# Dissecting the role of hepatocyte Notch receptors in obesity-driven metabolic disease.

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $253,565

## Abstract

Project Abstract
With the increasing prevalence of obesity, the health burden of obesity-driven diseases such as
type 2 diabetes (T2D) has risen markedly. T2D is now one of the most prevalent diseases
worldwide and exacts a tremendous toll population-wide in terms of decreased lifespan and
health-span. In T2D, hyperglycemia follows from impairment in pancreatic beta-cell insulin
production and insulin resistance in the liver and other metabolically active tissues.
Pioneering research from the Pajvani laboratory has implicated obesity-driven reactivation of the
Notch signaling pathway, previously thought to be only active during development and
organogenesis, as a crucial driver of hepatic insulin resistance. Forced activation of hepatocyte
Notch pathway signaling in mouse models is sufficient to cause glucose intolerance in chow-fed
mice. In contrast, overexpression of upstream components of Notch pathway signaling in
hepatocytes does not cause hyperglycemia unless an obesogenic diet is also provided,
implicating other, as yet unknown, nodes in the Notch pathway in the propagation of
maladaptive signals in obesity. In this grant application, I propose to identify the Notch pathway
receptors involved in obesity-driven metabolic disease. The work I propose builds on preliminary
experimental data from mice indicating that Notch2 is responsible for Notch activity in T2D, as
well an unexpected protective role for Notch1, which appears to be mediated by a paradoxical
increase in Notch2 protein followed by Notch1 depletion. I will investigate the impact of
hepatocyte-specific deletion of Notch2 on diet-driven development of hyperglycemia (Aim 1A)
and confirm in vitro whether this occurs in a hepatocyte-autonomous fashion (Aim 1B). I will
study the unexpected homeostatic role of Notch1 on Notch pathway activity in models of T2D
through hepatocyte-specific Notch1 deletion and Notch1-Notch2 double deletion to determine
epistasis between Notch1 and Notch2 (Aim 2A). Finally, I will use immunoprecipitation of
Notch2 followed by targeted western blotting as well as mass spectrometry to dissect the
mechanism by which Notch1 depletion leads to increased Notch2 protein (Aim 2B). Together,
our proposed work will clarify key steps in the transmission and regulation of Notch pathway
signals that drive metabolic dysfunction in obesity.

## Key facts

- **NIH application ID:** 11029703
- **Project number:** 3R01DK132661-03S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Utpal Pajvani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $253,565
- **Award type:** 3
- **Project period:** 2024-07-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11029703

## Citation

> US National Institutes of Health, RePORTER application 11029703, Dissecting the role of hepatocyte Notch receptors in obesity-driven metabolic disease. (3R01DK132661-03S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11029703. Licensed CC0.

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