Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study.

Abstract

A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (α1/β1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens.

• Authors: Elena Silvestri, Daniela Glinni, Federica Cioffi, Maria Moreno, Assunta Lombardi, Pieter de Lange, Rosalba Senese, Michele Ceccarelli, Anna Maria Salzano, Andrea Scaloni, Antonia Lanni, Fernando Goglia
• Journal: Molecular bioSystems (Mol Biosyst) Vol. 8 Issue 7 Pg. 1987-2000 (Jul 06 2012) ISSN: 1742-2051 [Electronic] England
• PMID: 22543897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acids
• Dietary Fats
• Thyronines
• complex V (mitochondrial oxidative phosphorylation system)
• Fructose
• TRC150094
• Mitochondrial Proton-Translocating ATPases
• Nitrogen
• Mannose

Topics

• Adiposity (drug effects)
• Amino Acids (metabolism)
• Animals
• Diet, High-Fat
• Dietary Fats (metabolism)
• Energy Metabolism (drug effects)
• Fructose (metabolism)
• Gluconeogenesis (drug effects)
• Glycolysis (drug effects)
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Male
• Mannose (metabolism)
• Metabolic Networks and Pathways (drug effects)
• Mitochondria, Liver (drug effects, metabolism)
• Mitochondria, Muscle (drug effects, metabolism)
• Mitochondrial Proton-Translocating ATPases (drug effects, metabolism)
• Muscle, Skeletal (drug effects, metabolism)
• Nitrogen (metabolism)
• Overweight (drug therapy)
• Proteomics
• Rats
• Rats, Wistar
• Thyronines (metabolism, pharmacology)