Rab8 attenuates Wnt signaling and is required for mesenchymal differentiation into adipocytes

Authors: STYPULKOWSKI, EWA - Rutgers University; FENG, QIANG - Rutgers University; JOSEPH, IVOR - Rutgers University; FARRELL, VICTORIA - Rutgers University; FLORES, JUAN - Rutgers University; YU, SHIYAN - Rutgers University; SAKAMORI, RYOTARO - Rutgers University; SUN, JIAXIN - Rutgers University; BANDYOPADHYAY, SHEILA - Rutgers University; DAS, SOUMYASHREE - Rutgers University; DOBROWOLSKI, RADEK - Rutgers University; BONDER, EDWARD - Rutgers University; CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC); GAO, NAN - Rutgers Cancer Institute Of New Jersey

Submitted to: Journal of Biological Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/18/2021
Publication Date: 3/1/2021
Citation: Stypulkowski, E., Feng, Q., Joseph, I., Farrell, V., Flores, J., Yu, S., Sakamori, R., Sun, J., Bandyopadhyay, S., Das, S., Dobrowolski, R., Bonder, E.M., Chen, M., Gao, N. 2021. Rab8 attenuates Wnt signaling and is required for mesenchymal differentiation into adipocytes. Journal of Biological Chemistry. 296:100488. https://doi.org/10.1016/j.jbc.2021.100488.
DOI: https://doi.org/10.1016/j.jbc.2021.100488

Interpretive Summary: Fat cells can store excessive energy as fat in our body and generate hormones to regulate metabolism. While the function of fat cells has been widely studied, the processes governing the generation of fat cells from the precursor cells are poorly understood. In this paper, we identified two genes that are critical for the generation of fat cells and showed how these genes cooperate to control the process of generating fat cells. Further studies are needed to further explore these two genes and their impact on adiposity.

Technical Abstract: Differentiation of mesenchymal stem cells into adipocyte requires coordination of external stimuli and depends upon the functionality of primary cilium. The Rab8 small-GTPases are regulators of intracellular transport of membrane-bound structural and signaling cargo. However, the physiological contribution of the intrinsic trafficking network controlled by Rab8 to mesenchymal tissue differentiation has not been fully defined in vivo and in primary tissue cultures. Here, we show that mouse embryonic fibroblasts (MEFs) lacking Rab8 have severely impaired adipocyte differentiation in vivo and ex vivo. Immunofluorescent localization and biochemical analyses of Rab8a-deficient, Rab8b-deficient, and Rab8a and Rab8b double deficient MEFs revealed that Rab8 controls the Lrp6 vesicular compartment, clearance of basal signalosome, traffic of Frizzled 2 receptor, and thereby a proper attenuation of Wnt signaling in differentiating MEFs. Upon induction of adipogenesis program, Rab8a- and Rab8b-deficient MEFs exhibited severely defective lipid droplet formation and abnormal cilia morphology, despite overall intact cilia growth and ciliary cargo transport. Our results suggest that intracellular Rab8 traffic regulates induction of adipogenesis via proper positioning of Wnt receptors for signaling control in mesenchymal cells.