Abstract 12522: Downregulation of Aryl-hydrocarbon Receptor Nuclear Translocator (ARNT) Exacerbates Cardiac Insulin Resistance After High Fat Diet
Introduction: Altered cardiac insulin sensitivity, substrate utilization, and energetics have been reported in diabetic cardiomyopathy. However, the mechanism behind insulin resistance in the heart in diabetes remain poorly understood. Hypoxia inducible factors (HIFs) have been linked to cellular metabolism, and their deletion in the heart resulted in metabolic changes. We have previously demonstrated that cardiac-specific knockout of ARNT, the obligatory binding partner of HIFs, causes spontaneous cardiomyopathy bearing similarity to diabetic cardiomyopathy, and its levels are reduced in genetic- and diet-induced obesity models. Here, we hypothesize that downregulation of ARNT in vivo exacerbates cardiac insulin resistance after high fat diet (HFD).
Results: Mice with cardiac-specific heterozygous deletion of ARNT (cs-ARNT+/-) had normal cardiac function at baseline, and had comparable food intake and weight gain during HFD treatment. We then evaluated cardiac substrate utilization using an ex vivo heart perfusion system. When perfused with a buffer without insulin, hearts from wild type (WT) and cs-ARNT+/- mice displayed comparable substrate utilization both after normal chow and after HFD. Addition of insulin to the perfusion system led to comparable increase in glucose utilization in hearts from normal chow-fed WT and ARNT+/- mice. However, the increased glucose utilization in response to insulin was attenuated in hearts from WT mice after HFD, while hearts from cs-ARNT+/- after HFD demonstrated virtually no increase in glucose utilization in response to insulin. This difference was not due to cardiac function as the cardiac work (assessed by heart rate and developing pressure) is comparable among all groups. Using neonatal rat cardiomyocytes, we also demonstrated that ARNT knockdown decreased glucose uptake and AKT phosphorylation in response to insulin, consistent with a blunted insulin-signaling pathway.
Conclusion: Cardiac-specific ARNT heterozygote deletion exacerbates insulin resistance in a diet-induced obesity model, and the reduction of ARNT levels in various mouse models of diabetes is likely be a maladaptive response. Therefore, increasing ARNT signaling can be a potential therapy for diabetic cardiomyopathy.
Author Disclosures: H. Chang: None. T. Sato: None. R. Wu: None. M. Shang: None. C. Chen: None. H. Ardehali: None.
- © 2016 by American Heart Association, Inc.