ArticleCell metabolism2020
Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3.
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Article in Cell metabolism, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 95 citations in OpenAlex.
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- Dahuang Huanglian Xiexin Decoction Ameliorates Obesity by Targeting the PPARγ/STAT3/PTGS2 Axis: Integrative Network Pharmacology and Experimental Validation.Chemistry & biodiversity · 2026Article
- Serum GDF3 is Associated with Visceral Obesity, Insulin Resistance, and Inflammation in Non-Diabetic Adults: A Cross-Sectional Study with an Interventional Component.Diabetes, metabolic syndrome and obesity : targets and therapy · 2026Article
- Immunometabolism in obesity: Understanding the beneficial and detrimental roles of inflammation.PLoS biology · 2026Article
- Glucosylceramide regulates depression through activating peroxisome proliferator-activated receptor gamma in dorsal striatum.Theranostics · 2026Article
- GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging.Nature aging · 2026Article
- Structural determinants of non-covalent PPARγ inverse agonism and their therapeutic implications.Nature communications · 2025Article
- Small molecule inhibitor of PPARγ acetylation promotes insulin sensitization and browning of white adipose tissue with improved safety.bioRxiv : the preprint server for biology · 2025Article
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- Dynamic Rendition of Adipose Genes Under Epigenetic Regulation: Revealing New Mechanisms of Obesity Occurrence.Current issues in molecular biology · 2025Review
- Insulin resistance in type 2 diabetes mellitus.Nature reviews. Endocrinology · 2025Review
- Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.Nature communications · 2025Article
- Multi Targeted Activity of Cocculus hirsutus through Modulation of DPP-IV and PTP-1B Leading to Enhancement of Glucose Uptake and Attenuation of Lipid Accumulation.Applied biochemistry and biotechnology · 2025Article
- Diet-induced Obesity: Pathophysiology, Consequences and Target Specific Therapeutic Strategies.Current protein & peptide science · 2025Review
- The status and trends of type 2 diabetic osteoporosis research: a global bibliometric and visualization analysis over the past 20 years.Frontiers in clinical diabetes and healthcare · 2025Article
- Discovery of a novel binding pocket in PPARγ for partial agonists: structure-based virtual screening identifies ginsenoside Rg5 as a partial agonist promoting beige adipogenesis.Frontiers in chemistry · 2025Article
- Impact of Maternal BPA Exposure during Pregnancy on Obesity in Male Offspring: A Mechanistic Mouse Study of Adipose-Derived Exosomal miRNA.Environmental health perspectives · 2025Article
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Authors and funding
22 authors at 4 institutions in 1 country.
Jessica A HallDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Deepti RamachandranDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Hyun C RohDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Joanna R DiSpiritoDepartment of Immunology, Harvard Medical School, Boston, MA 02115, USA.
Thiago BelchiorDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Peter-James H ZushinDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Colin PalmerDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Shangyu HongDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Amir I MinaDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Bingyang LiuDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Zhaoming DengDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Pratik AryalDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Christopher JacobsDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Danielle TenenDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Chester W BrownDepartment of Pediatrics, University of Tennessee Health Science Center, Memphis, Memphis, TN 38103, USA.
Julia F CharlesDepartment of Orthopedics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gerald I ShulmanDepartment of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510, USA.
Barbara B KahnDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Linus T Y TsaiDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Evan D RosenDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Bruce M SpiegelmanDepartment of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02215, USA.
Alexander S BanksDivision of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. Electronic address: asbanks@bidmc.harvard.edu.
Harvard University · USBeth Israel Deaconess Medical Center · USUniversity of Tennessee Health Science Center · USYale University · US
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MCoordinating and Bioinformatics Unit for the MMPC/DiaCompU24DK076169 · NIDDK · AUGUSTA UNIVERSITY · PI MCINDOE, RICHARD A. · 2006 to 2018
$42.4MSTRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4MTransgenic CoreP30DK046200 · NIDDK · TUFTS MEDICAL CENTER · PI CORKEY, BARBARA E. · 1992 to 2021
$25.0MTRAINING GRANT IN ACADEMIC ENDOCRINOLOGYT32DK007529 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI Ursula B. Kaiser, Anand Vaidya · 1986 to 2026
$6.3MTranscriptional Mechanisms of Human Insulin ResistanceR01DK102173 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI ROSEN, EVAN D · 2015 to 2022
$4.4MMechanism of Gdf3 action to limit insulin sensitivity in obesityR01DK107717 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI BANKS, ALEXANDER · 2016 to 2023
$3.8MTGFbeta-mediated Transcriptional Reprogramming of Mature Adipocytes in ObesityR01DK113669 · NIDDK · BETH ISRAEL DEACONESS MEDICAL CENTER · PI ROSEN, EVAN D · 2017 to 2020
$2.2MInstrumentation for Noninvasive Measurement of Glucose and Energy Balance in Mice with Continuous Glucose Telemetry and Indirect CalorimetryS10OD028635 · OD · BETH ISRAEL DEACONESS MEDICAL CENTER · PI BANKS, ALEXANDER · 2020 to 2020
$737kModulation of PPAR-gamma phosphorylation at S273 regulates insulin sensitivityK01DK093638 · NIDDK · DANA-FARBER CANCER INST · PI BANKS, ALEXANDER · 2012 to 2014
$430kComprehensive Lab Animal Monitor System (CLAMS) for the Study of Mouse MetabolismS10OD020100 · OD · BRIGHAM AND WOMEN'S HOSPITAL · PI BANKS, ALEXANDER · 2015 to 2015
$419kNCATS NIH HHS UL1 TR001863NIDDK NIH HHS K01 DK093638NIDDK NIH HHS P30 DK034854NIDDK NIH HHS P30 DK046200NIDDK NIH HHS R01 DK102173NIDDK NIH HHS R01 DK107717NIDDK NIH HHS R01 DK113669NIDDK NIH HHS T32 DK007529NIDDK NIH HHS U24 DK076169NIH HHS S10 OD020100NIH HHS S10 OD028635
Abstract
The thiazolidinediones (TZDs) are ligands of PPARγ that improve insulin sensitivity, but their use is limited by significant side effects. Recently, we demonstrated a mechanism wherein 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 hasn't been tested genetically. Here we demonstrate that mice encoding an allele of PPARγ that 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 insulin sensitivity. RNA-seq in these mice reveals reduced expression of Gdf3, a BMP family member. Ectopic expression of Gdf3 is sufficient to induce insulin resistance in lean, healthy mice. We find Gdf3 inhibits BMP signaling and insulin signaling in vitro. Together, these results highlight the diabetogenic role of PPARγ S273 phosphorylation and focus attention on a putative target, Gdf3.
Indexed as
AllelesAnimalsCells, CulturedGrowth Differentiation Factor 3HumansInsulin ResistanceMaleMiceMice, Inbred C57BLObesityPhosphorylationPPAR gammaThiazolidinedionesGrowth Differentiation Factor 3PPAR gammaThiazolidinedionesadipose tissueBMPdiabetesGDF3inflammationinsulin resistancemacrophageobesityPPARγTGF-β
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