# PPARα induces IL-6 to trigger diabetic cardiomyopathy

> **NIH NIH R01** · RBHS-NEW JERSEY MEDICAL SCHOOL · 2022 · $559,031

## Abstract

Obesity is accompanied by elevated plasma free fatty acid (FFA), which, in turn, induces insulin resistance and
diabetes. More than half of diabetic patients develop myocardial dysfunction, known as diabetic
cardiomyopathy, characterized by left ventricular hypertrophy, fibrosis and diastolic dysfunction. Some patients
develop heart failure with preserved ejection fraction (HFpEF). Thus, elucidating the underlying molecular
mechanism of diabetic cardiomyopathy is critically important. The hearts of patients with obesity, insulin
resistance, type II diabetes, and HFpEF often develop a low grade of inflammation. Pro-inflammatory cytokines
and chemokines, including TNF-, IL-1, IL-6, and MCP-1, produced in adipose tissues, infiltrating
inflammatory cells, and local cell types, including endothelial cells and cardiomyocytes (CMs), play an essential
role in mediating fibrosis, hypertrophy, diastolic dysfunction and insulin resistance, thereby contributing to the
development of diabetic cardiomyopathy. However, which cell types produce cytokines during the initial phase
of diabetic cardiomyopathy and what the underlying mechanism is are poorly understood. Furthermore, the
significance of the local mechanisms compared to systemic inflammation remains to be clarified. Our
preliminary results suggest that FFA activates IL-6 production in CMs through a PPAR-NF-B-dependent
mechanism, which, in turn, promotes the development of diabetic cardiomyopathy. In this study, we will clarify
the role of PPAR and IL-6 in CMs in mediating cardiac dysfunction in response to high fat diet (HFD)
consumption and the molecular mechanisms through which elevated FFA stimulates IL-6 in CMs. Our overall
hypotheses are: PPAR in CMs is a sensor of increased FFA that triggers diabetic cardiomyopathy through
production of IL-6. Increases in plasma FFA directly stimulates IL-6 transcription in CMs through increased
binding of PPAR-NF-B heterodimer to the NF-B element located in the IL-6 promoter. IL-6 produced in
CMs acts as an autocrine/paracrine factor to induce diabetic cardiomyopathy. Aim 1: Elucidate the role of
cardiac endogenous PPAR and IL-6 in mediating the initial development of diabetic cardiomyopathy. Aim 2:
Elucidate the molecular mechanism by which PPARstimulates transcription of IL-6 in CMs. Aim 3: Evaluate
whether suppression of PPAR-NF-B heterodimer formation inhibits CM production of IL-6 and the
development of diabetic cardiomyopathy in response to HFD consumption. We will address these issues using
newly generated CM-specific loss-of-function mouse models. In addition, we will obtain a proof-of-concept that
PPAR-NF-B heterodimer is a novel therapeutic target for diabetic cardiomyopathy. We expect that our study
should demonstrate a novel mechanism stimulating local innate production of IL-6 in CMs and its role in
mediating the initial development of diabetic cardiomyopathy which is highly relevant to many patients with
obesity and borderline metabo...

## Key facts

- **NIH application ID:** 10317052
- **Project number:** 5R01HL150881-03
- **Recipient organization:** RBHS-NEW JERSEY MEDICAL SCHOOL
- **Principal Investigator:** Junichi Sadoshima
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,031
- **Award type:** 5
- **Project period:** 2019-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317052

## Citation

> US National Institutes of Health, RePORTER application 10317052, PPARα induces IL-6 to trigger diabetic cardiomyopathy (5R01HL150881-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10317052. Licensed CC0.

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