Inhibition of the Mitochondrial Pyruvate Carrier by Tolylfluanid.

Abstract

Several recent studies have suggested that compounds known as endocrine-disrupting chemicals (EDCs) can promote obesity by serving as ligands for nuclear receptors, including the peroxisome proliferator-activated receptor γ (PPARγ) and the glucocorticoid receptor (GR). Thiazolidinedione insulin sensitizers, which act as ligands for PPARγ, also interact with and regulate the activity of the mitochondrial pyruvate carrier (MPC). We evaluated whether several EDCs might also affect MPC activity. Most of the EDCs evaluated did not acutely affect pyruvate metabolism. However, the putative endocrine disruptors tributyltin (TBT) and tolylfluanid (TF) acutely and markedly suppressed pyruvate metabolism in isolated mitochondria. Using mitochondria isolated from brown adipose tissue in mice with adipocyte-specific deletion of the MPC2 protein, we determined that the effect of TF on pyruvate metabolism required MPC2, whereas TBT did not. We attempted to determine whether the obesogenic effects of TF might involve MPC2 in adipose tissue. However, we were unable to replicate the published effects of TF on weight gain and adipose tissue gene expression in wild-type or fat-specific MPC2 knockout mice. Treatment with TF modestly enhanced adipogenic gene expression in vitro but had no effect on GR activation or phosphorylation in cultured cells. These data suggest that TF may affect mitochondrial pyruvate metabolism via the MPC complex but also call into question whether this compound affects GR activity and is obesogenic in mice.

• Authors: Yana Chen, Kyle S McCommis, Daniel Ferguson, Angela M Hall, Charles A Harris, Brian N Finck
• Journal: Endocrinology (Endocrinology) Vol. 159 Issue 2 Pg. 609-621 (02 01 2018) ISSN: 1945-7170 [Electronic] United States
• PMID: 29126303 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Endocrine Society.

Chemical References

• Anion Transport Proteins
• Endocrine Disruptors
• MPC1 pyruvate carrier protein, mouse
• Membrane Transport Proteins
• Mitochondrial Membrane Transport Proteins
• Monocarboxylic Acid Transporters
• Sulfonamides
• Toluidines
• N-dichlorofluoromethylthio-N',N'-dimethyl-N-p-tolylsulfamide
• Pyruvic Acid
• Pcsk2 protein, mouse
• Proprotein Convertase 2

Topics

• Adipocytes (drug effects, metabolism)
• Adipose Tissue, Brown
• Animals
• Anion Transport Proteins
• Biological Transport (drug effects)
• Endocrine Disruptors (pharmacology)
• Female
• Membrane Transport Proteins (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Mitochondria (drug effects, genetics, metabolism)
• Mitochondrial Membrane Transport Proteins
• Monocarboxylic Acid Transporters
• Proprotein Convertase 2 (genetics, metabolism)
• Pyruvic Acid (metabolism)
• Sulfonamides (pharmacology)
• Toluidines (pharmacology)