Lipolysis—Not inflammation, cell death, or lipogenesis—Is involved in adipose tissue loss in cancer cachexia

Abstract

Cancer cachexia is an important, negative prognostic marker that has been linked to systemic inflammation and cell death through unclear mechanisms. A key feature of cancer cachexia is loss of white adipose tissue (WAT) because of increased adipocyte lipolysis and possibly reduced lipid synthesis (lipogenesis). In this study, the authors investigated whether alterations in fat cell numbers, lipogenesis, or cytokine and/or leukocyte infiltration could account for some of the functional changes observed in WAT in cancer cachexia. Blood and subcutaneous WAT samples were obtained from a 10 weight-stable patients, from 13 weight losing (cachexia) patients with cancer, and from 5 patients without cancer (noncancer patients) who initially were classified with cancer. Systemic inflammation (increased circulating levels of interleukin 6 [IL-6]) and enhanced lipolysis were confirmed in the cachectic patients compared with the other patients. However, the messenger RNA expression of IL-6 and other cytokine or leukocyte markers, as well as WAT secretion of IL-6, were not altered in the patients with cachexia. Thus, the elevated serum levels of IL-6 that were observed in cachexia were not derived from WAT. Insulin-induced lipogenesis in adipocytes from patients with cachexia was the same as that in adipocytes from patients with weight-stable cancer and from noncancer patients (2.5-fold maximal stimulation; half-maximum effective concentration, approximately 0.03 nmol/L). Fat cell size was decreased but adipocyte numbers were normal in cancer patients with cachexia, suggesting that there was no major fat cell death. The current findings indicated that subcutaneous WAT does not contribute to the systemic inflammatory reaction and does not induce adipocyte insulin resistance in cancer cachexia. Moreover, increased fat cell lipolysis, not reduced lipogenesis or adipocyte cell death, appeared to be the primary cause of fat loss in this condition.