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

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

  • Cell Mol Gastroenterol Hepatol. 2022;13(4):1057-1072. doi: 10.1016/j.jcmgh.2021.12.004.
Raja Gopal Reddy Mooli 1 Dhanunjay Mukhi 1 Anil K Pasupulati 1 Simon S Evers 2 Ian J Sipula 1 Michael Jurczak 1 Randy J Seeley 2 Yatrik M Shah 3 Sadeesh K Ramakrishnan 4
Affiliations

Affiliations

  • 1 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 2 Department of Surgery, Ann Arbor, Michigan.
  • 3 Department of Molecular and Integrative Physiology, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
  • 4 Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: ramaks@pitt.edu.
Abstract

Background & aims: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords

GLP-1; GPR40; HIF-2α; L-Cells; Nutrient-Sensing.

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