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.

The Effect of a Diiodothyronine Mimetic on Insulin Sensitivity in Male Cardiometabolic Patients: A Double-Blind Randomized Controlled Trial

“…In line, hepatic fat content and lipid profile were unaltered. This apparent discrepancy between the marked impact of TRC150094 on glycemic profile, hepatic fat accumulation and serum lipids in experimental protocols [8], [9], [20], [21] and the absence of any metabolic improvement in the present clinical study may have several explanations, consisting of the mechanism of action, the dose and concentration of TRC150094 and study population.…”

“…[8] In line, TRC150094 improved glucose tolerance and hepatic steatosis in obese Zucker spontaneously hypertensive fatty (ZSF1) rats with a concomitant reduction in plasma cholesterol and triglycerides in ZSF1 rats. [9], [10] Most importantly, TRC150094 was not associated with any adverse safety signal in experimental models up to 24 weeks. [8], [9] In phase I clinical studies, once daily oral administration of TRC150094 at doses of 50 mg and 150 mg for 28 days were well tolerated without any adverse safety signals in the obese subjects.…”

“…[9], [10] Most importantly, TRC150094 was not associated with any adverse safety signal in experimental models up to 24 weeks. [8], [9] In phase I clinical studies, once daily oral administration of TRC150094 at doses of 50 mg and 150 mg for 28 days were well tolerated without any adverse safety signals in the obese subjects.…”

3,5-T2 alters murine genes relevant for xenobiotic, steroid, and thyroid hormone metabolism

“…Proteomic approaches in HFD rats that were treated with 3,5-T 2 (0.25 µg/g bw) or TRC150094, a novel 3,5-T 2 analogue, showed strong effects on hepatic mitochondrial and fatty acid metabolism; however, only minor similarities with regard to the expression profiles reported in this study were observed (Silvestri et al 2010;Silvestri et al 2012). Treatment of mice with 2.5 µg/g bw 3,5-T 2 exerted marked transcriptional effects in liver.…”

MECHANISMS IN ENDOCRINOLOGY: The crosstalk between thyroid gland and adipose tissue: signal integration in health and disease

“…The selective activation of different TR-mediated pathways is a promising strategy for treating lipid disorders and obesity (172,173,174,175,176). Indeed, studies on animals suggested that thyro-mimetics might be useful in the treatment of obesity, hepatic steatosis, and atherosclerosis (177).…”