Thermogenic Adipose Supports Cardiometabolic Health in Heart Failure with Preserved Ejection Fraction
Creators: name: Jousma, Jordan
Publisher: name: University of Illinois Chicago
Year: 2025

description: In recent years, there has been a rise in the prevalence of heart failure with preserved ejection fraction (HFpEF). Unfortunately, existing cardiac therapies have been largely ineffective in treating this condition. Thus, there is a need to develop treatments that better target pathologically relevant sources of cardiac dysfunction in HFpEF patients. Comorbidities, such as obesity, are thought to contribute to the development of a systemic inflammatory state, which in turn leads to cardiovascular dysfunction in HFpEF patients. In the clinical setting, adiposity has been associated with worsening diastolic function. Thermogenic adipose tissue activity, however, is associated with various improvements in aspects of cardiometabolic health. However, the role of thermogenic adipose tissue in the context of obesity-related HFpEF remains unclear. Therefore, the objective of this study was to experimentally evaluate this relationship and obtain knowledge that might support the development of new therapeutic strategies in cardiovascular medicine. The central findings directly implicate adipose tissue as a source of cardiac dysfunction in obesity-related HFpEF and highlight the beneficial effects that thermogenic adipose tissue has on the heart in this context. This was demonstrated using pharmacological, surgical, and genetic approaches. These findings support a conceptually innovative framework in cardiovascular medicine by revealing how adipose tissue may be targeted as the pathologically relevant source of cardiac dysfunction in obesity-related HFpEF.
 For the pharmacological approach, mice were pre-treated with the β3-AR agonist CL-316243 (CL) to induce adipose tissue thermogenesis. CL-treated mice were then observed to be resilient to the effects of HFpEF treatment on adipose tissue remodeling. Moreover, metabolic deficits induced by HFpEF, including reduced energy expenditure (EE), were significantly elevated in CL-treated mice. Echocardiography revealed that diastolic function, as measured by E/A and E/E’, was significantly improved in CL-treated mice, whereas cardiomyocyte hypertrophy was attenuated. The role of thermogenic adipose tissue was also directly assessed via transplantation studies, where adipose tissues from CL-treated donor mice were transferred to wild-type (WT) untreated mice. The degree of cardioprotection conferred by transplanted tissues from CL-treated mice was similar to that provided by CL treatment in previous experiments. A genetic model (AdipoqCre; Prdm16fl/fl), which blunts the induction of thermogenesis, was then used to demonstrate that thermogenic adipose tissue function was required for CL-mediated cardioprotection. An additional genetic model (Ucp1CreERT2; Cdkn2αfl/fl), which enhances thermogenic capabilities, was used as an alternative approach to evaluate the effects of thermogenic adipose tissue. In the HFpEF model, the expansion of beige adipose tissue led to significant improvements in diastolic function and hypertrophic remodeling, thus providing further support for the beneficial role of thermogenic adipose tissue in this context. This model highlights beige adipocyte precursors as a precise cellular target with significant potential in determining cardiac outcomes in HFpEF. Finally, after establishing a link between thermogenic adipose tissue and the cardiac lipid composition, LC-MS/MS was performed to profile the cardiac lipidome. Here, adipose tissue-derived lipids were identified as the most significantly affected lipids distinguishing HFpEF hearts from HFpEF+CL hearts. Moreover, HFpEF hearts were characterized by increased deposition of long-chain, and highly saturated fatty acids, which are known to be detrimental to cardiac health. Overall, these findings highlight that adipose tissue has a role in determining outcomes in HFpEF and emphasize the importance of cardiac lipid composition as a pathologically relevant feature of HFpEF.