Abstract 447: ZAG promotes cachexia-associated white adipose tissue browning and energy wastage
Authors: Sawsan Elattar, Satyanarayana Ande
Journal: Cancer Research (2017)

Abstract Cancer cachexia is a complex condition of tissue wasting that affects up to 80% of cancer patients. To date, there is no effective treatment for cachexia due to the complex nature of this condition. Energy wasting in cachexia is caused by excessive lipid and protein turnover in the body, browning of white adipose tissue (WAT), and futile metabolic cycling such as glucose recycling between the liver and tumor. Therefore, identifying and inhibiting factors that promote WAT browning, and glucose and lipid recycling can reduce energy wasting and ameliorate cachexia in cancer patients. Zinc-α2-glycoprotein (ZAG), a lipid mobilizing factor secreted by multiple cancers, has been shown to promote lipolysis and inhibit lipogenesis in WAT. However, whether ZAG plays any role beyond lipolysis and participates in other energy wasting mechanisms of cachexia such as glucose and lipid recycling, and WAT browning has not been explored. Our initial studies indicate that while ZAG is highly expressed in the heart, kidney, and liver of wild-type mice, the basal expression of ZAG is very low in WAT at both the mRNA and protein levels. To investigate the metabolic functions of ZAG in vivo, ZAG-expressing 293 cells were implanted subcutaneously in athymic nude mice, and analyzed them after 3 and 6 weeks. We detected a 3-fold increase in the circulating plasma levels of ZAG. Importantly, the increase in ZAG levels was associated with a decrease in body weight gain without any differences in food consumption and physical activity. Morphological examination of eFAT pads of ZAG-cell implanted mice showed smaller size compared to controls. In addition, histological examination of eFAT showed cell shrinkage and almost complete depletion of fat stores, suggesting enhanced lipolysis in the WAT. Notably, ZAG induced the expression of beige, mitochondrial, and thermogenesis genes at mRNA level in the eFAT. Moreover, the expression of brown adipocyte-specific thermogenic genes such as Ebf2, Prdm16, PGC1α, UCP1, SRC1 and IRF4 were strongly induced at the protein level in eWAT of ZAG-cell implanted mice suggesting that ZAG causes WAT browning. Furthermore, metabolic analysis revealed increased O2 consumption and heat production in ZAG-cell implanted mice compared to controls indicating increased total body energy expenditure. ZAG-cell implanted mice also displayed reduced respiratory exchange ratio indicating increased consumption of lipids. Overall, our findings suggest that ZAG functions beyond lipolysis and causes significant energy wasting by causing WAT browning and promoting glucose and lipid catabolism in the beige cells. These findings suggest that ZAG plays a predominant role in the development of cachexia, and thus, may represent a novel therapeutic target to block energy wasting and delay or prevent cachexia in cancer patients. Citation Format: Sawsan Elattar, Satyanarayana Ande. ZAG promotes cachexia-associated white adipose tissue browning and energy wastage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 447. doi:10.1158/1538-7445.AM2017-447