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Obesity is a main pathogenic driver of HFpEF and accompanied by pronounced disturbances of lipid metabolism which, to a large extent, are based on adipose tissue (AT) dysfunction. In parallel, obesity results in cardiac mitochondrial dysfunction during HFpEF. It is currently unknown whether this mitochondrial dysfunction results from an intrinsic cardiac damage or whether it is, more likely, a cardiac response to systemic, non-cardiac dysfunction finally inducing HFpEF. Thus, the main research question of this project has been defined as follows: Does AT-lipid metabolism control cardiac and mitochondrial function in HFpEF, in particular in obese phenotypes? To answer this question, we will manipulate lipid uptake in AT-specific knockout mouse models which will be challenged with HFpEF. To delineate critical cardiac pathways relevant for AT-controlled cardiac function, the mouse model will be complemented by a Drosophila model (lean/obese) of heart failure with diastolic dysfunction and impaired lipid uptake in the fly fat body.
Graphical Abstract: Adipose tissue metabolism will be altered by adipose tissue-specific deletion of ANGPTL4, a key regulator of LPL and lipid uptake. Mice will undergo comprehensive cardiac phenotyping. We will focus on the analysis of cardiac mitochondrial function which is known to be regulated by alterations of lipid metabolism. Mouse experiments will be combined with studies in Drosophila melanogaster for genetic screening and pathway analysis.
Luettges K, Bode M, Diemer JN, Schwanbeck J, Wirth EK, Klopfleisch R, Kappert K, Thiele A, Ritter D, Foryst-Ludwig A, Kolkhof P, Wenzel UO, Kintscher U. Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage. Am J Nephrol. 2022;53(7):552-564. doi: 10.1159/000524940. Epub 2022 Jun 8. PMID: 35675794.
Lohr D, Thiele A, Stahnke M, Braun V, Smeir E, Spranger J, Brachs S, Klopfleisch R, Foryst-Ludwig A, Schreiber LM, Kintscher U, Beyhoff N. Assessment of Myocardial Microstructure in a Murine Model of Obesity-Related Cardiac Dysfunction by Diffusion Tensor Magnetic Resonance Imaging at 7T. Front Cardiovasc Med. 2022 Apr 5;9:839714. doi: 10.3389/fcvm.2022.839714. PMID: 35449873; PMCID: PMC9016133.