Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity

Authors: ZHANG, ZHUZHEN - University Of Texas Southwestern Medical Center; FUNCKE, JAN-BERND - University Of Texas Southwestern Medical Center; ZI, ZHENZHEN - University Of Texas Southwestern Medical Center; ZHAO, SHANGANG - University Of Texas Southwestern Medical Center; STRAUB, LEON - University Of Texas Southwestern Medical Center; ZHU, YI - Children'S Nutrition Research Center (CNRC); ZHU, QINGZHANG - University Of Texas Southwestern Medical Center; CREWE, CLAIR - University Of Texas Southwestern Medical Center; AN, YU - University Of Texas Southwestern Medical Center; CHEN, SHIUHWEI - University Of Texas Southwestern Medical Center; LI, NA - University Of Texas Southwestern Medical Center; WANG, MAY-YUN - University Of Texas Southwestern Medical Center; GHABEN, ALEXANDRA - University Of Texas Southwestern Medical Center; LEE, CHARLOTTE - University Of Texas Southwestern Medical Center; GAUTRON, LAURENT - University Of Texas Southwestern Medical Center; ENGELKING, LUKE - University Of Texas Southwestern Medical Center; RAJ, PRITHVI - University Of Texas Southwestern Medical Center; DENG, YINGFENG - University Of Texas Southwestern Medical Center; GORDILLO, RUTH - University Of Texas Southwestern Medical Center; KUSMINSKI, CHRISTINE - University Of Texas Southwestern Medical Center; SCHERER, PHILIPP - University Of Texas Southwestern Medical Center

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/20/2021
Publication Date: 8/3/2021
Citation: Zhang, Z., Funcke, J., Zi, Z., Zhao, S., Straub, L.G., Zhu, Y., Zhu, Q., Crewe, C., An, Y.A., Chen, S., Li, N., Wang, M., Ghaben, A.L., Lee, C., Gautron, L., Engelking, L.J., Raj, P., Deng, Y., Gordillo, R., Kusminski, C.M., Scherer, P.E. 2021. Adipocyte iron levels impinge on a fat-gut crosstalk to regulate intestinal lipid absorption and mediate protection from obesity. Cell Metabolism. 33:1-16. https://doi.org/10.1016/j.cmet.2021.06.001.
DOI: https://doi.org/10.1016/j.cmet.2021.06.001

Interpretive Summary: How iron affects adipose tissue, obesity, and the development of diabetes remains incompletely understood. This paper used genetic models with altered expression of irons import and export proteins in adipocytes. We demonstrated that low iron levels in adipocytes protected mice from diet-induced obesity. Mechanistically, adipocyte with low iron levels communicates with intestinal cells to reduce lipid absorption. This study highlights the essential role of adipocyte iron in the maintenance of systemic metabolism through an adipose tissue - intestine crosstalk.

Technical Abstract: Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption.