Final Report Summary - OBESITY AND IMMUNITY (Prevention of Obesity-Related Inflammation)
Current treatments against type two diabetes, dyslipidemia and cardiovascular disease are modestly successful and with numerous side effects. For instance, the thiazolidinedione (TZD) class of antidiabetic drugs has been shown to cause weight gain, hepatotoxicity and congestive heart failure. For instance, the TZD troglitazone (Rezulin) was launched in 1997 and withdrawn from the market in March of 2000 due to reports of serious liver injury when compared to other TZDs. While other Food and Drug Administration (FDA)-approved TZDs for T2D treatment, including rosiglitazone (Avandia) and pioglitazone (Actos®), continue to be widely prescribed, concerns regarding their safety persist. In this regard, the U.S. FDA has restricted the use of Avandia due to its increased risk of myocardial infarction and death from cardiovascular disease. TZDs are synthetically generated drugs that elicit their antidiabetic and anti-inflammatory actions by activating the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma), a widely expressed transcription factor member of the nuclear receptor superfamily that regulates inflammation, immunity and metabolism.
The long-term goal of my laboratory is to identify novel, naturally occurring, orally active and safe agonists of PPAR gamma that modulate inflammation and improve insulin sensitivity. In line with our goal, we investigated the insulin-sensitizing and anti-inflammatory actions of a novel putative agonist of PPAR gamma, abscisic acid (ABA), based on structural similarities of several of its isomers and enantiomers to other natural agonists such as conjugated linoleic acid (CLA) or the TZD class of synthetic ligands. While the role of ABA as a phytohormone has been studied extensively, its possible role as an anti-inflammatory and insulin-sensitizing compound is only beginning to be uncovered. The identification of novel agonists of PPAR gamma such as ABA and the elucidation of their mechanisms of action will facilitate the development of safer and more effective treatments against obesity and its associated co-morbidities. Based on this background, the specific aims of this proposal are:
1) To test the hypothesis that ABA down-modulates monocyte chemoattractant protein-1 (MCP-1) production through a PPAR gamma-mediated blockade of nuclear factor-kappaB (NF-kappaB).
2) To test the hypothesis that ABA modulates macrophage inflammatory function through a PPAR gamma-dependent mechanism.
We demonstrate that ABA increases PPAR gamma reporter activity in RAW 264.7 macrophages and increases PPAR gamma expression in vivo although it does not bind to the ligand-binding domain (LBD) of PPAR gamma. Lanthionice synthetase c-like protein 2 (LANCL2) knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR gamma is dependent on LANCL2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced PGE2 and MCP-1 production via a PPAR gamma-dependent mechanism possibly involving activation of PPAR gamma and suppression of NF-kappaB and NFAT. LPS challenge studies in PPAR gamma-expressing and immune cell-specific PPAR gamma null mice demonstrate that ABA down-regulates toll-like receptor-4 expression in macrophages and T cells in vivo through a PPAR gamma-dependent mechanism. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, LBD-independent mechanism of PPAR gamma activation.
The long-term goal of my laboratory is to identify novel, naturally occurring, orally active and safe agonists of PPAR gamma that modulate inflammation and improve insulin sensitivity. In line with our goal, we investigated the insulin-sensitizing and anti-inflammatory actions of a novel putative agonist of PPAR gamma, abscisic acid (ABA), based on structural similarities of several of its isomers and enantiomers to other natural agonists such as conjugated linoleic acid (CLA) or the TZD class of synthetic ligands. While the role of ABA as a phytohormone has been studied extensively, its possible role as an anti-inflammatory and insulin-sensitizing compound is only beginning to be uncovered. The identification of novel agonists of PPAR gamma such as ABA and the elucidation of their mechanisms of action will facilitate the development of safer and more effective treatments against obesity and its associated co-morbidities. Based on this background, the specific aims of this proposal are:
1) To test the hypothesis that ABA down-modulates monocyte chemoattractant protein-1 (MCP-1) production through a PPAR gamma-mediated blockade of nuclear factor-kappaB (NF-kappaB).
2) To test the hypothesis that ABA modulates macrophage inflammatory function through a PPAR gamma-dependent mechanism.
We demonstrate that ABA increases PPAR gamma reporter activity in RAW 264.7 macrophages and increases PPAR gamma expression in vivo although it does not bind to the ligand-binding domain (LBD) of PPAR gamma. Lanthionice synthetase c-like protein 2 (LANCL2) knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR gamma is dependent on LANCL2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced PGE2 and MCP-1 production via a PPAR gamma-dependent mechanism possibly involving activation of PPAR gamma and suppression of NF-kappaB and NFAT. LPS challenge studies in PPAR gamma-expressing and immune cell-specific PPAR gamma null mice demonstrate that ABA down-regulates toll-like receptor-4 expression in macrophages and T cells in vivo through a PPAR gamma-dependent mechanism. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, LBD-independent mechanism of PPAR gamma activation.