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Targeting Adipose Tissue Function Protects Against Heart Failure with Preserved Ejection Fraction
Jordan Jousma1, Zhenbo Han1, Jooman Park2
1Department of Pharmacology & Regenerative Medicine, University of Illinois College of Medicine, Chicago, IL, 60612, USA.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|November 24, 2025
Summary
Targeting thermogenic adipose tissue (AT) improves cardiac function in obesity-related heart failure with preserved ejection fraction (HFpEF). Activating or enhancing thermogenic AT offers a promising therapeutic strategy for cardiometabolic health.
Area of Science:
- Cardiovascular Research
- Metabolic Health
- Adipose Tissue Biology
Background:
- Obesity is a major risk factor for heart failure with preserved ejection fraction (HFpEF).
- The role of thermogenic adipose tissue (AT) in obesity-related HFpEF remains unclear.
- Understanding the adipose-heart axis is crucial for developing novel therapeutic strategies.
Purpose of the Study:
- To investigate how targeting thermogenic adipose tissue (AT) influences cardiac function in a model of heart failure with preserved ejection fraction (HFpEF).
- To evaluate the effects of pharmacological, surgical, and genetic interventions on thermogenic AT and cardiac outcomes.
- To elucidate the underlying mechanisms connecting AT thermogenesis and cardiac health.
Main Methods:
- Utilized a "two-hit" HFpEF mouse model.
- Administered the β3-adrenergic receptor agonist CL-316,243 (CL) to activate thermogenic AT.
- Employed genetic manipulations (Adipoq-Cre; Prdm16fl/fl and Ucp1-CreERT2; Cdkn2afl/fl) to suppress or enhance AT thermogenesis.
- Performed lipidomic analysis (LC/MS-MS) to assess cardiac lipid profiles.
- Conducted AT transplantation experiments.
Main Results:
- Activation of thermogenic AT via CL improved cardiac function and reduced HFpEF-induced cardiac remodeling.
- Enhanced energy expenditure was observed with thermogenic AT activation.
- Transplantation of AT from CL-treated mice conferred cardioprotection.
- Genetic suppression of thermogenesis abolished CL's beneficial effects.
- Genetic enhancement of thermogenic AT improved cardiac structure and function.
- AT thermogenesis significantly altered the cardiac lipidome.
Conclusions:
- Thermogenic adipose tissue plays a critical role in mediating cardiac function in the context of obesity-related HFpEF.
- Targeting the adipose-heart axis, specifically enhancing AT thermogenesis, represents a viable therapeutic approach for obesity-related HFpEF.
- Alterations in the cardiac lipidome are mechanistically linked to the benefits of AT thermogenesis on heart health.
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