Adipocyte KO of adipose triglyceride lipase (ATGL) aggravates cardiac dysfunction post-MI by increasing scar formation and inducing mechanical stress in the remote zone

H. Zabri (Düsseldorf)¹, A. Ucar (Düsseldorf)¹, L. Wang (Düsseldorf)², S. Gorreßen (Düsseldorf)³, T. Lautwein (Düsseldorf)⁴, M. Balan (Düsseldorf)¹, S. Lehr (Düsseldorf)⁵, A. Heinen (Düsseldorf)⁶, A. Gödecke (Düsseldorf)⁶, J. W. Fischer (Düsseldorf)⁷, K. Bottermann (Düsseldorf)^3
1Düsseldorf, Deutschland; ²Institute of Pharmacology Düsseldorf, Deutschland; ³Universitätsklinikum Düsseldorf Institut für Pharmakologie Düsseldorf, Deutschland; ⁴Heinrich-Heine-Universität Düsseldorf Biologisch-Medizinisches Forschungszentrum (BMFZ) Düsseldorf, Deutschland; ⁵DDZ- Deutsches Diabetes-Zentrum Institut für Klinische Biochemie und Pathobiochemie Düsseldorf, Deutschland; ⁶Universitätsklinikum Düsseldorf Institut für Herz- und Kreislaufphysiologie Düsseldorf, Deutschland; ⁷Universitätsklinikum Düsseldorf Institut für Pharmakologie und Klinische Pharmakologie Düsseldorf, Deutschland

Myocardial infarction (MI) leads to acute sympathetic stimulation of peripheral lipolysis and chronic activation of white adipose tissue, including an upregulation of the first and rate limiting enzyme of triglyceride breakdown ATGL (adipocyte triglyceride lipase). ATGL was identified as a promising therapeutic target in cardiovascular disease. 
The role of adipocyte ATGL in cardiac remodeling after MI was analysed in a mouse model of experimentally induced cardiac ischemia and reperfusion (I/R) by using a tamoxifen-inducible, adipose tissue-specific knockout of ATGL (iatATGL-KO). Mice underwent 60 minutes cardiac closed-chest ischemia and up to 28 days reperfusion. 
iatATGL-KO led to reduced circulating NEFA levels after 30 minutes I/R. Cardiac dysfunction after 28 days I/R was aggravated, in line with this, also scar size was enlarged. Spatial transcriptomic analysis of hearts after 24 hours I/R identified five main cardiac, transcriptionally unique niches (remote zone, border zone 1 and 2, ischemic zone, surgery wound). From these, the remote zone exhibited the highest number of differentially expressed genes. Overrepresentation analysis revealed several terms related to cardiac oxidative metabolism but also extracellular matrix remodeling. Interestingly, several genes indicating mechanical stress were upregulated in the remote zone as Nppa, Nppb, Ankrd1 and Xirp1. This finding was supported by extracellular flux measurements showing a higher oxygen consumption rate (OCR) and higher dependency on glucose as a substrate in the non-ischemic remote zone after 24 hours I/R. Next to the cardiac phenotype also structure of adipose tissue was highly disturbed in iatATGL-KO mice with depot specific differences. Especially the subcutaneous depot (iWAT) and brown adipose tissue (BAT) showed major alterations with respect to inflammation, lipogenesis and adipokine expression. Interestingly, the cardioprotective adipokine adiponectin was downregulated in iWAT and BAT as well as reduced in the circulation. 
Taken together, iatATGL-KO leads to strong disturbances in subcutaneous and brown adipose tissue, which affects post-MI cardiac oxidative metabolism and scar formation. Our data suggest a major role of ATGL from different adipose tissue depots early after cardiac ischemia, possibly via reduced protective adipokine signaling.