# Role of Hypoxia-inducible factor-2a in L-cell nutrient sensing and metabolic homeostasis

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $459,942

## Abstract

In type 2 diabetic patients, glucagon-like peptide (GLP)1-based therapies profoundly lower
hyperglycemia without hypoglycemic risk. However, adverse intestinal events with these
therapies limit dose escalations and decrease patient compliance. Studies show that
endogenous GLP1 do not cause such intestinal events and yield superior metabolic effects.
Despite such evidence, no GLP1 secretagogue targeting L-cells is available due to a gap in
understanding GLP1 secretory mechanisms. Our preliminary data show that intestinal hypoxia-
inducible factor (HIF) signaling enhances GLP1 secretion in mice and improves glucose
tolerance in a GLP1-dependent manner. We found that intestinal HIF, particularly HIF-2α,
potentiates fatty acid-stimulated GLP1 secretion by inducing the expression of the lipid sensor
G-protein coupled receptor (GPR) 40, enriched in intestinal L-cells. Given that nutrients regulate
GLP1 secretion, our study investigates whether intestinal HIF-2α signaling links dietary cues
with GLP1 secretion via a nutrient-sensing mechanism and elucidates its metabolic implications.
In support, we show that disruption of intestinal HIF-2α in mice reduces GPR40 expression and
decreases GLP1 levels. Moreover, acute inhibition of HIF-2α during fasting attenuates GPR40
expression and abolishes lipid-stimulated GLP1 secretion, demonstrating a novel role of
intestinal HIF-2α in postprandial GLP1 secretion. We identified an altered flux of TCA metabolite
α-ketoglutarate (α-KG) is associated with the induction of HIF-2α signaling in epithelial cells.
Thus, Aim 1 will elucidate whether epithelial metabolic flux dynamically regulates L-cell HIF-2α
signaling. And Aim 2 will determine the molecular mechanism by which HIF-2α regulates GLP1
secretion. Our data show that activation of intestinal HIF-2α attenuates diet-induced glucose
intolerance and hepatic steatosis, associated with elevated GLP1 levels. Given that elevated
postprandial GLP1 ameliorates glucose intolerance, Aim 3 will test our postulation that L-cell
HIF2α will protect against diet-induced metabolic perturbations by elevating GLP1 levels using
mice with gain or loss of HIF-2α in L-cells. Lastly, we will establish whether activating HIF-2α
will induce GLP1 in humans using the human intestinal organoid system. Given that potent HIF-
2 inducers are available understanding the role of intestinal HIF-2α in nutrient sensing and
metabolic homeostasis may lead to novel strategies to induce endogenous GLP1 secretion in
metabolic diseases.

## Key facts

- **NIH application ID:** 10501449
- **Project number:** 1R01DK133406-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Sadeesh Kumar Ramakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $459,942
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501449

## Citation

> US National Institutes of Health, RePORTER application 10501449, Role of Hypoxia-inducible factor-2a in L-cell nutrient sensing and metabolic homeostasis (1R01DK133406-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10501449. Licensed CC0.

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