The thiazolidinediones (TZDs) are anti-diabetic drugs whose use in treating type 2 diabetes is limited by adverse side effects. The goal of this proposal is a biochemical investigation into a mechanism that separates the positive metabolic effects of TZDs from their side effects. PPAR³, the molecular target of the TZDs, is a key regulator of systemic insulin sensitivity, adipogenesis, inflammation, and energy homeostasis. In adipose tissue, phosphorylation of PPAR³ at serine 273 (S273) is observed shortly after the initiation of high fat diet feeding and increases with progressive obesity. This phosphorylation correlates with dysregulation of PPAR³ target genes. ERK is the primary kinase responsible for phosphorylating PPAR³ S273, inhibitors of the MEK/ERK kinase pathway block PPAR³ S273 phosphorylation. Surprisingly, MEK/ERK inhibitors had anti-diabetic effects in obese mice demonstrating markedly improved glucose homeostasis. Similarly, ligands of PPAR³ which lack the capacity to promote adipogenesis but still block S273 phosphorylation retain anti-diabetic effects. These two pharmacological interventions blocking PPAR³ S273 phosphorylation both promote improved peripheral metabolic homeostasis like the TZDs while also appearing safer as they do not trigger the side effects associated with TZDs. Our hypothesis is that ERK-mediated phosphorylation of PPAR³ in obesity and inflammation causes altered impaired glucose homeostasis by targeting adipose tissue transcriptional regulation. We will test this hypothesis using a novel genetically modified mouse where PPAR³ cannot be phosphorylated on S273 (S273A).
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