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 tissues1. 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-agonists2. 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 

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. Access through your

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BEING VIEWED BY OTHERS CDK6 INHIBITS DE NOVO LIPOGENESIS IN WHITE ADIPOSE TISSUES BUT NOT IN THE LIVER Article Open access 05 February 2024 THE CYCLIN DEPENDENT KINASE INHIBITOR ROSCOVITINE

PREVENTS DIET-INDUCED METABOLIC DISRUPTION IN OBESE MICE Article Open access 13 October 2021 P21-ACTIVATED KINASE 4 COUNTERACTS PKA-DEPENDENT LIPOLYSIS BY PHOSPHORYLATING FABP4 AND HSL

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4, 207–214 (2007) CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS We thank E. Rosen for providing us with the adiponectin Cre mice before their initial publication; members

of the Spiegelman laboratory (Dana-Farber Cancer Institute) and D. Cohen (Brigham and Women's Hospital) for discussions; and C. Palmer and K. LeClair for reading the manuscript. B.M.S.

acknowledges National Institutes of Health (NIH) grant DK31405. A.B. acknowledges NIH grant DK93638, the Harvard University Milton Fund, and the Harvard Digestive Disease Center, Core D.

AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115,

Massachusetts, USA Alexander S. Banks & Peter-James H. Zushin * Department of Cell Biology, Harvard Medical School, Boston, 02115, Massachusetts, USA Fiona E. McAllister, Steven P. Gygi 

& Bruce M. Spiegelman * Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven,

06510, Connecticut, USA João Paulo G. Camporez, Michael J. Jurczak & Gerald I. Shulman * Dana-Farber Cancer Institute, Boston, 02115, Massachusetts, USA Dina Laznik-Bogoslavski & 

Bruce M. Spiegelman Authors * Alexander S. Banks View author publications You can also search for this author inPubMed Google Scholar * Fiona E. McAllister View author publications You can

also search for this author inPubMed Google Scholar * João Paulo G. Camporez View author publications You can also search for this author inPubMed Google Scholar * Peter-James H. Zushin View

author publications You can also search for this author inPubMed Google Scholar * Michael J. Jurczak View author publications You can also search for this author inPubMed Google Scholar *

Dina Laznik-Bogoslavski View author publications You can also search for this author inPubMed Google Scholar * Gerald I. Shulman View author publications You can also search for this author

inPubMed Google Scholar * Steven P. Gygi View author publications You can also search for this author inPubMed Google Scholar * Bruce M. Spiegelman View author publications You can also

search for this author inPubMed Google Scholar CONTRIBUTIONS A.B., B.M.S., F.E., S.G., J.P.C., M.J. and G.S. designed the experiments. A.B., D.B., F.E., J.C.P. and P.Z. performed the

experiments. A.B., B.M.S. and F.E. wrote the manuscript. CORRESPONDING AUTHORS Correspondence to Alexander S. Banks or Bruce M. Spiegelman. ETHICS DECLARATIONS COMPETING INTERESTS B.M.S. is

a consultant to and shareholder in Ember Therapeutics. The remaining authors declare no competing interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 METABOLIC PROFILING OF

ADIPOSE-SPECIFIC CDK5-KO MICE ON A STANDARD CHOW DIET. A–E, Fasting plasma levels of glucose (A), insulin (B), total triacylglycerols (C), free fatty acids (FFA) (D) and total cholesterol

(E) (_n_ = 16 (control) and 17 (KO)). F, G, Body weights (F) and intraperitoneal glucose tolerance test (G). Mice were 12 weeks of age (_n_ = 14 (control) and 11 (KO)). No significant

differences were observed. Error bars indicate s.e.m. EXTENDED DATA FIGURE 2 ENERGY HOMEOSTASIS OF ADIPOSE-SPECIFIC CDK5-KO MICE MAINTAINED ON A HIGH-FAT DIET. A–F, After a 48-h

acclimatization period, singly housed mice were monitored for oxygen consumption (_V_O2) (A), carbon dioxide production (_V_CO2) (B), respiratory exchange ratio (RER) (C), ambulatory

locomotor activity (D), cumulative food intake (E) and body weights (F) (_n_ = 8 per group). Shaded areas signify the dark phase of the light cycle. No significant differences were observed.

Error bars indicate s.e.m. EXTENDED DATA FIGURE 3 ACTIVITY OF ALTERNATIVE KINASES IN ADIPOSE TISSUE FROM CDK5-KO MICE. Brown adipose tissue protein lysates from mice maintained on a

high-fat diet for 12 weeks. Blotting for phospho-p38, phospho-JNK and phospho-S473 and pT308 AKT was performed before loading for total protein amounts. EXTENDED DATA FIGURE 4 CONSERVATION

OF THE SITES ON MEK2 PHOSPHORYLATED BY CDK5. Mouse MEK2 T395/T397 corresponds to human MEK2 T394/T396. These sites share identity with MEK1 T386/T388 in both humans and mouse. Cdk5 has

previously been shown to phosphorylate MEK1 at T286, a site not shared with MEK2. ERK has been shown to phosphorylate MEK1 T386 and contribute to regulation of kinase activity31. Homo, _Homo

sapiens_; trog, _Pan troglodytes_; mus, _Mus musculus_; rat, _Rattus norvegicus_; bos, _Bos taurus_; canis, _Canis lupus familiaris_. EXTENDED DATA FIGURE 5 BODY WEIGHT OF CONTROL AND OF

ADIPOSE-SPECIFIC CDK5-KO MICE MAINTAINED ON A HIGH-FAT DIET AFTER TREATMENT WITH PD0325901. Treatment similar to that in Fig. 4a–c. The body weights are not significantly different by ANOVA.

Error bars indicate s.e.m. EXTENDED DATA FIGURE 6 EFFECTS OF PD0325901 TREATMENT ON _OB_/_OB_ MICE. A–C, Glucose tolerance test (A), adiponectin levels (B) and body weights (C) of _ob_/_ob_

mice treated with PD0325901 (_n_ = 7 (vehicle) and 8 (PD)). *_P_ ≤ 0.05 by Student’s _t_-test. Error bars indicate s.e.m. EXTENDED DATA FIGURE 7 INFLAMMATORY MARKERS IN EPIDIDYMAL WHITE

ADIPOSE TISSUE FROM _OB_/_OB_ MICE TREATED WITH MEK INHIBITORS. Gene expression analysis was performed on M1 macrophage markers Nos2 and tumour necrosis factor-α (TNF-α); M2 macrophage

markers Arg1, Chil3, Il10, Itgax, Clec10a/Mgl1 and Mgl2; chemotactic ligand Ccl2 and receptor Ccr2; and macrophage surface markers Emr1, Cd68 and Csf1r (_n_ = 7 or 8 mice per group as in

Fig. 5f, h). Gene expression was analysed by ANOVA. Error bars indicate s.e.m. *_P_ < 0.05; **_P_ < 0.01; ***_P_ < 0.001. EXTENDED DATA FIGURE 8 SCHEMATIC MODEL OF PPARΓ REGULATION

AT S273. A, In the lean state, PPARγ is not phosphorylated. B, In the obese state, S273 phosphorylation is driven by both Cdk5 and ERK with CDK5 repressing MEK and ERK activity. C, Cdk5-KO

results in derepression of MEK and ERK kinases and increased phosphorylation of S273 PPARγ. D, MEK inhibition markedly decreases S273 PPARγ phosphorylation. E, PPARγ ligands, including the

thiazolidinediones, block the accessibility of S273 PPARγ by either ERK or CDK5 kinases. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3

POWERPOINT SLIDE FOR FIG. 4 POWERPOINT SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Banks, A., McAllister, F., Camporez, J. _et al._

An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ. _Nature_ 517, 391–395 (2015). https://doi.org/10.1038/nature13887 Download citation * Received: 16 January 2014 * Accepted: 22

September 2014 * Published: 17 November 2014 * Issue Date: 15 January 2015 * DOI: https://doi.org/10.1038/nature13887 SHARE THIS ARTICLE Anyone you share the following link with will be able

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