ATGL From iWAT and BAT Is Crucial for Cardiac Remodeling and Metabolism After Myocardial Ischemia/Reperfusion

TL;DR

This study shows that ATGL in white and brown fat is essential for protecting the heart after a heart attack and reperfusion.

Contribution

The study reveals a depot- and time-specific role of adipocyte ATGL in cardiac ischemia/reperfusion injury.

Findings

iatATGL-KO mice showed worsened cardiac function and increased scar formation after I/R.

ATGL deficiency reduced BAT activation and adiponectin secretion, contributing to worse outcomes.

Remote myocardium in iatATGL-KO mice exhibited higher oxygen consumption and mechanical stress.

Abstract

Adipose tissue ATGL has emerged as an important player in cardiovascular disease. Myocardial infarction is accompanied by sympathetic stimulation and activation of white adipose tissue and peripheral lipolysis. We therefore investigate here the role of adipocyte ATGL in a murine model of cardiac ischemia and reperfusion (I/R) by using an inducible, adipocyte specific KO of ATGL (iatATGL‐KO). Notably this led to successfully inhibited lipolysis during cardiac ischemia, and KO mice exhibited aggravated cardiac dysfunction and enhanced scar formation after 28 days I/R. This phenotype went along with multiple structural and molecular alterations mainly in the subcutaneous white adipose tissue depot (iWAT) and brown adipose tissue (BAT). The iatATGL‐KO mainly reduced BAT activation as well as adiponectin‐secretion. In the heart spatial transcriptomic analysis suggested higher mechanical stress in the remote myocardium, which went along with higher oxygen consumption rates (OCR) and higher dependency on glucose as substrate after 24 h I/R. Taken together, iatATGL‐KO hearts after I/R seem to be affected in multiple ways, such as a reduction in cardioprotective factors from iWAT and BAT as well as an oxygen wasting effect in the remote zone of the heart, which contribute to the worse outcome. This indicates a time and depot‐specific role of adipocyte ATGL in cardiac ischemia and reperfusion injury.

Cardiac I/R activates adipose tissue. iatATGL‐KO increases adipocyte size and reduces lipogenesis in WAT, induces whitening and inflammation in BAT, and reduces circulating NEFA and adiponectin levels. As a consequence, cardiac function is reduced, scar formation enhanced, and remote myocardium shows elevated mechanical stress and oxygen consumption.

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