The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

Kathrin Landgraf; Nora Klöting; Martin Gericke; Nitzan Maixner; Esther Guiu-Jurado; Markus Scholz; A. Veronica Witte; Frauke Beyer; Julian T. Schwartze; Martin Lacher; Arno Villringer; Peter Kovacs; Assaf Rudich; Matthias Blüher; Wieland Kiess; Antje Körner

doi:10.1016/j.celrep.2020.108295

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

Kathrin Landgraf, Nora Klöting, Martin Gericke, Nitzan Maixner, Esther Guiu-Jurado, Markus Scholz, A. Veronica Witte, Frauke Beyer, Julian T. Schwartze, Martin Lacher, Arno Villringer, Peter Kovacs, Assaf Rudich, Matthias Blüher, Wieland Kiess, Antje Körner

Ben-Gurion University of the Negev

Research output: Contribution to journal › Article › peer-review

Abstract

TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.

Original language	American English
Article number	108295
Journal	Cell Reports
Volume	33
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2020.108295
State	Published - 20 Oct 2020

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

PPARG
TMEM18
adipogenesis
adipose progenitor cells
adipose tissue
adipose tissue dysfunction
children
obesity
zebrafish

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2020.108295

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Landgraf, K., Klöting, N., Gericke, M., Maixner, N., Guiu-Jurado, E., Scholz, M., Witte, A. V., Beyer, F., Schwartze, J. T., Lacher, M., Villringer, A., Kovacs, P., Rudich, A., Blüher, M., Kiess, W., & Körner, A. (2020). The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG. Cell Reports, 33(3), Article 108295. https://doi.org/10.1016/j.celrep.2020.108295

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title = "The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG",

abstract = "TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.",

keywords = "PPARG, TMEM18, adipogenesis, adipose progenitor cells, adipose tissue, adipose tissue dysfunction, children, obesity, zebrafish",

author = "Kathrin Landgraf and Nora Kl{\"o}ting and Martin Gericke and Nitzan Maixner and Esther Guiu-Jurado and Markus Scholz and Witte, \{A. Veronica\} and Frauke Beyer and Schwartze, \{Julian T.\} and Martin Lacher and Arno Villringer and Peter Kovacs and Assaf Rudich and Matthias Bl{\"u}her and Wieland Kiess and Antje K{\"o}rner",

note = "Publisher Copyright: {\textcopyright} 2020 The Authors",

year = "2020",

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doi = "10.1016/j.celrep.2020.108295",

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Landgraf, K, Klöting, N, Gericke, M, Maixner, N, Guiu-Jurado, E, Scholz, M, Witte, AV, Beyer, F, Schwartze, JT, Lacher, M, Villringer, A, Kovacs, P, Rudich, A, Blüher, M, Kiess, W & Körner, A 2020, 'The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG', Cell Reports, vol. 33, no. 3, 108295. https://doi.org/10.1016/j.celrep.2020.108295

TY - JOUR

T1 - The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

AU - Landgraf, Kathrin

AU - Klöting, Nora

AU - Gericke, Martin

AU - Maixner, Nitzan

AU - Guiu-Jurado, Esther

AU - Scholz, Markus

AU - Witte, A. Veronica

AU - Beyer, Frauke

AU - Schwartze, Julian T.

AU - Lacher, Martin

AU - Villringer, Arno

AU - Kovacs, Peter

AU - Rudich, Assaf

AU - Blüher, Matthias

AU - Kiess, Wieland

AU - Körner, Antje

PY - 2020/10/20

Y1 - 2020/10/20

N2 - TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.

AB - TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.

KW - PPARG

KW - TMEM18

KW - adipogenesis

KW - adipose progenitor cells

KW - adipose tissue

KW - adipose tissue dysfunction

KW - children

KW - obesity

KW - zebrafish

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DO - 10.1016/j.celrep.2020.108295

M3 - Article

C2 - 33086065

SN - 2211-1247

VL - 33

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 108295

ER -

The Obesity-Susceptibility Gene TMEM18 Promotes Adipogenesis through Activation of PPARG

Abstract

UN SDGs

Keywords

All Science Journal Classification (ASJC) codes

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