The therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes.

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dc.contributor.authorFrkic, R.L.
dc.contributor.authorRichter, K.
dc.contributor.authorBruning, J.B.
dc.date.issued2021
dc.description.abstractA promising approach for treating type 2 diabetes mellitus (T2DM) is to target the Peroxisome Proliferator-Activated Receptor γ (PPARγ) transcription factor, which regulates the expression of proteins critical for T2DM. Mechanisms involved in PPARγ signaling are poorly understood, yet globally increasing T2DM prevalence demands improvements in drug design. Synthetic, nonactivating PPARγ ligands can abolish the phosphorylation of PPARγ at Ser273, a posttranslational modification correlated with obesity and insulin resistance. It is not understood how these ligands prevent phosphorylation, and the lack of experimental mechanistic information can be attributed to previous ambiguity in the field as well as to limitations in experimental approaches; in silico modeling currently provides the only insight into how ligands block Ser273 phosphorylation. The future availability of experimental evidence is critical for clarifying the mechanism by which ligands prevent phosphorylation and should be the priority of future T2DM-focused research. Following this, the properties of ligands that enable them to block phosphorylation can be improved upon to generate ligands tailored for blocking phosphorylation and therefore restoring insulin sensitivity. This would represent a significant step forward for treating T2DM. This review summarizes current knowledge of the roles of PPARγ in T2DM as well as the effects of synthetic ligands on the modulation of these roles. We hypothesize potential factors that contribute to the reduction in recent developments and summarize what has currently been done to shed light on this critical field of research.
dc.description.statementofresponsibilityRebecca L. Frkic, Katharina Richter, and John B. Bruning
dc.identifier.citationJournal of Biological Chemistry, 2021; 297(3):101030-1-101030-9
dc.identifier.doi10.1016/j.jbc.2021.101030
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.orcidFrkic, R.L. [0000-0003-0071-9018]
dc.identifier.orcidRichter, K. [0000-0003-2979-8215]
dc.identifier.orcidBruning, J.B. [0000-0002-6919-1824]
dc.identifier.urihttps://hdl.handle.net/2440/146428
dc.language.isoen
dc.publisherElsevier
dc.rights© 2021 The Authors. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttps://doi.org/10.1016/j.jbc.2021.101030
dc.subjectdrug design; phosphorylation; PPARγ; T2DM
dc.subject.meshHumans
dc.subject.meshDiabetes Mellitus, Type 2
dc.subject.meshInsulin Resistance
dc.subject.meshSerine
dc.subject.meshPPAR gamma
dc.subject.meshLigands
dc.subject.meshProtein Processing, Post-Translational
dc.subject.meshPhosphorylation
dc.titleThe therapeutic potential of inhibiting PPARγ phosphorylation to treat type 2 diabetes.
dc.typeJournal article
pubs.publication-statusPublished

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