No abstract

Cachexia is responsible for nearly 20% of all cancer-related deaths, yet effective therapies to prevent or treat the disease are lacking. Clinical studies have shown that male patients lose weight at a faster rate than females. Additionally, an ‘obesity paradox’ may exist where excess adiposity may confer survival to patients with cancer cachexia. To further explore these phenomena, the aim of this study was to evaluate the role of changes of adipose tissue mass, sex status, and tumor mass on outcomes of male, female and ovariectomized (OVX) mice with C-26 adenocarcinoma-induced cachexia. We used EchoMRI to assess body composition and grip strength to measure muscle function. Body weights and food intake were measured daily. Mice were euthanized 19 days post-inoculation. Post-necropsy, muscle fiber cross-sectional areas were quantified and real-time PCR was performed for genes relating to proteolysis. Survival curve, correlation and multiple linear regression analyses were performed to identify predictors of cachexia. Female and OVX tumor mice developed cachexia similarly to males, as evidenced by loss of skeletal and adipose masses, decreased grip strength, and increased proteolytic gene expression. Notably, female and OVX tumor mice had earlier onset of cachexia (≥5% weight loss) than male tumor mice. Larger tumor mass and lower adipose mass were the strongest predicting factors for increased severity of cachexia, regardless of sex or ovariectomy status. These results indicated that the impact of sex status may be subtle in comparison to the predictive effect of tumor and adipose mass in mice with C-26-induced cachexia.

Polyunsaturated fats are energy substrates and precursors to the biosynthesis of lipid mediators of cellular processes. Adipose tissue not only provides energy storage, but influences whole-body energy metabolism through endocrine functions. How diet influences adipose–lipid mediator balance may have broad impacts on energy metabolism. To determine how dietary lipid sources modulate brown and white adipose tissue and plasma lipid mediators, mice were fed low-fat (15% kcal fat) isocaloric diets, containing either palm oil (POLF) or linoleate-rich safflower oil (SOLF). Baseline and post body weight, adiposity, and 2-week and post fasting blood glucose were measured and lipid mediators were profiled in plasma, and inguinal white and interscapular brown adipose tissues. We identified over 30 species of altered lipid mediators between diets and found that these changes were unique to each tissue. We identified changes to lipid mediators with known functional roles in the regulation of adipose tissue expansion and function, and found that there was a relationship between the average fold difference in lipid mediators between brown adipose tissue and plasma in mice consuming the SOLF diet. Our findings emphasize that even with a low-fat diet, dietary fat quality has a profound effect on lipid mediator profiles in adipose tissues and plasma.

Scope Cancer cachexia is characterized by the loss of skeletal muscle resulting in functional impairment, reduced quality of life and mortality. Naringenin, a flavonoid found in citrus fruits, improves insulin sensitivity and reduces inflammation and tumor growth in preclinical models. Therefore, the study hypothesizes that dietary supplementation of naringenin will improve insulin sensitivity, decrease inflammation, slow body weight loss, and delay tumor growth in a mouse model of cancer cachexia. Methods and Results Mice are fed 2 wt% dietary naringenin before and during initiation of cancer cachexia using inoculated adenocarcinoma‐26 cells (C‐26). Food intake, body weight, body composition, muscle function, insulin tolerance, and inflammatory status are assessed. Although naringenin‐fed tumor‐bearing mice exhibit reductions in body weight and food intake earlier than control diet‐fed tumor‐bearing mice, dietary naringenin is protective against loss of muscle strength, and attenuates the onset of insulin resistance and markers of inflammation. Conclusions Dietary supplementation of naringenin improves multiple aspects of metabolic disturbance and inflammation during cancer cachexia progression in [C‐26 tumor‐bearing] mice. However, the acceleration of anorexia and weight loss is also observed. These findings emphasize the link between inflammation and insulin resistance as a basis for understanding their roles in the pathogenesis of cancer cachexia.