An immune‐neuron axis guides adipose tissue loss in cancer‐associated cachexia

Abstract

Cancer-associated cachexia (CAC) is a hypermetabolic syndrome characterized by weight loss due to the atrophy of adipose tissue and skeletal muscle. CAC occurs in almost 80% of neoplastic diseases and causes death in more than 20% of cancer patients. The underlying mechanisms of the disease are poorly understood and no effective treatment for CAC is currently available. Recently, we and others demonstrated that a phenotypic switch from white- to beige adipocytes, a phenomenon called browning, accompanies CAC and contributes to increased energy dissipation. However, detailed mechanisms underlying this white to beige transition in CAC remained elusive. Here we show that cachexigenic tumors cause the activation of a type 2 immune response in white adipose tissue (WAT), which is functionally intertwined with neuron outgrowth, beta-adrenergic activation, and subsequent WAT browning. Immunohistochemical- and whole-mount immunofluorescence analyses revealed enhanced peripheral sympathetic neuron projections in cachectic WAT of mice and human patients. Using peripheral dopamine beta-hydroxylase (DBH) deficient mice, we demonstrate that local production of catecholamines by intra-adipose tissue neurons is responsible for increased lipolysis and initiation of the browning process. In vitro studies revealed that the increase in neuron arborization is promoted by alternatively activated macrophages which generate a neuroprotective environment covering the neurotoxic proinflammatory signals produced by cachexigenic tumors. In accordance with this concept, tumor-bearing mice that lack the interleukin-4 receptor exhibited a diminished type-2 immune response, attenuated neuronal outgrowth, and reduced browning of WAT compared to tumor-bearing wild type mice. Overall, our findings indicate that an immune–sympathetic neuron crosstalk increases local catecholamine production, lipolysis, and UCP-1 expression in WAT, thereby contributing to energy dissipation, and adipose tissue loss in CAC.