Heart failure decreases adipocyte progenitors with impaired differentiation capacity toward mature adipocytes.

Cardiac cachexia, characterized by adipose tissue atrophy, has the most unfavorable outcome in heart failure (HF). Adipose dysfunction might worsen HF as adipose tissue has been found to have cardioprotective effects mediated through its metabolic and endocrine functions, and therefore, could serve as a novel therapy target. In the context of adipose tissue homeostasis, adipocyte progenitor cells (APCs) play critical roles in maintaining the number and function of mature adipocytes, including lipid metabolism and hormone secretion. However, the mechanism by which HF affects APCs has not been elucidated. In this study, we aimed to evaluate the number and functions of Lin^-CD24⁺ APCs in the subcutaneous adipose tissue of mice subjected to transverse aortic constriction-induced HF. This HF model greatly reduced the number of APCs and increased their apoptosis, resulting in lipodystrophy. In vitro assays revealed that HF limited APC proliferation and senescence. With respect to the mechanism of impaired APC function in HF, we identified that augmented sympathetic nerve activity partially mediated the decrease in APC counts via unilateral adipose tissue denervation (ATD). Furthermore, ATD mitigated HF-induced APC senescence. We elucidated that HF and excess sympathetic nerve activity impaired the adipogenic differentiation capacity of APCs. In conclusion, HF induced APC loss and senescence by augmenting sympathetic nerve activity. The impaired adipogenic capacity of APCs results in reduced healthy adipose tissue mass, suggesting that this phenomenon could be responsible for the worsening of HF.NEW & NOTEWORTHY Our work elucidated the negative feedback between heart failure (HF) and the number and function of adipocyte progenitor cells (APCs). HF drastically decreases CD24⁺ APC number and proliferative capacity. Furthermore, we discovered that HF impaired the capacity of APCs to differentiate into mature adipocytes. In conclusion, impaired APC function in HF would be a new research target to ameliorate severe HF outcomes in patients with cachexia.