show improvement in oral glucose tolerance with chemogenetic inhibition of AGRP-B cells (4 weeks old at initiation of high-fat feeding). The males were on a 60% fat diet 4 weeks before glucose testing. Also shown are body weight gains during 4-day intervals before and during Compound 21 treatment. Four of the five animals showed a reduction in body weight gain (P = 0.68, 1-way paired t test). #P < 0.05, 1-tailed paired t test. @ denotes the given P value of a 1-way paired t test.