Regulation of white and brown adipocyte differentiation by RhoGAP DLC1
Sim C.K. Kim S.-Y. Brunmeir R. Zhang Q. Li H. Dharmasegaran D. Leong C. Lim Y.Y. Han W. Xu F.
Sim C.K.
Kim S.-Y.
Zhang Q.
Li H.
Dharmasegaran D.
Leong C.
Lim Y.Y.
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Alternative Title
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 superenhancer associated gene in both white and brown adipocytes through analyzing the genome-wide binding profiles of PPAR?, 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, PPAR? 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 PPAR? and Rho pathways. © 2017 Sim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords
F actin, peroxisome proliferator activated receptor gamma, Rho kinase, DLC1 protein, human, guanosine triphosphatase activating protein, peroxisome proliferator activated receptor gamma, rho GTPase-activating protein, small interfering RNA, tumor suppressor protein, adipogenesis, animal cell, animal tissue, Article, brown adipocyte, brown adipose tissue, cell differentiation, controlled study, DLC1 gene, embryo, female, fibroblast, gene, gene control, gene expression, gene identification, gene silencing, limit of quantitation, male, mitochondrial respiration, mouse, nonhuman, phenotype, protein binding, white adipocyte, brown adipocyte, cell culture, cell differentiation, chromatin immunoprecipitation, cytology, genetics, human, indirect calorimetry, metabolism, oxygen consumption, physiology, Western blotting, white adipocyte, Adipocytes, Brown, Adipocytes, White, Adipogenesis, Blotting, Western, Calorimetry, Indirect, Cell Differentiation, Cells, Cultured, Chromatin Immunoprecipitation, GTPase-Activating Proteins, Humans, Oxygen Consumption, PPAR gamma, RNA, Small Interfering, Tumor Suppressor Proteins
Source Title
PLoS ONE
Publisher
Series/Report No.
Collections
Rights
Attribution 4.0 International
Date
2017
DOI
10.1371/journal.pone.0174761
Type
Article