MaR2-bridged brown adipose tissue–heart crosstalk underlies protection of exercise on diabetic cardiomyopathy and HFpEF

Background Obesity and diabetes mellitus induced diabetic cardiomyopathy (DbCM) and heart failure with preserved ejection fraction (HFpEF) are the leading causes of morbidity and mortality in cardiometabolic diseases, which remain largely refractory to clinical interventions. Exercise confers robust cardioprotection, for which activation of brown adipose tissue (BAT) to secrete signalling metabolites plays a considerable role. However, the functional role and precise mechanism of exercise-facilitated BAT–heart crosstalk in DbCM are largely unknown, particularly with respect to the modulation of inflammation. Purpose This study aims to investigate the role and mechanism of exercise in DbCM and HFpEF. Methods Mice received a combination of high-fat diet and streptozotocin to establish a DbCM model with HFpEF, followed by exposure to voluntary exercise. Surgical ablation of interscapular BAT was conducted to elucidate the role of BAT. To identify the bioactive signalling molecules secreted by BAT, targeted liquid chromatography with tandem mass spectrometry was performed. Flow cytometry was employed to quantify the abundance of macrophage subsets. In addition, bone marrow-derived macrophages (BMDMs) were treated with high glucose plus palmitic acid to recapitulate the DbCM phenotype in vitro. Results BAT removal markedly blunted the cardioprotective effect of voluntary exercise against pathological cardiac remodelling and HFpEF, a phenomenon resulting from the shortage of maresin 2 (MaR2), as exercise robustly promoted BAT to secrete MaR2 into the systemic circulation and cardiac parenchyma. Exogenous MaR2 administration significantly expanded the population of Trem2+ (triggering receptor expressed on myeloid cells-2) CCR2+ (C-C chemokine receptor type 2) macrophages in hearts, and concurrently suppressed NLRP3 inflammasome activation in cardiac macrophages and subsequent release of the proinflammatory cytokines, IL-1β and IL-18. Genetic ablation of Trem2 abolished MaR2-mediated suppression of NLRP3 inflammasome activation and IL-1β/IL-18 release both in cardiac macrophages and BMDMs; accordingly, Trem2 depletion reversed the protective effects of exercise in the setting of DbCM. Conclusions Our current study suggests that exercise confers a cardioprotective effect partially via BAT-derived MaR2. Specifically, MaR2 mitigates cardiac inflammation by upregulating Trem2 in macrophages, highlighting that targeting the MaR2/Trem2/NLRP3 axis may represent a promising approach against DbCM and HFpEF.