The thiazolidinediones (TZDs) are powerful 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, making it possible to design a better class of agents. PPAR?, the molecular target of the TZDs, is a key regulator of systemic insulin sensitivity, adipogenesis, inflammation, and energy homeostasis. In adipose tissue, phosphorylation of PPAR? 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 PPAR? target genes, such as decreased expression of the insulin-sensitizing hormone adiponectin. ERK is the primary kinase responsible for phosphorylating PPAR? S273, inhibitors of the MEK/ERK kinase pathway block PPAR? S273 phosphorylation. Surprisingly, MEK/ERK inhibitors had potent anti-diabetic effects in obese mice demonstrating markedly improved glucose homeostasis. Similarly, high-affinity ligands of PPAR??which lack the capacity to promote adipogenesis but still block S273 phosphorylation retain anti-diabetic effects. These two pharmacological interventions blocking PPAR? 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 PPAR? 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 PPAR? cannot be phosphorylated on S273 (S273A). Our preliminary data suggest that blocking this phosphorylation is sufficient to improve insulin sensitivity in obesity. In this proposal we will utilize three approaches to understand the contribution of PPAR? phosphorylation to the pathogenesis of obesity.
In Aim 1, we will interrogate the effects of PPAR? S273 phosphorylation on glucose homeostasis and the ability of PPAR? S273A mice to respond to PPAR? ligands.
In Aim 2, we will investigate the relative contribution of blocking S273 phosphorylation in the immune system to adipose tissue inflammation and insulin resistance.
In Aim 3, we will examine the genome-wide set of mRNA transcripts regulated and cis-regulatory elements bound to either wild-type PPAR? or phosphorylation independent S273A PPAR?. Understanding how obesity and inflammation modulates PPAR? by ERK- mediated phosphorylation will be important for the future design of new therapeutic molecules.

Public Health Relevance

While great progress has been made in decreasing the rate of death from cardiovascular diseases, stroke, and even cancer, diabetes related morbidity and mortality remain a steady threat to the US population. This work will help to test whether a specific protein found in fat and the immune system can be safely targeted for anti- diabetic modifications, leading towards development of novel therapeutics for the treatment of diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
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Silva, Corinne M
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Beth Israel Deaconess Medical Center
United States
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Mina, Amir I; LeClair, Raymond A; LeClair, Katherine B et al. (2018) CalR: A Web-Based Analysis Tool for Indirect Calorimetry Experiments. Cell Metab 28:656-666.e1
Hong, Shangyu; Song, Wei; Zushin, Peter-James H et al. (2018) Phosphorylation of Beta-3 adrenergic receptor at serine 247 by ERK MAP kinase drives lipolysis in obese adipocytes. Mol Metab 12:25-38
Khandekar, Melin J; Banks, Alexander S; Laznik-Bogoslavski, Dina et al. (2018) Noncanonical agonist PPAR? ligands modulate the response to DNA damage and sensitize cancer cells to cytotoxic chemotherapy. Proc Natl Acad Sci U S A 115:561-566
Palmer, Colin J; Bruckner, Raphael J; Paulo, Joao A et al. (2017) Cdkal1, a type 2 diabetes susceptibility gene, regulates mitochondrial function in adipose tissue. Mol Metab 6:1212-1225