Adipose Triglyceride Lipase Contributes to Cancer-Associated Cachexia

Abstract

Cachexia is a multifactorial wasting syndrome most common in patients with cancer that is characterized by the uncontrolled loss of adipose and muscle mass. We show that the inhibition of lipolysis through genetic ablation of adipose triglyceride lipase (Atgl) or hormone-sensitive lipase (Hsl) ameliorates certain features of cancer-associated cachexia (CAC). In wild-type C57BL/6 mice, the injection of Lewis lung carcinoma or B16 melanoma cells causes tumor growth, loss of white adipose tissue (WAT), and a marked reduction of gastrocnemius muscle. In contrast, Atgl-deficient mice with tumors resisted increased WAT lipolysis, myocyte apoptosis, and proteasomal muscle degradation and maintained normal adipose and gastrocnemius muscle mass. Hsl-deficient mice with tumors were also protected although to a lesser degree. Thus, functional lipolysis is essential in the pathogenesis of CAC. Pharmacological inhibition of metabolic lipases may help prevent cachexia.

The role of adipose tissue in cancer-associated cachexia

“…However, lipolysis and lipid wasting may occur to an extent before muscle loss. 63 Additionally, studies in a mouse model of colon cancer demonstrated an increase in protein kinase-A-mediated lipolysis in early stage cachexia, 65 and this ''early'' lipolysis was implicated in (1) the inception of a negative energy balance that worsens over the course of CAC progression, and (2) a direct loss of skeletal muscle. 66 Lipolysis results in increased free fatty acids in circulation, which then get taken up by skeletal muscle; the excess of intramuscular free fatty acids results in several biochemical changes, such as the expression of ubiquitin lipases Atrogin-1 and MuRF 67 that lead to skeletal muscle atrophy.…”

“…61,62 The importance of lipolysis in CAC was demonstrated in a study that showed that the inhibition of lipid mobilization can improve the CAC state. 63 A murine model of animals implanted with murine adenocarcinoma 16 (MAC16) tumors reported changes in adipose tissue that included shrunken adipocytes and decreased expression of adipose tissue transcription factors. 64 From a clinical perspective, a critical component of the body mass loss observed in CAC is the depletion of muscle mass, which usually precedes the observation of significant changes in adipose tissue mass and is associated with decrease in muscle function and mobility.…”

Mechanism-Based Therapeutic Approaches to Cachexia

“…Indeed, many years ago Argilés and coworkers (2005) proposed the existence of a cross talk between the two tissue compartments. Such hypothesis has been clearly demonstrated in a recent report (Das et al, 2011), showing that inhibition of lipolysis in tumor-bearing mice by genetic ablation of lipolytic enzymes prevents hyperlipidemia and adipose mass depletion, but also skeletal muscle wasting.…”

“…In cancer patients, in particular, lipase expression is inversely correlated with body mass index (see Bing, 2011). Finally, genetic manipulations aimed at deleting each of the two lipases result in restoration of normal adipose tissue mass in tumor-bearing mice (Das et al, 2011;see above). Lipolysis-derived fatty acids, through the action of the adipocyte-specific gene cell death-inducing DNA fragmentation factor-[alpha]-like effector A (CIDEA), may serve as substrates for energy production through oxidation (Laurencikiene et al, 2008).…”

“…This likely arises from the notion that skeletal muscle mass is the limiting factor for patient survival (see above). This concept, however, should be promptly revised, in view of the results showing that inhibition of lipolytic enzymes in tumor-bearing mice reverses the loss muscle mass, in addition to restoring normal adipose depots (Das et al, 2011;see above).…”