TY - JOUR
T1 - The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting
AU - Elattar, Sawsan
AU - Dimri, Manali
AU - Satyanarayana, Ande
N1 - Funding Information:
The authors thank Dr. Patrick Seale (University of Pennsylvania, Philadelphia, PA, USA) for providing control and Prdm16 luciferase reporter vectors, and Dr. Mark Christian (University of Warwick, Coventry, United Kingdom) for providing Ucp1 luciferase vector. The authors thank Jinling Yuan (Georgia Cancer Center) for animal care and Georgia Cancer Center Small Animal Imaging Resource (Augusta, GA, USA) for technical help with multispectral optical imaging. The authors thank Dr. Rhea-Beth Markowitz (Augusta University) for reviewing and editing the manuscript. This research is supported by the U.S. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (Grant DP2DK105565 to A.S.). The authors declare no conflicts of interest.
Publisher Copyright:
© FASEB
PY - 2018/9
Y1 - 2018/9
N2 - Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-a 2 -glycoprotein (ZAG) induces WAT browning in mice. Increased circulating levels of ZAG not only induced lipolysis in adipose tissues but also caused robust browning in WAT. Stimulating WAT progenitors with ZAG recombinant protein or expression of ZAG in mouse embryonic fibroblasts (MEFs) strongly enhanced brown-like differentiation. At the molecular level, ZAG stimulated peroxisome proliferator–activated receptor g (PPARg) and early B cell factor 2 expression and promoted their recruitment to the PR/SET domain 16 (Prdm16) promoter, leading to enhanced expression of Prdm16, which determines brown cell fate. In brown adipose tissue, ZAG stimulated the expression of PPARg and PPARg coactivator 1a and promoted recruitment of PPARg to the uncoupling protein 1 (Ucp1) promoter, leading to increased expression of Ucp1. Overall, our results reveal a novel function of ZAG in WAT browning and highlight the targeting of ZAG as a potential therapeutic application in humans with cachexia.—Elattar, S., Dimri, M., Satyanarayana, A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.
AB - Cachexia is a complex tissue-wasting syndrome characterized by inflammation, hypermetabolism, increased energy expenditure, and anorexia. Browning of white adipose tissue (WAT) is one of the significant factors that contribute to energy wasting in cachexia. By utilizing a cell implantation model, we demonstrate here that the lipid mobilizing factor zinc-a 2 -glycoprotein (ZAG) induces WAT browning in mice. Increased circulating levels of ZAG not only induced lipolysis in adipose tissues but also caused robust browning in WAT. Stimulating WAT progenitors with ZAG recombinant protein or expression of ZAG in mouse embryonic fibroblasts (MEFs) strongly enhanced brown-like differentiation. At the molecular level, ZAG stimulated peroxisome proliferator–activated receptor g (PPARg) and early B cell factor 2 expression and promoted their recruitment to the PR/SET domain 16 (Prdm16) promoter, leading to enhanced expression of Prdm16, which determines brown cell fate. In brown adipose tissue, ZAG stimulated the expression of PPARg and PPARg coactivator 1a and promoted recruitment of PPARg to the uncoupling protein 1 (Ucp1) promoter, leading to increased expression of Ucp1. Overall, our results reveal a novel function of ZAG in WAT browning and highlight the targeting of ZAG as a potential therapeutic application in humans with cachexia.—Elattar, S., Dimri, M., Satyanarayana, A. The tumor secretory factor ZAG promotes white adipose tissue browning and energy wasting.
KW - Beige adipocyte
KW - Cachexia
KW - Ebf2
KW - Prdm16
KW - Ucp1
UR - http://www.scopus.com/inward/record.url?scp=85052473664&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052473664&partnerID=8YFLogxK
U2 - 10.1096/fj.201701465RR
DO - 10.1096/fj.201701465RR
M3 - Article
C2 - 29570397
AN - SCOPUS:85052473664
SN - 0892-6638
VL - 32
SP - 4727
EP - 4743
JO - FASEB Journal
JF - FASEB Journal
IS - 9
ER -