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Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3

Jessica A. Hall, Deepti Ramachandran, Hyun C. Roh, Joanna R. DiSpirito, Thiago Belchior, Peter-James H. Zushin, Colin J. Palmer, Shangyu Hong, Amir I. Mina, Bingyang Liu, Zhaoming Deng, Pratik Aryal, Christopher Jacobs, Danielle Tenen, Chester W. Brown, Julia F. Charles, Gerald I. Shulman, Barbara B. Kahn, Linus T.Y. Tsai, Evan D. Rosen, Bruce M. Spiegelman, View ORCID ProfileAlexander S. Banks
doi: https://doi.org/10.1101/2020.01.13.904953
Jessica A. Hall
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Deepti Ramachandran
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Hyun C. Roh
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Joanna R. DiSpirito
2Department of Immunology, Harvard Medical School, Boston, MA
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Thiago Belchior
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Peter-James H. Zushin
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Colin J. Palmer
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Shangyu Hong
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Amir I. Mina
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Bingyang Liu
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Zhaoming Deng
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Pratik Aryal
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Christopher Jacobs
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Danielle Tenen
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Chester W. Brown
3Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Memphis, TN
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Julia F. Charles
4Department of Orthopedics, Brigham and Women’s Hospital, and Harvard Medical School Boston, MA
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Gerald I. Shulman
5Department of Internal Medicine, Yale University School of Medicine, New Haven, CT
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Barbara B. Kahn
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Linus T.Y. Tsai
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Evan D. Rosen
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Bruce M. Spiegelman
6Dana-Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA
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Alexander S. Banks
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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  • ORCID record for Alexander S. Banks
  • For correspondence: asbanks@bidmc.harvard.edu
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Abstract

Overnutrition and obesity promote adipose tissue dysfunction, often leading to systemic insulin resistance. The thiazolidinediones (TZDs) are a potent class of insulin-sensitizing drugs and ligands of PPARγ that improve insulin sensitivity, but their use is limited due to significant side effects. Recently, we demonstrated a mechanism by which TZDs improve insulin sensitivity distinct from receptor agonism and adipogenesis: reversal of obesity-linked phosphorylation of PPARγ at Serine 273. However, the role of this modification has not been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ which cannot be phosphorylated at S273 are protected from insulin resistance, without exhibiting differences in body weight or TZD-associated side effects. Indeed, hyperinsulinemic-euglycemic clamp experiments confirm improved insulin sensitivity, as evidenced by increased whole-body glucose uptake. RNA-seq experiments reveal PPARγ S273 phosphorylation specifically enhances transcription of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find that Gdf3 can impact metabolism by inhibition of BMP signaling. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focuses attention on a putative target, Gdf3.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 14, 2020.
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Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3
Jessica A. Hall, Deepti Ramachandran, Hyun C. Roh, Joanna R. DiSpirito, Thiago Belchior, Peter-James H. Zushin, Colin J. Palmer, Shangyu Hong, Amir I. Mina, Bingyang Liu, Zhaoming Deng, Pratik Aryal, Christopher Jacobs, Danielle Tenen, Chester W. Brown, Julia F. Charles, Gerald I. Shulman, Barbara B. Kahn, Linus T.Y. Tsai, Evan D. Rosen, Bruce M. Spiegelman, Alexander S. Banks
bioRxiv 2020.01.13.904953; doi: https://doi.org/10.1101/2020.01.13.904953
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Obesity-linked PPARγ S273 phosphorylation promotes insulin resistance through Growth Differentiation Factor 3
Jessica A. Hall, Deepti Ramachandran, Hyun C. Roh, Joanna R. DiSpirito, Thiago Belchior, Peter-James H. Zushin, Colin J. Palmer, Shangyu Hong, Amir I. Mina, Bingyang Liu, Zhaoming Deng, Pratik Aryal, Christopher Jacobs, Danielle Tenen, Chester W. Brown, Julia F. Charles, Gerald I. Shulman, Barbara B. Kahn, Linus T.Y. Tsai, Evan D. Rosen, Bruce M. Spiegelman, Alexander S. Banks
bioRxiv 2020.01.13.904953; doi: https://doi.org/10.1101/2020.01.13.904953

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