# Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $694,067

## Abstract

ABSTRACT
Intermittent fasting and caloric restriction are newly identified therapeutic interventions against cardiometabolic
disease. Our laboratory discovered that activating the hepatic glucose fasting response is sufficient to convey
several of the key therapeutic effects of generalized caloric restriction. This is clinically relevant because
targeting hepatic glucose transport is highly amenable to small-molecule and nutraceutical therapy. Therefore,
our long-term goal is to understand adaptive liver glucose metabolism during fasting to produce new therapies
that leverage these pathways against cardiometabolic disease.
Intermittent fasting in rodents blocks pathological remodeling and infarct expansion after myocardial infarction,
and treating mice with FGF21 – a liver-derived peptide hormone secreted in response to fasting – prevents
experimental cardiac left ventricular hypertrophy (LVH) and LV dysfunction. We demonstrated that blocking
hepatic glucose transport using the naturally occurring disaccharide, trehalose, recapitulates the hepatic
adaptive fasting response. Our new data now demonstrate that oral trehalose recapitulates the effects of
intermittent fasting on cardiac protection against pathological remodeling. Specifically, trehalose induces hepatic
FGF21, and prevents pathological LVH and LV dysfunction in response to chronic pressure overload. We also
identified a novel trehalose analog that resists degradation by host and microbial metabolism, and which
activates hepatic fasting-like signal transduction to a greater extent than native trehalose. This study’s objective
is thus to define mechanisms and contexts of cardioprotection by trehalose-class compounds as a prelude to
the use of these compounds in human trials. Our central hypothesis is that hepatic GLUT inhibition blocks LVH
and LVD by activating canonical hepatic fasting signals to the myocardium.
We propose three Specific Aims to test this hypothesis. In Aim 1, we will delineate mechanisms by which
trehalose prevents LVH and LVD. In Aim 2, we define pathophysiological contexts in which trehalose attenuates
secondary cardiomyopathies. In Aim 3, we examine the impact of trehalose catabolism on its efficacy against
secondary cardiomyopathies.
The innovation of this proposal is that we our team has identified and will examine further: 1) a novel and
tractable cardioprotective pathway, and 2) a novel compound class that activates this cardioprotective pathway.
Completing these aims will define how hepatocyte fasting responses protect from pathological remodeling and
dysfunction; and nominate specific clinical contexts in which the adaptive hepatic fasting response is
cardioprotective. The impact of this work is that it will mechanistically inform next-generation glucose fasting-
mimetics, which also leverage the adaptive fasting response against cardiac disease, and will justify further
efforts toward clinical trials that utilize trehalose-class compounds to ameliorate second...

## Key facts

- **NIH application ID:** 10049131
- **Project number:** 1R01HL147968-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Brian Jesse DeBosch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $694,067
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10049131

## Citation

> US National Institutes of Health, RePORTER application 10049131, Treating secondary cardiomyopathies by mimicking the adaptive hepatic glucose fasting response (1R01HL147968-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10049131. Licensed CC0.

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