ArticleNature2015
An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 178 papers.
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Who cites it
178 citing papers in PubMed, 290 citations in OpenAlex.
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- 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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- RAF1 in AgRP neurons involved in the regulation of energy metabolismJournal of biomedical research · 2025Article
- A tethering mechanism underlies Pin1-catalyzed prolineProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.Nature communications · 2025Article
- Diverse Physiological Roles of Kynurenine Pathway Metabolites: Updated Implications for Health and Disease.Metabolites · 2025Review
- CDK5: Insights into its roles in diseases.Molecular biology reports · 2025Review
- Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.Signal transduction and targeted therapy · 2025Review
- Macrophage MST1 protects against schistosomiasis-induced liver fibrosis by promoting the PPARγ-CD36 pathway and suppressing NF-κB signaling.PLoS pathogens · 2024Article
- SPA Promotes Atherosclerosis Through Mediating Macrophage Foam Cell Formation-Brief Report.Arteriosclerosis, thrombosis, and vascular biology · 2024Article
- Pharmacology of Aging:Aging biology · 2024Article
- Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation.Cells · 2024Article
- Diet-Induced Obesity Induces Transcriptomic Changes in Neuroimmunometabolic-Related Genes in the Striatum and Olfactory Bulb.International journal of molecular sciences · 2024Article
118 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 5 institutions in 1 country.
Funding
Abstract
Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.