期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：9
DOI：10.1073/pnas.2112840119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
More than a half of cancer patients suffer a complex metabolic syndrome termed cancer-associated cachexia (CAC). This disorder is characterized by unintended loss of body weight and largely reduces quality of life, effectiveness of chemotherapy, and survival of cancer patients. Here, we provide a potential mechanism underlying the metabolic reprogramming and atrophy of adipose tissue in CAC. We demonstrate that miscommunication between immune cells and sympathetic neurons in adipose tissue generates a perpetual catabolic state that leads to adipose tissue loss in cachexigenic tumor-bearing mice. Targeting the signals involved in this communication process may provide therapeutic options to treat CAC.
Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by unintended weight loss due to the atrophy of adipose tissue and skeletal muscle. A phenotypic switch from white to beige adipocytes, a phenomenon called browning, accelerates CAC by increasing the dissipation of energy as heat. Addressing the mechanisms of white adipose tissue (WAT) browning in CAC, we now show that cachexigenic tumors activate type 2 immunity in cachectic WAT, generating a neuroprotective environment that increases peripheral sympathetic activity. Increased sympathetic activation, in turn, results in increased neuronal catecholamine synthesis and secretion, β-adrenergic activation of adipocytes, and induction of WAT browning. Two genetic mouse models validated this progression of events. 1) Interleukin-4 receptor deficiency impeded the alternative activation of macrophages, reduced sympathetic activity, and restrained WAT browning, and 2) reduced catecholamine synthesis in peripheral dopamine β-hydroxylase (DBH)–deficient mice prevented cancer-induced WAT browning and adipose atrophy. Targeting the intraadipose macrophage-sympathetic neuron cross-talk represents a promising therapeutic approach to ameliorate cachexia in cancer patients.
