Cancer cachexia is a progressive metabolic disorder that results in depletion of adipose tissue and skeletal muscle. A growing body of literature suggests that maintaining adipose tissue mass in cachexia may improve quality-of-life and survival outcomes. Studies of lipid metabolism in cachexia, however, have generally focused on later stages of the disorder when severe loss of adipose tissue has already occurred. Here, we investigated lipid metabolism in adipose, liver and muscle tissues during early stage cachexia - before severe fat loss - in the colon-26 murine model of cachexia. White adipose tissue mass in cachectic mice was moderately reduced (34-42%) and weight loss was less than 10% of initial body weight in this study of early cachexia. In white adipose depots of cachectic mice, we found evidence of enhanced protein kinase A - activated lipolysis which coincided with elevated total energy expenditure and increased expression of markers of brown (but not white) adipose tissue thermogenesis and the acute phase response. Total lipids in liver and muscle were unchanged in early cachexia while markers of fatty oxidation were increased. Many of these initial metabolic responses contrast with reports of lipid metabolism in later stages of cachexia. Our observations suggest intervention studies to preserve fat mass in cachexia should be tailored to the stage of cachexia. Our observations also highlight a need for studies that delineate the contribution of cachexia stage and animal model to altered lipid metabolism in cancer cachexia and identify those that most closely mimic the human condition.
Keywords: ACOX, acyl CoA oxidase; ATGL, adipose triglyceride lipase; COX, cytochrome c oxidase subunits; CPT, carnitine palmitoyltransferase; CRP, C-reactive protein; DIO, iodothyronine deiodinase; GYK, glycerokinase; H&E, hematoxylin and eosin; HSL, hormone sensitive lipase; LPL, lipoprotein lipase; MuRF, muscle ring finger protein; PGC, peroxisome proliferator activated receptor gamma coactivator; PKA, protein kinase A; PPAR, peroxisome proliferator activated receptor; PRDM, PR domain zinc finger protein; RER, respiratory exchange ratio.; TEE, total energy expenditure; UCP, uncoupling protein; colon-26 adenocarcinoma; eWAT, epididymal white adipose tissue; early cachexia; energy expenditure; iBAT, interscapular brown adipose tissue; iWAT, inguinal white adipose tissue; lipid metabolism; lipolysis; thermogenesis.