Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance

Cecile Vernochet; Arnaud Mourier; Olivier Bezy; Yazmin Macotela; Jeremie Boucher; Matthew J Rardin; Ding An; Kevin Y Lee; Olga R Ilkayeva; Cristina M Zingaretti; Brice Emanuelli; Graham Smyth; Saverio Cinti; Christopher B Newgard; Bradford W Gibson; Nils-Göran Larsson; C Ronald Kahn

doi:10.1016/j.cmet.2012.10.016

Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance

Cecile Vernochet, Arnaud Mourier, Olivier Bezy, Yazmin Macotela, Jeremie Boucher, Matthew J Rardin, Ding An, Kevin Y Lee, Olga R Ilkayeva, Cristina M Zingaretti, Brice Emanuelli, Graham Smyth, Saverio Cinti, Christopher B Newgard, Bradford W Gibson, Nils-Göran Larsson, C Ronald Kahn

130 Citationer (Scopus)

Abstract

Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole-body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance, and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects, suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity.

Originalsprog	Engelsk
Tidsskrift	Cell Metabolism
Vol/bind	16
Udgave nummer	6
Sider (fra-til)	765-76
Antal sider	12
ISSN	1550-4131
DOI	https://doi.org/10.1016/j.cmet.2012.10.016
Status	Udgivet - 5 dec. 2012

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Vernochet, C., Mourier, A., Bezy, O., Macotela, Y., Boucher, J., Rardin, M. J., An, D., Lee, K. Y., Ilkayeva, O. R., Zingaretti, C. M., Emanuelli, B., Smyth, G., Cinti, S., Newgard, C. B., Gibson, B. W., Larsson, N-G., & Kahn, C. R. (2012). Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance. Cell Metabolism, 16(6), 765-76. https://doi.org/10.1016/j.cmet.2012.10.016

Vernochet, C, Mourier, A, Bezy, O, Macotela, Y, Boucher, J, Rardin, MJ, An, D, Lee, KY, Ilkayeva, OR, Zingaretti, CM, Emanuelli, B, Smyth, G, Cinti, S, Newgard, CB, Gibson, BW, Larsson, N-G & Kahn, CR 2012, 'Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance', Cell Metabolism, bind 16, nr. 6, s. 765-76. https://doi.org/10.1016/j.cmet.2012.10.016

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title = "Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance",

abstract = "Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole-body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance, and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects, suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity.",

keywords = "Adipose Tissue, Brown, Adipose Tissue, White, Animals, Cell Line, DNA, Mitochondrial, DNA-Binding Proteins, Electron Transport Complex I, Energy Metabolism, Insulin Resistance, Mice, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Obesity, Oxidative Phosphorylation, Oxygen, Transcription Factors",

author = "Cecile Vernochet and Arnaud Mourier and Olivier Bezy and Yazmin Macotela and Jeremie Boucher and Rardin, {Matthew J} and Ding An and Lee, {Kevin Y} and Ilkayeva, {Olga R} and Zingaretti, {Cristina M} and Brice Emanuelli and Graham Smyth and Saverio Cinti and Newgard, {Christopher B} and Gibson, {Bradford W} and Nils-G{\"o}ran Larsson and Kahn, {C Ronald}",

year = "2012",

month = dec,

day = "5",

doi = "10.1016/j.cmet.2012.10.016",

language = "English",

volume = "16",

pages = "765--76",

journal = "Cell Metabolism",

issn = "1550-4131",

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TY - JOUR

T1 - Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance

AU - Vernochet, Cecile

AU - Mourier, Arnaud

AU - Bezy, Olivier

AU - Macotela, Yazmin

AU - Boucher, Jeremie

AU - Rardin, Matthew J

AU - An, Ding

AU - Lee, Kevin Y

AU - Ilkayeva, Olga R

AU - Zingaretti, Cristina M

AU - Emanuelli, Brice

AU - Smyth, Graham

AU - Cinti, Saverio

AU - Newgard, Christopher B

AU - Gibson, Bradford W

AU - Larsson, Nils-Göran

AU - Kahn, C Ronald

PY - 2012/12/5

Y1 - 2012/12/5

N2 - Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole-body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance, and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects, suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity.

AB - Obesity and type 2 diabetes are associated with mitochondrial dysfunction in adipose tissue, but the role for adipose tissue mitochondria in the development of these disorders is currently unknown. To understand the impact of adipose tissue mitochondria on whole-body metabolism, we have generated a mouse model with disruption of the mitochondrial transcription factor A (TFAM) specifically in fat. F-TFKO adipose tissue exhibit decreased mtDNA copy number, altered levels of proteins of the electron transport chain, and perturbed mitochondrial function with decreased complex I activity and greater oxygen consumption and uncoupling. As a result, F-TFKO mice exhibit higher energy expenditure and are protected from age- and diet-induced obesity, insulin resistance, and hepatosteatosis, despite a greater food intake. Thus, TFAM deletion in the adipose tissue increases mitochondrial oxidation that has positive metabolic effects, suggesting that regulation of adipose tissue mitochondria may be a potential therapeutic target for the treatment of obesity.

KW - Adipose Tissue, Brown

KW - Adipose Tissue, White

KW - Animals

KW - Cell Line

KW - DNA, Mitochondrial

KW - DNA-Binding Proteins

KW - Electron Transport Complex I

KW - Energy Metabolism

KW - Insulin Resistance

KW - Mice

KW - Mice, Knockout

KW - Mitochondria

KW - Mitochondrial Proteins

KW - Obesity

KW - Oxidative Phosphorylation

KW - Oxygen

KW - Transcription Factors

U2 - 10.1016/j.cmet.2012.10.016

DO - 10.1016/j.cmet.2012.10.016

M3 - Journal article

C2 - 23168219

SN - 1550-4131

VL - 16

SP - 765

EP - 776

JO - Cell Metabolism

JF - Cell Metabolism

IS - 6

ER -

Adipose-specific deletion of TFAM increases mitochondrial oxidation and protects mice against obesity and insulin resistance

Abstract

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