Mechanism of Increased Lipolysis in Cancer Cachexia

Abstract

Loss of fat mass is a key feature of cancer cachexia and has been attributed to increased adipocyte lipolysis. The mechanism behind this alteration is unknown and was presently investigated. We studied mature s.c. fat cells and differentiated preadipocytes from 26 cancer patients with and without cachexia. Hormone-induced lipolysis and expression of lipolysis-regulating genes were determined together with body composition and in vivo lipolytic activity ( fasting plasma glycerol or fatty acids related to body fat). Body fat was reduced by 40% and in vivo lipolytic activity was 2-fold increased in cachexia (P = 0.001). In mature adipocytes, the lipolytic effects of catecholamines and natriuretic peptide were 2-to 3-fold increased in cachexia (P < 0.001). This was completely counteracted by inhibiting the rate-limiting lipolysis enzyme hormone-sensitive lipase (HSL). In cachexia, the expression levels of HSL mRNA and protein were increased by 50% and 100%, respectively (P = 0.005-0.03), which strongly correlated with in vitro lipolytic stimulation (r = 0.7-0.9). The antilipolytic effect of insulin in mature fat cells and the stimulated lipolytic effect in differentiated preadipocytes were unaltered in cachexia. Patients who lost weight due to other factors than cancer cachexia had no change in adipocyte lipolysis. In conclusion, adipocyte lipolysis is increased in cancer cachexia not due to nonepigenic factors or to weight loss per se, but most probably because of enhanced expression and function of adipocyte HSL. The selective inhibition of this enzyme may prevent fat loss in cancer patients. [Cancer Res 2007;67(11):5531-7]

Loss of Prkar1a leads to Bcl-2 family protein induction and cachexia in mice

“…The cachexia in the Prkar1a-deleted mice was also characterized by atrophy of Tibialis anterior and depletion of subscapular and epididymal fat deposits (Figure 5b). Consistent with increased lipolysis in cachexia, 27 we found increased phosphor-HSL (hormonestimulated lipase) levels in adipose tissues and increased free triglycerides in the sera from the Prkar1a-deleted mice (Figures 5c and d). Upon Prkar1a deletion, all mice underwent rapid weight loss and muscle wasting.…”

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

“…However, even considering the important role of ECM to AT homeostasis, there is limited information regarding quantitative EMC analysis in cachectic cancer patients. The few studies that have addressed this question propose that AT solely adjusts its extracellular environment to adapt to the shrinking volume of the fat cells 11, 38. Contrary to this view, we show a robust increase in total collagen content and additionally, that, even before any morphofunctional disruption in AT occurs, as reported for WSC patients, AT is already affected by the syndrome.…”

“…This is one of the initial steps to trigger inflammatory response and consequently increase Mϕs subset in AT. In CC, high MCP‐1 levels found in WSC might be suggestive of a pre‐cachexia stage, once increased gene expression of CD68, IL‐6 and IL‐10 was already demonstrated in such CC patients11. However, the relationship between MCP‐1‐associated ATMϕs augment and the initial signals of cachexia, as well as the importance of this process for the development and progression of cachexia complications, remains unclear.…”

Semaphorin 3C is a novel adipokine linked to extracellular matrix composition

“…None of the participants were on any regular medication that might be expected to affect adipocyte function. Cachexia was defined as described in [13]. BMI was classified according to the WHO definition.…”