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

Abstract

Background: Cancer 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.

Methods: In 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.

Results: Clinical 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.

Conclusions: Based 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.

Keywords: Beige adipocyte; Cancer cachexia; Interleukin-6; Lipolysis.

Fig. 1

Association between serum inflammatory cytokines and WAT lipolysis in cachectic patients. a Correlation analysis between serum IL-6 and FFA in early-stage cachexia (n = 40). b Correlation analysis between serum TNF-α and FFA in early-stage cachexia (n = 40). c Correlation analysis between serum IL-6 and FFA in late-stage cachexia (n = 28). d Correlation analyses between serum TNF-α and FFA in late-stage cachexia (n = 28)

Fig. 2

Comparisons of subcutaneous WAT among patients with non-cachexia (n = 50), patients with early-stage cachexia (n = 40), and patients with late-stage cachexia (n = 28). a Representative Ucp1 staining of subcutaneous WAT in different groups of patients. b Mean sizes of adipocyte in different groups of patients. c mRNA expression of WAT lipolysis and browning associated genes in different groups of patients. *P < 0.05

Fig. 3

Comparison among control mice (n = 8), cachexic mice (n = 8), and anti-IL-6 receptor antibody (IL-6R Ab) treated mice (n = 8). a Weight of inguinal WAT, epididymal WAT, BAT, and skeletal muscle in different groups of mice. b Serum concentrations of FFA in different groups of mice. c Representative Ucp1 staining of inguinal WAT in different groups of mice. d mRNA expression of WAT lipolysis and browning associated genes of inguinal WAT in different groups of mice. e The protein expression of Cgi58 and Tbx1 of inguinal WAT in different groups of mice *P < 0.05