ArticleCell2015
Genetic Variation Determines PPARγ Function and Anti-diabetic Drug Response In Vivo.
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Article in Cell, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers.
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90citing papers in PubMed
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Who cites it
90 citing papers in PubMed, 123 citations in OpenAlex.
- Extensive enhancer crosstalk controls PPARG2 activation during adipogenesis.Nature communications · 2026Article
- The GPR124‑Wnt‑PPARγ regulatory axis: Molecular mechanisms and therapeutic implications in chronic inflammatory diseases (Review).International journal of molecular medicine · 2026Review
- Genetic variation shapes the chromatin accessibility landscape and transcriptional responses in mouse adipose tissue.PLoS genetics · 2026Article
- Molecular mechanism of the crosstalk between glucocorticoid receptor (GR) and hypoxia-inducible factor 3α (HIF-3α) pathways.Marine life science & technology · 2025Article
- Genetics-nutrition interactions control diurnal enhancer-promoter dynamics and liver lipid metabolism.Cell metabolism · 2025Article
- Transcriptional control of brown adipocyte differentiation and function by NFIA: recent perspectives on deciphering metabolic diseases.Journal of biochemistry · 2025Review
- Integrative multi-omic analysis reveals a PAX8-driven gene network linking tumor stemness to therapy response in ovarian cancer.NAR genomics and bioinformatics · 2025Article
- PPARG-centric transcriptional re-wiring during differentiation of human trophoblast stem cells into extravillous trophoblasts.Nucleic acids research · 2025Article
- Human genetic variation determines 24-hour rhythmic gene expression and disease risk.Nature communications · 2025Article
- Regulatory mechanisms of steroid hormone receptors on gene transcription through chromatin interaction and enhancer reprogramming.Cellular oncology (Dordrecht, Netherlands) · 2024Review
- Genetic variation is a key determinant of chromatin accessibility and drives differences in the regulatory landscape of C57BL/6J and 129S1/SvImJ mice.Nucleic acids research · 2024Article
- Interactions between diabetic and hypertensive drugs: a pharmacogenetics approach.Molecular genetics and genomics : MGG · 2023Review
- PPARγ lipodystrophy mutants reveal intermolecular interactions required for enhancer activation.Nature communications · 2022Article
- Transcriptional control of energy metabolism by nuclear receptors.Nature reviews. Molecular cell biology · 2022Review
- NFIA determines theiScience · 2022Article
- Structures and consequences of pioneer factor binding to nucleosomes.Current opinion in structural biology · 2022Review
- HNF4A modulates glucocorticoid action in the liver.Cell reports · 2022Article
- CHD7 regulates bone-fat balance by suppressing PPAR-γ signaling.Nature communications · 2022Article
- Isoform-specific functions of PPARγ in gene regulation and metabolism.Genes & development · 2022Article
- Gut microbiota specifically mediates the anti-hypercholesterolemic effect of berberine (BBR) and facilitates to predict BBR's cholesterol-decreasing efficacy in patients.Journal of advanced research · 2022Article
30 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 4 institutions in 1 country.
Raymond E SoccioDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Eric R ChenDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Satyajit R RajapurkarDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Pegah SafabakhshDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Jill M MarinisDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Joanna R DispiritoDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Matthew J EmmettDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Erika R BriggsDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Bin FangDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Logan J EverettDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Hee-Woong LimInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Kyoung-Jae WonInstitute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
David J StegerDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Ying WuDepartment of Genetics, University of North Carolina, Chapel Hill, NC 27599, USA.
Mete CivelekDepartment of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Benjamin F VoightDepartment of Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Mitchell A LazarDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: lazar@mail.med.upenn.edu.
University of Pennsylvania · USTranslational Therapeutics (United States) · USUniversity of California, Los Angeles · USUniversity of North Carolina at Chapel Hill · US
Funding
Systems genomics of metabolic syndrome traitsP01HL028481 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI REUE, KAREN · 1985 to 2019
$50.2MVIRAL VECTOR COREP30DK019525 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI MITCHELL A. LAZAR · 1986 to 2026
$48.3MZINC FINGER PROTEINS IN EARLY KIDNEY DEVELOPMENTP01DK049210 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI AHIMA, REXFORD S. · 1995 to 2016
$26.9MNuclear Receptors in Metabolic TissuesR01DK049780 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI LAZAR, MITCHELL A. · 1995 to 2025
$10.8MDiabetes, Endocrine, and MetabolismT32DK007314 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI DORIS A STOFFERS, Patrick Seale · 1986 to 2026
$9.0MAlgorithms to identify non-coding mutational burden and disease-relevant pathwaysR01DK101478 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI VOIGHT, BENJAMIN FRANKLIN · 2014 to 2018
$2.9MTranscriptional and epigenomic control of adipose tissue development and functionR01DK098542 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI STEGER, DAVID J. · 2013 to 2017
$1.7MTranslating human PPARy binding regions to gene regulation and metabolic diseaseK08DK094968 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI SOCCIO, RAYMOND EDWARD · 2012 to 2016
$775kSystems genetics analysis of cardiometabolic trait loci in humans R00HL121172 · NHLBI · UNIVERSITY OF VIRGINIA · PI CIVELEK, METE · 2016 to 2018
$741kAn Integrative Approach to Construct a Regulatory Network Effected by TDZsR21DK098769 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI WON, KYOUNG JAE · 2013 to 2014
$440kSystems genetics analysis of cardiometabolic trait loci in humans K99HL121172 · NHLBI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CIVELEK, METE · 2014 to 2015
$247kControl of Brown Adipose Physiology Via Genomic Recruitment of Histone Deacetylase 3F30DK104513 · NIDDK · UNIVERSITY OF PENNSYLVANIA · PI EMMETT, MATTHEW J · 2014 to 2016
$106kNHLBI NIH HHS K99 HL121172NHLBI NIH HHS K99-HL121172NHLBI NIH HHS P01 HL028481NHLBI NIH HHS P01-HL028481NHLBI NIH HHS R00 HL121172NIDDK NIH HHS F30 DK104513NIDDK NIH HHS K08 DK094968NIDDK NIH HHS K08-DK094968NIDDK NIH HHS P01 DK049210NIDDK NIH HHS P30 DK019525NIDDK NIH HHS P30-DK19525NIDDK NIH HHS R01 DK049780NIDDK NIH HHS R01 DK098542NIDDK NIH HHS R01 DK101478NIDDK NIH HHS R01-DK101478NIDDK NIH HHS R01-DK49780NIDDK NIH HHS R21 DK098769NIDDK NIH HHS R21-DK098769NIDDK NIH HHS T32 DK007314
Abstract
SNPs affecting disease risk often reside in non-coding genomic regions. Here, we show that SNPs are highly enriched at mouse strain-selective adipose tissue binding sites for PPARγ, a nuclear receptor for anti-diabetic drugs. Many such SNPs alter binding motifs for PPARγ or cooperating factors and functionally regulate nearby genes whose expression is strain selective and imbalanced in heterozygous F1 mice. Moreover, genetically determined binding of PPARγ accounts for mouse strain-specific transcriptional effects of TZD drugs, providing proof of concept for personalized medicine related to nuclear receptor genomic occupancy. In human fat, motif-altering SNPs cause differential PPARγ binding, provide a molecular mechanism for some expression quantitative trait loci, and are risk factors for dysmetabolic traits in genome-wide association studies. One PPARγ motif-altering SNP is associated with HDL levels and other metabolic syndrome parameters. Thus, natural genetic variation in PPARγ genomic occupancy determines individual disease risk and drug response.
Indexed as
Polymorphism, Single NucleotideAdipose TissueAnimalsGene ExpressionHumansHypoglycemic AgentsMiceMice, 129 StrainMice, Inbred C57BLPPAR gammaTranscription FactorsHypoglycemic AgentsPPAR gammaTranscription Factors
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