Journal article
The beneficial metabolic effects of insulin sensitizers are not attenuated by mitochondrial pyruvate carrier 2 hypomorphism
Experimental physiology, Vol.102(8), pp.985-999
08/01/2017
DOI: 10.1113/EP086380
PMCID: PMC5667918
PMID: 28597936
Abstract
What is the central question of this study? The antidiabetic effects of thiazolidinedione (TZD) drugs may be mediated in part by a molecular interaction with the constituent proteins of the mitochondrial pyruvate carrier complex (MPC1 and MPC2). We examined the ability of a mutant mouse strain expressing an N-terminal truncation of MPC2 (Mpc2Δ16 mice) to respond to TZD treatment. What is the main finding and its importance? The response of Mpc2Δ16 mice to TZD treatment was not significantly different from that of wild-type C57BL6/J control animals, suggesting that the 16 N-terminal amino acids of MPC2 are dispensable for the effects of TZD treatment. Rosiglitazone and pioglitazone are thiazolidinedione (TZD) compounds that have been used clinically as insulin-sensitizing drugs and are generally believed to mediate their effects via activation of the peroxisome proliferator-activated receptor γ (PPARγ). Recent work has shown that it is possible to synthesize TZD compounds with potent insulin-sensitizing effects and markedly diminished affinity for PPARγ. Both clinically used TZDs and investigational PPARγ-sparing TZDs, such as MSDC-0602, interact with the mitochondrial pyruvate carrier (MPC) and inhibit its activity. The MPC complex is composed of two proteins, MPC1 and MPC2. Herein, we used mice expressing a hypomorphic MPC2 protein missing 16 amino acids in the N-terminus (Mpc2Δ16 mice) to determine the effects of these residues in mediating the insulin-sensitizing effects of TZDs in diet-induced obese mice. We found that both pioglitazone and MSDC-0602 elicited their beneficial metabolic effects, including improvement in glucose tolerance, attenuation of hepatic steatosis, reduction of adipose tissue inflammation and stimulation of adipocyte browning, in both wild-type and Mpc2Δ16 mice after high-fat diet feeding. In addition, truncation of MPC2 failed to attenuate the interaction between TZDs and the MPC in a bioluminescence resonance energy transfer-based assay or to affect the suppression of pyruvate-stimulated respiration in cells. Collectively, these data suggest that the interaction between TZDs and MPC2 is not affected by loss of the N-terminal 16 amino acids nor are these residues required for the insulin-sensitizing effects of these compounds.
Details
- Title: Subtitle
- The beneficial metabolic effects of insulin sensitizers are not attenuated by mitochondrial pyruvate carrier 2 hypomorphism
- Creators
- Patrick A Vigueira - Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USAKyle S McCommis - Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USAWesley T Hodges - Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USAGeorge G Schweitzer - Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USASerena L Cole - Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USALalita Oonthonpan - Department of Biochemistry and Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52240, USAEric B Taylor - Department of Biochemistry and Fraternal Order of the Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52240, USAWilliam G McDonald - Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USARolf F Kletzien - Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USAJerry R Colca - Metabolic Solutions Development Company, Kalamazoo, MI, 49007, USABrian N Finck - Department of Medicine, Washington University School of Medicine, St Louis, MO, 63110, USA
- Resource Type
- Journal article
- Publication Details
- Experimental physiology, Vol.102(8), pp.985-999
- Publisher
- England
- DOI
- 10.1113/EP086380
- PMID
- 28597936
- PMCID
- PMC5667918
- ISSN
- 0958-0670
- eISSN
- 1469-445X
- Grant note
- R01 DK104998 / NIDDK NIH HHS R01 DK104735 / NIDDK NIH HHS T32 HL007081 / NHLBI NIH HHS P60 DK020579 / NIDDK NIH HHS P30 DK020579 / NIDDK NIH HHS R00 AR059190 / NIAMS NIH HHS T32 DK007296 / NIDDK NIH HHS R00 HL136658 / NHLBI NIH HHS P30 DK056341 / NIDDK NIH HHS K99 HL136658 / NHLBI NIH HHS R42 AA021228 / NIAAA NIH HHS T32 DK007120 / NIDDK NIH HHS
- Language
- English
- Date published
- 08/01/2017
- Academic Unit
- Molecular Physiology and Biophysics; Biochemistry and Molecular Biology
- Record Identifier
- 9984025597402771
Metrics
17 Record Views