title: The signalling mechanisms of a novel mitochondrial complex I inhibitor prevent lipid accumulation and attenuate TNF-α-induced insulin resistance in vitro.
abstract: RTC-1 has recently been identified as a member of a new class of anti-diabetic compounds acting through the inhibition of complex I of the mitochondrial respiratory chain (NADH:ubiquinone oxidoreductase) to improve glucose handling and inhibit weight gain in mice fed a high-fat diet (HFD). The exact mechanism by which the reduced activity of NADH:ubiquinone oxidoreductase, in response to RTC-1, promotes these improved metabolic parameters remains to be established. Through extensive in vitro analysis, new molecular insights into these downstream signalling pathways have been obtained. RTC-1-induced inhibition of NADH:ubiquinone oxidoreductase was found to promote glucose uptake in C2C12 myotubes in vitro, through the activation of the Akt substrate of 160kDa (AS160), in response to the increased activity of Akt and AMP-activated protein kinase (AMPK). RTC-1-induced phosphorylation of the AMPK substrate, acetyl-CoA carboxylase (ACC) in vitro, was associated with a decrease in lipid accumulation in 3T3-L1 adipocytes and murine mesenchymal stromal cells (MSC). The novel compound also prevented tumour necrosis factor-alpha (TNF-α)-induced insulin resistance and demonstrated insulin sensitising effects in C2C12 myotubes. Taken together, these results present a systematic analysis of the signalling mechanisms responsible for the potent anti-diabetic and anti-obesogenic effects of this modulator of mitochondrial function, strengthening the potential use of such compounds for the treatment of type 2 diabetes mellitus (T2DM).
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland. Electronic address: Siobhan.Leonard@nuim.ie.
authors.forename: Siobhán
authors.initials: S
authors.lastname: Leonard
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Tobin
authors.affiliation: Department of Biology, National University of Ireland Maynooth, Maynooth, Co. Kildare, Ireland.
authors.forename: John B C
authors.initials: JB
authors.lastname: Findlay
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D013876:Thiophenes / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010879:Piperazines; C000617571:RTC-1 compound; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; D042967:Electron Transport Complex I
keywords: AMPK; Akt; Insulin resistance; Lipid accumulation; NADH:ubiquinone oxidoreductase; Type 2 diabetes mellitus