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 2

Regulation of AGRP mRNA variants by fasting, leptin, and the bile acid taurocholic acid.

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Regulation of AGRP mRNA variants by fasting, leptin, and the bile acid t...
RNA from the hypothalamic blocks, including the median eminence and pars tuberalis, was used to detect and quantify the amounts of the 3 AGRP mRNA variants by quantitative RT-PCR with mRNA variant–specific assays. (A) Mice were fasted for more than 20 hours or fed ad libitum, and sacrificed between 10 am and 12 pm. (B) We compared the concentrations of AGRP mRNAs in leptin-deficient (ob/ob) male mice versus wild-type males. In A and B, note the greater amount of AGRP-A mRNA in fasted and ob/ob mice. (C) We used male mice that had been gavaged with taurocholate (TC) for 5 days with controls gavaged with saline. Note the reduced amount of AGRP-B mRNA in taurocholate-treated mice. All groups had 4–5 male mice except for A with 15 fed and 12 fed mice. #P < 0.05, 1-tailed t test. Relative mRNA concentrations are reported as ΔΔCt values.