Activation of Thermogenesis in Brown Adipose Tissue and Dysregulated Lipid Metabolism Associated with Cancer Cachexia in Mice

Cancer Pharmacology Unit, Centre for Education and Research on Ageing, ANZAC Research Institute, Concord, Australia.
Cancer Research (Impact Factor: 9.33). 06/2012; 72(17):4372-82. DOI: 10.1158/0008-5472.CAN-11-3536
Source: PubMed


Cancer cachexia/anorexia is a complex syndrome that involves profound metabolic imbalances and is directly implicated as a cause of death in at least 20% to 30% of all cancers. Brown adipose tissue (BAT) plays a key role in thermogenesis and energy balance and potentially contributes to the physiologic perturbations associated with cachexia. In this study, we investigated the impact of cachexia-inducing colorectal tumor on BAT in mice. We found that brown adipocytes were smaller and exhibited profound delipidation in cachectic tumor-bearing mice. Diurnal expression profiling of key regulators of lipid accumulation and fatty acid β-oxidation and their corresponding target genes revealed dramatic molecular changes indicative of active BAT. Increased Ucp1, Pbe, and Cpt1α expression at specific points coincided with higher BAT temperatures during the dark cycle, suggestive of a temporal stimulation of thermogenesis in cachexia. These changes persisted when cachectic mice were acclimatized to 28°C confirming inappropriate stimulation of BAT despite thermoneutrality. Evidence of inflammatory signaling also was observed in the BAT as an energetically wasteful and maladaptive response to anorexia during the development of cachexia.

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    • "Circulating levels of IL-6 correlate with weight loss and reduced survival in pancreatic cancer patients (Ebrahimi et al., 2004; Martignoni et al., 2005; Moses et al., 2009). Although the role of IL-6 in lipolysis is not well established, a recent study has shown enhanced IL-6 signaling in brown adipose tissue in cachectic tumor-bearing mice suggesting that it may play a direct role in the activation of thermogenesis (Tsoli et al., 2012). More importantly, IL-6 is known to activate the hepatic APPR and trigger tissue catabolism. "
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