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

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.

Energy metabolism in cachexia

“…Increased UCP1 mRNA and protein levels are also described in both patients and mice with cachexia [117,118], as is increased energy uptake, measured by oxygen consumption rate but also heat generation. IL-6 was identified as one of the drivers for this browning effect [106,117].…”

“…While multiple lines of evidence suggest that brite fat-induced thermogenesis contributes to increased energy expenditure in cachexia [106,[117][118][119][120], there is also data questioning the prominent role of browning for adipose and body wasting. Brown or brite adipose tissue thermogenesis contributes to the body's ability to defend against cold temperatures, so more brown/brite AT would suggest elevated body temperature or cold tolerance.…”

“…Finally, mice housed at thermoneutrality develop cachexia exactly parallel to mice housed at room temperature (a mild cold stress activating brown/brite AT) [97]-in contrast, tumor growth and inflammation are aggravated by housing at room temperature [121]. While increased AT UCP1 levels are recorded for several murine and human cancers [106,[117][118][119][120], this is not consistently seen, as some reports demonstrate unchanged or even reduced adipose UCP1 levels [97,122]. Mice lacking UCP1 are not protected from cachexia development or adipose tissue loss, questioning the prominent role of browning for wasting [97].…”

Updates on the pathogenesis of advanced lung cancer‐induced cachexia

“…Free fatty acids in the serum are mainly derived from the breakdown of body fat, especially white adipose tissue. In the early stage of cachexia, the increase in serum free fatty acids is particularly apparent . Hormone‐sensitive lipase (HSL) is activated in adipose tissue, and increased lipolysis enhances the expression of the stimulatory protein Gas and downregulates expression of the inhibitory protein Gai.…”

“…The effect of IL‐6 is more significant. TNF‐α and IL‐6 likely accelerate the breakdown of adipose tissues, thereby causing weight loss under a cachectic state …”