title: Cross regulation of sirtuin 1, AMPK, and PPARγ in conjugated linoleic acid treated adipocytes.
abstract: Trans-10, cis-12 conjugated linoleic acid (t10c12 CLA) reduces triglyceride (TG) levels in adipocytes through multiple pathways, with AMP-activated protein kinase (AMPK) generally facilitating, and peroxisome proliferator-activated receptor γ (PPARγ) generally opposing these reductions. Sirtuin 1 (SIRT1), a histone/protein deacetylase that affects energy homeostasis, often functions coordinately with AMPK, and is capable of binding to PPARγ, thereby inhibiting its activity. This study investigated the role of SIRT1 in the response of 3T3-L1 adipocytes to t10c12 CLA by testing the following hypotheses: 1) SIRT1 is functionally required for robust TG reduction; and 2) SIRT1, AMPK, and PPARγ cross regulate each other. These experiments were performed by using activators, inhibitors, or siRNA knockdowns that affected these pathways in t10c12 CLA-treated 3T3-L1 adipocytes. Inhibition of SIRT1 amounts or activity using siRNA, sirtinol, nicotinamide, or etomoxir attenuated the amount of TG loss, while SIRT1 activator SRT1720 increased the TG loss. SRT1720 increased AMPK activity while sirtuin-specific inhibitors decreased AMPK activity. Reciprocally, an AMPK inhibitor reduced SIRT1 activity. Treatment with t10c12 CLA increased PPARγ phosphorylation in an AMPK-dependent manner and increased the amount of PPARγ bound to SIRT1. Reciprocally, a PPARγ agonist attenuated AMPK and SIRT1 activity levels. These results indicated SIRT1 increased TG loss and that cross regulation between SIRT1, AMPK, and PPARγ occurred in 3T3-L1 adipocytes treated with t10c12 CLA.
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jess
authors.initials: J
authors.lastname: Miner
authors.forename: Michael
authors.initials: M
authors.lastname: Fromm
mesh_terms: D041721:3T3-L1 Cells; D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D005227:Fatty Acids; D044243:Linoleic Acids, Conjugated; D016328:NF-kappa B; D047495:PPAR gamma; D051546:Cyclooxygenase 2; D000263:Adenylate Kinase; D056564:Sirtuin 1