Takeda Yusuke, Inoue Oto, Nomura Ayano, Hashimuko Daiki, Yamaguchi Kosei, Goten Chiaki, Takashima Shinichiro, Takamura Masayuki, Usui Soichiro
Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan.
Department of Endocrinology/Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States.
Am J Physiol Regul Integr Comp Physiol. 2025 Aug 1;329(2):R287-R296. doi: 10.1152/ajpregu.00191.2024. Epub 2025 Jul 2.
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 LinCD24 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. 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.
心脏恶病质以脂肪组织萎缩为特征，在心力衰竭（HF）中预后最为不利。脂肪功能障碍可能会使HF恶化，因为已发现脂肪组织通过其代谢和内分泌功能具有心脏保护作用，因此可作为一个新的治疗靶点。在脂肪组织稳态的背景下，脂肪细胞祖细胞（APC）在维持成熟脂肪细胞的数量和功能（包括脂质代谢和激素分泌）方面发挥着关键作用。然而，HF影响APC的机制尚未阐明。在本研究中，我们旨在评估经主动脉缩窄诱导HF的小鼠皮下脂肪组织中LinCD24 APC的数量和功能。这种HF模型大大减少了APC的数量并增加了它们的凋亡，导致脂肪营养不良。体外试验表明，HF限制了APC的增殖和衰老。关于HF中APC功能受损的机制，我们发现增强的交感神经活动通过单侧脂肪组织去神经支配（ATD）部分介导了APC数量的减少。此外，ATD减轻了HF诱导的APC衰老。我们阐明，HF和过度的交感神经活动损害了APC的成脂分化能力。总之，HF通过增强交感神经活动诱导APC丢失和衰老。APC成脂能力受损导致健康脂肪组织量减少，表明这种现象可能是HF恶化的原因。我们的工作阐明了心力衰竭（HF）与脂肪细胞祖细胞（APC）数量和功能之间的负反馈。HF显著降低了CD24 APC的数量和增殖能力。此外，我们发现HF损害了APC分化为成熟脂肪细胞的能力。总之，HF中APC功能受损将是改善恶病质患者严重HF结局的一个新的研究靶点。
