PPARα-NFκB heterodimer mediates obesity-induced diastolic dysfunction through autocrine production of IL-6

Obesity is accompanied by increases in free fatty acids (FFAs) in the systemic circulation, and obese patients 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 one 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 NFκB 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 Ppara or Il6, as well as by interference with the PPARα-NFκB heterodimer formation by a molecular decoy. These results suggest that elevated FFAs directly upregulate Il6 through the PPARα-NFκB heterodimer in cardiomyocytes and highlight autocrine production of IL-6 as a key downstream mechanism in the initial development of diastolic dysfunction.