Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

Stephanie Pearson, Anne Loft, Prashant Rahbhandari, Judith Simcox, Sanghoon Lee, Peter Tontonoz, Susanne Mandrup, Claudio J Villanueva

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Resumé

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

OriginalsprogEngelsk
TidsskriftGenes & Development
Vol/bind33
Udgave nummer13-14
Sider (fra-til)747-762
Antal sider17
ISSN0890-9369
DOI
StatusUdgivet - 1. jul. 2019

Fingeraftryk

Transducin
Mitochondrial Genes
White Adipose Tissue
Chromatin Immunoprecipitation
Oxidative Phosphorylation
Adipocytes
Energy Metabolism
Beige Adipocytes
Adipose Tissue

Citer dette

Pearson, S., Loft, A., Rahbhandari, P., Simcox, J., Lee, S., Tontonoz, P., ... Villanueva, C. J. (2019). Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism. Genes & Development, 33(13-14), 747-762. https://doi.org/10.1101/gad.321059.118
Pearson, Stephanie ; Loft, Anne ; Rahbhandari, Prashant ; Simcox, Judith ; Lee, Sanghoon ; Tontonoz, Peter ; Mandrup, Susanne ; Villanueva, Claudio J. / Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism. I: Genes & Development. 2019 ; Bind 33, Nr. 13-14. s. 747-762.
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title = "Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism",
abstract = "Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.",
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Pearson, S, Loft, A, Rahbhandari, P, Simcox, J, Lee, S, Tontonoz, P, Mandrup, S & Villanueva, CJ 2019, 'Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism', Genes & Development, bind 33, nr. 13-14, s. 747-762. https://doi.org/10.1101/gad.321059.118

Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism. / Pearson, Stephanie; Loft, Anne; Rahbhandari, Prashant; Simcox, Judith; Lee, Sanghoon; Tontonoz, Peter; Mandrup, Susanne; Villanueva, Claudio J.

I: Genes & Development, Bind 33, Nr. 13-14, 01.07.2019, s. 747-762.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Loss of TLE3 promotes the mitochondrial program in beige adipocytes and improves glucose metabolism

AU - Pearson, Stephanie

AU - Loft, Anne

AU - Rahbhandari, Prashant

AU - Simcox, Judith

AU - Lee, Sanghoon

AU - Tontonoz, Peter

AU - Mandrup, Susanne

AU - Villanueva, Claudio J

N1 - © 2019 Pearson et al.; Published by Cold Spring Harbor Laboratory Press.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

AB - Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.

KW - TLE3

KW - adipocytes

KW - beige adipocytes

KW - development

KW - diabetes

KW - metabolism

KW - thermogenesis

U2 - 10.1101/gad.321059.118

DO - 10.1101/gad.321059.118

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JO - Genes & Development

JF - Genes & Development

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