An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.
An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia.
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DOI：
10.1073/pnas.2112840119
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发表时间：
2022-03-01
影响因子：
11.1
通讯作者：
Zechner R
中科院分区：
文献类型：
--
作者：
Xie H;Heier C;Meng X;Bakiri L;Pototschnig I;Tang Z;Schauer S;Baumgartner VJ;Grabner GF;Schabbauer G;Wolinski H;Robertson GR;Hoefler G;Zeng W;Wagner EF;Schweiger M;Zechner R
超过一半的癌症患者患有一种称为癌症相关恶病质（CAC）的复杂代谢综合征。这种疾病的特点是体重意外下降，极大地降低了癌症患者的生活质量、化疗的有效性和生存率。在这里，我们提供了CAC中脂肪组织代谢重编程和萎缩的潜在机制。我们证明，脂肪组织中免疫细胞和交感神经元之间的错误通信产生永久的分解代谢状态，导致恶病质肿瘤小鼠的脂肪组织损失。靶向参与这一通信过程的信号可能为治疗CAC提供治疗选择。癌症相关恶病质（CAC）是一种以脂肪组织和骨骼肌萎缩导致体重意外减轻为特征的高代谢综合征。从白色到米黄色脂肪细胞的表型转换，一种被称为褐变的现象，通过增加能量作为热量的消散来加速CAC。针对CAC中白色脂肪组织（WAT）褐变的机制，我们现在表明，恶病质肿瘤激活恶病质WAT中的2型免疫，产生神经保护环境，增加周围交感神经活动。交感神经激活增加，进而导致神经元儿茶酚胺合成和分泌增加，脂肪细胞β-肾上腺素能激活，并诱导WAT褐变。两个遗传小鼠模型证实了这一过程。1)白细胞介素-4受体缺乏阻碍巨噬细胞的选择性活化，降低交感神经活性，抑制WAT褐变；2)外周多巴胺β-羟化酶（DBH）缺乏小鼠儿茶酚胺合成减少，可防止癌症诱导的WAT褐变和脂肪萎缩。靶向脂肪内巨噬细胞-交感神经元串导是改善癌症患者恶病质的一种有希望的治疗方法。
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.
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DOI：
10.1002/jcsm.12126
发表时间：
2016-06
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Stewart Coats AJ;Ho GF;Prabhash K;von Haehling S;Tilson J;Brown R;Beadle J;Anker SD;for and on behalf of the ACT‐ONE study group
通讯作者：
for and on behalf of the ACT‐ONE study group
影响因子：
82.9
作者：
Fischer K;Ruiz HH;Jhun K;Finan B;Oberlin DJ;van der Heide V;Kalinovich AV;Petrovic N;Wolf Y;Clemmensen C;Shin AC;Divanovic S;Brombacher F;Glasmacher E;Keipert S;Jastroch M;Nagler J;Schramm KW;Medrikova D;Collden G;Woods SC;Herzig S;Homann D;Jung S;Nedergaard J;Cannon B;Tschöp MH;Müller TD;Buettner C
通讯作者：
Buettner C
影响因子：
56.9
作者：
Das, Suman K.;Eder, Sandra;Hoefler, Gerald
通讯作者：
Hoefler, Gerald
影响因子：
9
作者：
Abdullahi A;Auger C;Stanojcic M;Patsouris D;Parousis A;Epelman S;Jeschke MG
通讯作者：
Jeschke MG
影响因子：
50.3
作者：
Huang J;Duran A;Reina-Campos M;Valencia T;Castilla EA;Müller TD;Tschöp MH;Moscat J;Diaz-Meco MT
通讯作者：
Diaz-Meco MT