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Circulation. 2020;142:e36–e37. DOI: 10.1161/CIRCULATIONAHA.120.048259 e36 Si Chen, MS Chen Yan, PhD In Response: We appreciate Wang et al for their interest in our recent publication1 and their comments regarding the potential impact of noncardiac PDE10A (cyclic nucleotide phosphodiesterase 10A) in heart failure, such as the regulation of body weight, metabolic homeostasis, and thyroid hormone production. PDE10A expression is significantly induced in mouse and human failing hearts, predominantly in cardiomyocytes and activated cardiac fibroblasts.1 By using isolated cardiomyocytes and cardiac fibroblasts, we proved that PDE10A expression/activity directly contributes to cardiomyocyte hypertrophy and cardiac fibroblast activation.1 Thus, we believe that the cardiac PDE10A at least partially contributes to the role of PDE10A in heart failure. Wang et al also pointed out an interesting future direction of linking the roles of PDE10A in metabolism and energy homeostasis with cardiac diseases. Undeniably, PDE10A in other tissues may indirectly modify the cardiac phenotype. Thus, we agree that this is an imperative area of research. Cell-type specific PDE10A depletion or expression is required to evaluate the relative contributions of PDE10A from cardiomyocytes, cardiac fibroblasts, and other cells in heart diseases. Also, different directions addressed below may be taken in the future. Adipose tissue, as the primary site for energy storage, serves as an endocrine organ regulating metabolic homeostasis and cardiac functions through synthesizing/ secreting biologically active molecules.2 It has been shown that PDE10A is expressed in mouse brown/white adipose tissues.3 In addition, chronic PDE10A-inhibition increases thermogenesis and insulin sensitivity.3 Impaired thermogenesis and insulin response are well known in the development of heart failure. Thus, it is possible that the protective effects of global PDE10A-ablation/inhibition against transverse aortic constriction–induced cardiac hypertrophy and dysfunction observed in our study may be partially contributed to by the beneficial metabolic effects from targeting the adipose PDE10A. It would be interesting to determine the metabolic contribution of adipose PDE10A in cardiac remodeling and dysfunction in the future. The heart also functions as an endocrine organ to regulate the metabolic phenotype of other tissue/cell types. For example, it has been found that the insulin signaling and thermogenic gene expression in adipose tissues were increased at the early stage with compensated hypertrophy but decreased at the late stage with functional decline after transverse aortic constriction.4 Thus, the role of cardiac PDE10A in regulating systemic and peripheral organ metabolism and energy homeostasis requires further study. PDE10A deficiency/inhibition decreases body weight in obese mice but not in mice with normal chow diet.3 This is consistent with our finding that PDE10A inhibitor TP-10 did not cause significant weight loss in C57Bl/6J mice with sham or transverse aortic constriction under the normal chow.1 Obesity has increased incidence and prevalence of heart failure. Thus, the role of PDE10A should be evaluated in © 2020 American Heart Association, Inc. RESPONSE TO LETTER TO THE EDITOR