Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 285, Issue 16, Pages 12321-12333Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.091512
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Funding
- National Institutes of Health [R01 HL58115, R01 HL64937, P30 DK046204-15, T32DK007052-34, DK071662, DK066202, HL089301, HL68878, HL089544, HL75397]
- The Hartwell Foundation
- American Diabetes Association [7-08-JF-52]
- American Heart Association [0665418U, 0840025N]
- Deutsche Forschungsgemeinschaft
- Deutsche Herzstiftung
- Jay and Betty Van Andel Foundation
- Complexa, Inc
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The peroxisome proliferator-activated receptor-gamma (PPAR gamma) binds diverse ligands to transcriptionally regulate metabolism and inflammation. Activators of PPAR gamma include lipids and anti-hyperglycemic drugs such as thiazolidinediones (TZDs). Recently, TZDs have raised concern after being linked with increased risk of peripheral edema, weight gain, and adverse cardiovascular events. Most reported endogenous PPAR gamma ligands are intermediates of lipid metabolism and oxidation that bind PPAR gamma with very low affinity. In contrast, nitro derivatives of unsaturated fatty acids (NO2-FA) are endogenous products of nitric oxide ((NO)-N-center dot) and nitrite (NO2-)-mediated redox reactions that activate PPAR gamma at nanomolar concentrations. We report that NO2-FA act as partial agonists of PPAR gamma and covalently bind PPAR gamma at Cys-285 via Michael addition. NO2-FA show selective PPAR gamma modulator characteristics by inducing coregulator protein interactions, PPAR gamma-dependent expression of key target genes, and lipid accumulation is distinctively different from responses induced by the TZD rosiglitazone. Administration of this class of signaling mediators to ob/ob mice revealed that NO2-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs.
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