Inhibition of cisplatin-induced lipid catabolism and weight loss by ghrelin in male mice.

Cachexia, defined as an involuntary weight loss ≥ 5%, is a serious and dose-limiting side effect of chemotherapy that decreases survival in cancer patients. Alterations in lipid metabolism are thought to cause the lipodystrophy commonly associated with cachexia. Ghrelin has been proposed to ameliorate the alterations in lipid metabolism due to its orexigenic and anabolic properties. However, the mechanisms of action through which ghrelin could potentially ameliorate chemotherapy-associated cachexia have not been elucidated. The objectives of this study were to identify mechanisms by which the chemotherapeutic agent cisplatin alters lipid metabolism and to establish the role of ghrelin in reversing cachexia. Cisplatin-induced weight and fat loss were prevented by ghrelin. Cisplatin increased markers of lipolysis in white adipose tissue (WAT) and of ß-oxidation in liver and WAT and suppressed lipogenesis in liver, WAT, and muscle. Ghrelin prevented the imbalance between lipolysis, ß-oxidation, and lipogenesis in WAT and muscle. Pair-feeding experiments demonstrated that the effects of cisplatin and ghrelin on lipogenesis, but not on lipolysis and ß-oxidation, were due to a reduction in food intake. Thus, ghrelin prevents cisplatin-induced weight and fat loss by restoring adipose tissue functionality. An increase in caloric intake further enhances the anabolic effects of ghrelin.

Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia.

CONTEXT: Male cancer patients suffer from fatigue, sexual dysfunction, and decreased functional performance and muscle mass. These symptoms are seen in men with hypogonadism and/or inflammatory conditions. However, the relative contribution of testosterone and inflammation to symptom burden in cancer has not been well-established. OBJECTIVE: The aim of this study was to measure testosterone levels in male cancer patients and determine the relationship between testosterone, inflammation, and symptom burden. DESIGN/SETTING: This cross-sectional study enrolled patients from a tertiary-care center. SUBJECTS/OUTCOME MEASURES: Subjects included males with cancer-cachexia (CC; n = 45) and cancer without cachexia (CNC; n = 50), as well as noncancer controls (CO; n = 45). Total testosterone (TT), bioavailable testosterone, C-reactive protein (CRP), and IL-6 were measured in plasma. Functional performance was assessed by the ECOG (Eastern Cooperative Oncology Group) and KPS (Karnofsky Performance Scales), and sexual function was assessed by the IIEF (International Index of Erectile Function). RESULTS: Low testosterone levels were seen in more than 70% of CC cases. TT was lower in CC compared to CNC (P < 0.05). Also, CC had lower bioavailable testosterone, grip strength, IIEF scores, appendicular lean body mass, and fat mass and higher IL-6 and CRP compared to controls (P ≤ 0.05). ECOG and KPS were lower in CC and CNC compared to controls (P ≤ 0.05). On multiple regression analysis, TT, albumin, and CRP predicted symptoms differentially in cancer patients. CONCLUSIONS: CC patients have higher inflammation and lower testosterone, grip strength, functional status, erectile function, fat mass, and appendicular lean body mass. Inflammation, TT, and albumin are associated with heavier symptom burden in this population. Interventional trials are needed to determine whether testosterone replacement and/or antiinflammatory agents benefit cancer patients.

Adipokines in patients with cancer anorexia and cachexia.

BACKGROUND: Anorexia, cachexia, and insulin resistance are commonly seen in patients with cancer. Adipocyte-derived hormones or adipokines play a role in the regulation of appetite, body weight, and insulin sensitivity. However, their role in cancer-induced cachexia has not been well-established. The objective of this study was to determine the levels of adipokines and their relation to appetite, weight loss, insulin resistance, and other hormones in cancer cachexia. METHODS: We measured adiponectin, resistin, and leptin plasma levels in 21 men with cancer cachexia, 24 noncachectic cancer subjects, and 25 noncancer controls matched by age, sex, and pre-illness body weight. Body weight change, appetite scores, insulin resistance assessed by homeostasis model assessment, and other cytokines and hormones were also measured. Differences between groups were measured by analysis of covariance. Relations between variables were examined by linear regression analyses. RESULTS: Adiponectin levels were similarly elevated in cachectic and noncachectic cancer patients compared with noncancer controls. Leptin levels were significantly decreased in cancer cachexia and were directly associated with appetite and insulin resistance, explaining 37% and 19% of the variance seen in cancer patients, respectively. Resistin levels were not different between groups. CONCLUSIONS: Leptin may play a role in the increased insulin resistance seen in cancer patients. However, these patients are resistant to the orexigenic effects of hypoleptinemia. Other mechanisms besides weight loss are responsible for the increased adiponectin level seen in cancer patients. It is unlikely that resistin plays a major metabolic role in this setting.