According to the World Health Organization (WHO), 1.6 billion adults are overweight and 300 million people are obese worldwide. One of the major consequences of these high rates is manifested by the increased prevalence of Type II Diabetes Mellitus (T2D). The search for novel therapies requires a better understanding of the T2D pathophysiology. In this regard, there is still a considerable lack of knowledge concerning the immunopathogenesis of T2D. We discovered a natural phytohormone -- abscisic acid (ABA) -- with significant glucose normalizing and immunomodulatory properties, which may prove instrumental in exploring the links between immunity and T2D. Our preliminary data suggest that ABA ameliorates glucose tolerance and white adipose tissue (WAT) inflammation by acting on peroxisome proliferator-activated receptor γ (PPAR γ). Our long-term goal is to characterize the mechanisms by which ABA ameliorates obesity-related inflammation. Specific aim 1 will test the hypothesis that ABA down-modulates monocyte chemoattractant protein-1 (MCP-1) production through a PPAR γ-mediated blockade of nuclear factor-κB (NF-κB). More specifically, we will dissect the mechanisms of transcriptional regulation of MCP-1 expression by ABA by: 1) Determining the influence of ABA treatment on the DNA-binding activity of NF-κB in macrophages; 2) Investigating whether ABA represses the expression of NF-κB subunits or induces IκBα expression under inflammatory conditions, 3) Assessing the physical interaction of ABA-activated PPAR γ and RelA and its role in inhibiting MCP-1 expression in macrophages; and 4) Determining if ABA suppresses obesity-induced MCP-1 expression by activating PPAR γ and inhibiting NF-κB. Specific Aim 2 will evaluate the differential ability of ABA’s enantiomers and isomers to bind and activate PPAR γ in vitro and determine whether macrophage PPAR γ is required for ABA’s induced improvement of insulin resistance during diet-induced obesity.
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