Interleukin-6 induces fat loss in cancer cachexia by promoting white adipose tissue lipolysis and browning

Jun Han,Qingyang Meng,Guohao Wu,Lei Shen

doi:10.1186/s12944-018-0657-0

Abstract

BackgroundCancer cachexia is a progressive and multi-factorial metabolic syndrome characterized by loss of adipose tissue and skeletal muscle. White adipose tissue (WAT) lipolysis and white-to-brown transdifferentiation of WAT (WAT browning) are proposed to contribute to WAT atrophy in cancer cachexia. Chronic inflammation, mediated by cytokines such as tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), has been reported to promote cancer cachexia. However, whether chronic inflammation promotes cancer cachexia by regulating WAT metabolism and the underlying mechanism remains unclear.MethodsIn this study, we first analyzed the association between chronic inflammation and WAT metabolism in gastric and colorectal cancer cachectic patients. In cachectic mice treated with anti-IL-6 receptor antibody, we clarified whether WAT lipolysis and browning were regulated by IL-6.ResultsClinical analyses showed positive significant association between serum IL-6 and free fatty acid (FFA) both in early- and late-stage cancer cachexia. However, serum TNF-α was positively associated with serum FFA in the early- but not late-stage cachexia. WAT lipolysis was increased in early- and late-stage cachexia, while WAT browning was detected only in late-stage cachexia. Anti-IL-6 receptor antibody inhibited WAT lipolysis and browning in cachectic mice.ConclusionsBased on these findings, we conclude that chronic inflammation (especially that mediated by IL-6) might promote cancer cachexia by regulating WAT lipolysis in early-stage cachexia and browning in late-stage cachexia.

Highlights

Cancer cachexia is a progressive and multi-factorial metabolic syndrome characterized by loss of adipose tissue and skeletal muscle
There were no differences in serum triglyceride among the three groups, the concentration of serum free fatty acid (FFA) was significantly increased in cachectic patients, especially in early-stage cachexia
Serum TNF-α was positively associated with only serum FFA in early- but not late-stage cachexia (Fig. 1)

Summary

Introduction

Cancer cachexia is a progressive and multi-factorial metabolic syndrome characterized by loss of adipose tissue and skeletal muscle. Whether chronic inflammation promotes cancer cachexia by regulating WAT metabolism and the underlying mechanism remains unclear. Cancer cachexia is a wasting syndrome defined by an ongoing loss of skeletal muscle and fat mass that cannot be fully reversed by conventional nutritional support [1]. Loss of adipose tissue has been reported to be associated with reduced quality of life and shorter survival independent of body mass index (BMI) in advanced cancer patients [8, 9]. Increased lipolysis and fat oxidation, decreased lipogenesis, impaired lipid deposition and adipogenesis, as well as browning of white adipose tissue (WAT) may underlie adipose atrophy in cancer cachexia [10]

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Conclusion