Evidence for a Novel Serum Factor Distinct From Zinc Alpha-2 Glycoprotein That Promotes Body Fat Loss Early in the Development of Cachexia

Abstract

We provide evidence that a factor other than the previously identified lipid mobilizing factor, zinc alpha-2 glycoprotein, promotes lipolysis in the MCA-induced sarcoma-bearing cachexia model. Cachexia is characterized by progressive loss of adipose tissue and skeletal muscle without a concurrent increase in food intake to restore lost tissue stores. We compared tumor-bearing ad lib fed (TB) animals to nontumor bearing ad lib fed (NTB) animals or nontumor-bearing pair-fed (PF) animals at various time points throughout development of tumor derived cachexia. Prior to cachexia, the TB animals lost more than 10 ± 0.7% of their body fat before losing protein mass and decreasing their food intake. Fat loss occurred because adipocyte size, not number, was reduced. Increased turnover of palmitate and significantly higher serum triglyceride levels prior to cachexia were further indicators of an early loss of lipid from the adipocytes. Yet, circulating levels of norepinephrine, epinephrine, TNF-α, and zinc α-2 glycoprotein were not increased prior to the loss of fat mass. We provide evidence for a serum factor(s), other than zinc alpha-2 glycoprotein, that stimulates release of glycerol from 3T3-L1 adipocytes and promotes the loss of stored adipose lipid prior to the loss of lean body mass in this model.

ACKNOWLEDGMENTS

We thank Sadie Hebert, Jun Zhou, Judy Wiles, Suzanne Trunick, and J. Mark Morris for their scientific contributions to this research. We graciously thank Laura Hale for supplying her mouse zinc alpha-2 glycoprotein antibodies and Luis Sanchez for supplying a human zinc alpha-2 glycoprotein standard to test ZAG antibodies as well as his expert comments and suggestions. This research was generously supported by a grant from the National Cancer Institute (R29CA060137), American Institute for Cancer Research, and institutional grants from Pennington Biomedical Research Center and the University of North Carolina at Charlotte.