Adipose tissue ATGL regulates cardiac energy metabolism in heart failure

• Applicant: Professor Dr. Ulrich Kintscher
• Subject Area: Cardiology, Angiology ; Pharmacology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431080330

• Final Report Year: 2024

Final Report Abstract

Heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF) is characterized by an overactivation of β-adrenergic signaling that directly contributes to impairment of myocardial function. In parallel, β-adrenergic overactivation induces adipose tissue lipolysis, which may further worsen the development of HF. Recently we demonstrated that adipose tissue-specific deletion of adipose triglyceride lipase (ATGL) prevents pressuremediated HF in mice. In this project, we investigated the underlying molecular mechanism how the inhibition of adipose lipolysis mediates cardiac protection during HF-development. For this, two different mouse models of cardiac damage and heart failure were applied. The isoproterenol (ISO) model, in which a short-term injection of ISO results in subendocardial fibrosis and impairment of systolic and diastolic function. And secondly, the two-hit model of HFpEF which includes a 15-week treatment with high-fat diet and L-NAME. Adipose tissue specific inhibition of ATGL was achieved by pharmacological inhibition with atglistatin or by the generation of inducible adipose tissue specific ATGL-deficient mice. We could show that adipose tissue specific inhibition of ATGL protects against ISO-induced cardiac dysfunction and against the development of HFpEF with an improvement of global longitudinal strain (GLS) and parameters of diastolic dysfunction. Regarding the underlying mechanisms we identified that the reduction of ATGL-mediated adipose tissue lipolysis reduced circulating and cardiac levels of toxic lipid species including ceramides and diacylglycerol. This resulted in the attenuation of cardiac apoptosis and fibrosis. In addition, ATGL-inhibition in adipose tissue mitigated the ISO- and HFpEF-induced inflammatory response in the left ventricle, which likely contributes to the cardioprotective actions. In summary, we identified that the inhibition of adipose tissue lipolysis protects against early processes of cardiac damage during HF and against HFpEF. This protective action is based on different mechanisms involving the reduction of cardiac apoptosis, inflammation, and fibrosis. Currently, adipose tissue-specific pharmacological ATGL-inhibitors are being developed for use in humans. If this development is successful, these substances could be tested for their use in patients with HFrEF and/or HFpEF, based on our results.

Publications

• The Role of Adipose Triglyceride Lipase and Cytosolic Lipolysis in Cardiac Function and Heart Failure. Cell Reports Medicine, 1(1), 100001.
  Kintscher, Ulrich; Foryst-Ludwig, Anna; Haemmerle, Guenter & Zechner, Rudolf
  
• Adipose tissue–heart crosstalk as a novel target for treatment of cardiometabolic diseases. Current Opinion in Pharmacology, 60, 249-254.
  Smeir, Elia; Kintscher, Ulrich & Foryst-Ludwig, Anna
  
• Cardioprotective Effects of Palmitoleic Acid (C16:1n7) in a Mouse Model of Catecholamine-Induced Cardiac Damage Are Mediated by PPAR Activation. International Journal of Molecular Sciences, 22(23), 12695.
  Betz, Iris Rosa; Qaiyumi, Sarah Julia; Goeritzer, Madeleine; Thiele, Arne; Brix, Sarah; Beyhoff, Niklas; Grune, Jana; Klopfleisch, Robert; Greulich, Franziska; Uhlenhaut, Nina Henriette; Kintscher, Ulrich & Foryst-Ludwig, Anna
  
• Depletion of cardiac cardiolipin synthase alters systolic and diastolic function. iScience, 24(11), 103314.
  Smeir, Elia; Leberer, Sarah; Blumrich, Annelie; Vogler, Georg; Vasiliades, Anastasia; Dresen, Sandra; Jaeger, Carsten; Gloaguen, Yoann; Klose, Christian; Beule, Dieter; Schulze, P. Christian; Bodmer, Rolf; Foryst-Ludwig, Anna & Kintscher, Ulrich
  
• Fat-body brummer lipase determines survival and cardiac function during starvation in Drosophila melanogaster. iScience, 24(4), 102288.
  Blumrich, Annelie; Vogler, Georg; Dresen, Sandra; Diop, Soda Balla; Jaeger, Carsten; Leberer, Sarah; Grune, Jana; Wirth, Eva K.; Hoeft, Beata; Renko, Kostja; Foryst-Ludwig, Anna; Spranger, Joachim; Sigrist, Stephan; Bodmer, Rolf & Kintscher, Ulrich
  
• Pharmacological inhibition of adipose tissue adipose triglyceride lipase by Atglistatin prevents catecholamine-induced myocardial damage. Cardiovascular Research, 118(11), 2488-2505.
  Thiele, Arne; Luettges, Katja; Ritter, Daniel; Beyhoff, Niklas; Smeir, Elia; Grune, Jana; Steinhoff, Julia S.; Schupp, Michael; Klopfleisch, Robert; Rothe, Michael; Wilck, Nicola; Bartolomaeus, Hendrik; Migglautsch, Anna K.; Breinbauer, Rolf; Kershaw, Erin E.; Grabner, Gernot F.; Zechner, Rudolf; Kintscher, Ulrich & Foryst-Ludwig, Anna
  
• An Altered Plasma Lipidome–Phenome Network Characterizes Heart Failure with Preserved Ejection Fraction. ESC Heart Failure, 11(3), 1553-1566.
  Jovanovic, Nina; Foryst-Ludwig, Anna; Klose, Christian; da Conceicao, Cristina Rozados; Alasfar, Lina; Birkner, Till; Forslund, Sofia K.; Kintscher, Ulrich & Edelmann, Frank