title: Regulation of white and brown adipocyte differentiation by RhoGAP DLC1.
abstract: Adipose tissues constitute an important component of metabolism, the dysfunction of which can cause obesity and type II diabetes. Here we show that differentiation of white and brown adipocytes requires Deleted in Liver Cancer 1 (DLC1), a Rho GTPase Activating Protein (RhoGAP) previously studied for its function in liver cancer. We identified Dlc1 as a super-enhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPARγ, the master regulator of adipogenesis. We further observed that Dlc1 expression increases during differentiation, and knockdown of Dlc1 by siRNA in white adipocytes reduces the formation of lipid droplets and the expression of fat marker genes. Moreover, knockdown of Dlc1 in brown adipocytes reduces expression of brown fat-specific genes and diminishes mitochondrial respiration. Dlc1-/- knockout mouse embryonic fibroblasts show a complete inability to differentiate into adipocytes, but this phenotype can be rescued by inhibitors of Rho-associated kinase (ROCK) and filamentous actin (F-actin), suggesting the involvement of Rho pathway in DLC1-regulated adipocyte differentiation. Furthermore, PPARγ binds to the promoter of Dlc1 gene to regulate its expression during both white and brown adipocyte differentiation. These results identify DLC1 as an activator of white and brown adipocyte differentiation, and provide a molecular link between PPARγ and Rho pathways.
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Choon Kiat
authors.initials: CK
authors.lastname: Sim
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.|Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore.
authors.forename: Sun-Yee
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Brunmeir
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Qiongyi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Li
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Dharmini
authors.initials: D
authors.lastname: Dharmasegaran
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Carol
authors.initials: C
authors.lastname: Leong
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Ying Yan
authors.initials: YY
authors.lastname: Lim
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
authors.affiliation: Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*STAR), Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Feng
authors.identifier: http://orcid.org/0000-0003-2016-7521
authors.initials: F
authors.lastname: Xu
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology* / Q000378:metabolism*; D052438:Adipocytes, White / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D002153:Calorimetry, Indirect; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010101:Oxygen Consumption / Q000235:genetics / Q000502:physiology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C112352:DLC1 protein, human; D020690:GTPase-Activating Proteins; D047495:PPAR gamma; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C085379:rho GTPase-activating protein