Reduced fatty acid uptake aggravates cardiac contractile dysfunction in streptozotocin-induced diabetic cardiomyopathy

Yogi Umbarawan,Hiroki Matsui,Hiroaki Sunaga,Takako Hishiki,Aiko Yamaguchi,Tatsuya Iso,Norimichi Koitabashi,Ryo Kawakami,Noriyo Hayakawa,Mas Rizky A A Syamsunarno,Hideru Obinata,Hirofumi Hanaoka,Masahiko Kurabayashi

doi:10.1038/s41598-020-77895-1

Yogi Umbarawan, Hiroki Matsui + Show 11 more

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https://doi.org/10.1038/s41598-020-77895-1

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Abstract

Diabetes is an independent risk factor for the development of heart failure. Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. We studied whether reduced FA uptake in the heart is protective against streptozotocin (STZ)-induced diabetic cardiomyopathy by using mice doubly deficient in fatty acid binding protein 4 (FABP4) and FABP5 (DKO mice). Cardiac contractile dysfunction was aggravated 8 weeks after STZ treatment in DKO mice. Although compensatory glucose uptake was not reduced in DKO-STZ hearts, total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. Tracer analysis with 13C6-glucose revealed that accelerated glycolysis in DKO hearts was strongly suppressed by STZ treatment. Levels of ceramides, cardiotoxic lipids, were similarly elevated by STZ treatment. These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Thus, enhanced FA uptake in diabetic hearts seems to be a compensatory response to reduced energy supply from glucose, and therefore, limited FA use could be detrimental to cardiac contractile dysfunction due to energy insufficiency.

Highlights

Diabetes is an independent risk factor for the development of heart failure
These findings suggest that contractile dysfunction in double knockout (DKO)-STZ mice is more prominent compared to that in WT-STZ cardiac atrophy is induced by STZ in both mice to a similar extent
We examined effects of diabetes on uptake of 18F-FDG, glucose tracer. 18F-FDG uptake was 20-fold higher in DKO hearts compared to WT at baseline to compensate for reduced fatty acid (FA) uptake (Fig. 2C). 18F-FDG uptake was not changed by STZ treatment in both groups in the fasted state (Fig. 2C)

Summary

Introduction

Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. Cardiotoxic lipids, were elevated by STZ treatment These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Cardiac dysfunction in DKO-TAC mice is associated with a reduction in total energy supply relative to energy demand, which is partially rescued by supplementation of medium chain FA These findings provided an important notion that long chain FA are pivotal fuels to generate sufficient energy for preserved cardiac contraction under increased workload and not toxic for pressure-overloaded hearts. We demonstrated that FABP4/5 DKO hearts are a useful model to evaluate contribution of reduced FA utilization to pathophysiology of heart failure m odels[18,19]

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