Intestinal HIF-2α Regulates GLP-1 Secretion via Lipid Sensing in L-Cells

Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increas...

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Published in:Cellular and molecular gastroenterology and hepatology 2022-01, Vol.13 (4), p.1057-1072
Main Authors: Mooli, Raja Gopal Reddy, Mukhi, Dhanunjay, Pasupulati, Anil K., Evers, Simon S., Sipula, Ian J., Jurczak, Michael, Seeley, Randy J., Shah, Yatrik M., Ramakrishnan, Sadeesh K.
Format: Article
Language:English
Subjects:
Animals
Basic Helix-Loop-Helix Transcription Factors - genetics
Basic Helix-Loop-Helix Transcription Factors - metabolism
GLP-1
Glucagon-Like Peptide 1 - metabolism
GPR40
HIF-2α
Humans
Intestines
L Cells
Lipids
Mice
Nutrient-Sensing
Original Research
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Summary:Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells. We used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1α and HIF-2α (VhlΔIE), conditional overexpression of intestinal HIF-2α (Hif-2αLSL;Vilin-Cre/ERT2), and intestine-specific HIF-2α knockout mice (Hif-2αΔIE) to show that HIF signaling, especially HIF-2α, regulates GLP-1 secretion. Our data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1–dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein–coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2α regulates GPR40 in L-cells and potentiates fatty acid–induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2α, we show that HIF-2α is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2α signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2α decreases GLP-1 secretion. In summary, we show that intestinal HIF signaling, particularly HIF-2α, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2α is a potential target to induce endogenous GLP-1 secretion. [Display omitted]
ISSN:2352-345X
2352-345X
DOI:10.1016/j.jcmgh.2021.12.004