PPARα–NF-κB heterodimer mediates obesity-induced diastolic dysfunction through autocrine production of IL-6
Year: 2026
Type: article
Abstract: Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and patients with obesity often develop cardiac hypertrophy and diastolic dysfunction, termed obesity cardiomyopathy. Proinflammatory cytokines, including IL-6, have been implicated in the pathogenesis of the cardiac dysfunction associated with obesity cardiomyopathy. Elevation of FFAs induced by high-fat diet (HFD) consumption induced diastolic dysfunction in the heart as early as after 1 month. HFD consumption directly stimulated IL-6 production in cardiomyocytes before local inflammation developed and induced diastolic dysfunction even in the presence of macrophage depletion with clodronate in the heart. PPARα played an essential role in mediating Il6 transcription in response to HFD consumption by forming a heterodimer with p50/RelA and binding to the NF-κB element in cardiomyocytes. Local production of IL-6 in cardiomyocytes, in turn, mediated the development of diastolic cardiac dysfunction. HFD-induced diastolic dysfunction was attenuated by cardiac-specific deletion of either Pparα or Il6, as well as by interference with the PPARα-NF-κB heterodimer formation by a molecular decoy. These results suggest elevated FFA levels directly upregulate Il6 through the PPARα-NF-κB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.
DOI: 10.1172/jci196238
Authors: Shin-ichi Oka, Eun-Ah Sung, Peiyong Zhai, Kevin B. Schesing, Santosh Bhat, Adave Chin, Jiyeon Park, Yeun-Jun Chung, Akihiro Shirakabe, Takanobu Yamamoto, Yoshiyuki Ikeda, Wataru Mizushima, Shohei Ikeda, Mingming Tong, Jaemin Byun, Michinari Nakamura, Samuel I. Kim, Jamie Francisco, Dominic P. Del Re, Junichi Sadoshima
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,200
Awards: G2295955150, G2348369761, PPARα induces IL-6 to trigger diabetic cardiomyopathy, G3129730382, G3134850677, FoxO1 protects the heart against ischemia, G3642352218, Modulating autophagy to treat cardiovascular disease, G3777667531, G4101633970, Removal of damaged mitochondria by alternative autophagy, G4258677604, REGULATION OF MYOCARDIAL GROWTH AND DEATH BY THE HIPPO PATHWAY, G5059533426, Cardioprotective effects of thioredoxin 1, Prevention myocardial injury by inhibition of autosis, G5804956950, G5806494660, G6269310686, Regulation of myocardial growth and death by autophagy, G6888827278, G7384925648, G7809128723, G8170205523, Pathogenic role of cardiomyocyte-initiating inflammatory signaling in diastolic heart failure, G8759340591, G8842179039, G9000069824, G9000200129, G9000214159
OpenAlex ID: W7128705268