3,5-Diiodo-l-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement

Abstract

,5-Diiodo-L-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement. Am J Physiol Endocrinol Metab 296: E497-E502, 2009. First published December 30, 2008 doi:10.1152/ajpendo.90642.2008.-Triiodothyronine regulates energy metabolism and thermogenesis. Among triiodothyronine derivatives, 3,5-diiodo-L-thyronine (T2) has been shown to exert marked effects on energy metabolism by acting mainly at the mitochondrial level. Here we investigated the capacity of T2 to affect both skeletal muscle mitochondrial substrate oxidation and thermogenesis within 1 h after its injection into hypothyroid rats. Administration of T2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (ϩ104%), palmitoylcarnitine (ϩ80%), or succinate (ϩ30%) was used as substrate, but it had no effect when pyruvate was used. T2 was able to 1) activate the AMPK-ACC-malonyl-CoA metabolic signaling pathway known to direct lipid partitioning toward oxidation and 2) increase the importing of fatty acids into the mitochondrion. These results suggest that T2 stimulates mitochondrial fatty acid oxidation by activating several metabolic pathways, such as the fatty acid import/␤-oxidation cycle/ FADH2-linked respiratory pathways, where fatty acids are imported. T 2 also enhanced skeletal muscle mitochondrial thermogenesis by activating pathways involved in the dissipation of the proton-motive force not associated with ATP synthesis ("proton leak"), the effect being dependent on the presence of free fatty acids inside mitochondria. We conclude that skeletal muscle is a target for T2, and we propose that, by activating processes able to enhance mitochondrial fatty acid oxidation and thermogenesis, T2 could play a role in protecting skeletal muscle against excessive intramyocellular lipid storage, possibly allowing it to avoid functional disorders. adenosine 5Ј-monophosphate; thyroid hormone; mitochondria AMONG THE ENDOCRINE FACTORS able to regulate substrate metabolism and thermogenesis, thyroid hormones (THs) play important roles. 3,5,3Ј-Triiodothyronine (T 3 ) exerts a plethora of effects, including upregulation of peripheral and hepatic glucose uptake, cholesterol reduction, loss of body weight and adiposity, cardiac acceleration, and increases in metabolic rate (28,32). In adults, T 3 regulates energy metabolism by increasing respiration and energy expenditure and by lowering metabolic efficiency (for review, see Ref. 11). Because of this, T 3 was tested in the past as an antiobesity and hypolipidemic agent. However, due to its undesirable side effects, particularly within the cardiovascular system, its use was not continued (19). The development of TH derivatives that, while retaining lipid-lowering and antiobesity efficacy, are devoid of cardiovascular side effects would represent a potentially valuable therapeutic tool for the reduction of some important risk factors. Many laboratories have demonstrated metabolic effects of 3,5-diiodothyronine (T 2 ; a...

Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage

“…11 Similarly, Escartin et al showed that enhancing astrocyte FAO is protective of neuronal and astrocyte cell death when astrocyte glycolysis is inhibited. 13 One way to potentially stimulate FAO involves treatment with thyroid hormones, which is known to increase FAO in the heart, 14 muscle, [15][16][17] liver, 18 and in skin cells. 19 We showed that mitochondrial energy production can be rapidly increased via a mitochondrial targeted thyroid hormone receptor (mTR) after treatment with 3,3 0 5-triiodo-L-thyronine (T3).…”

Urine Metabolomics by 1H-NMR Spectroscopy Indicates Associations between Serum 3,5-T2 Concentrations and Intermediary Metabolism in Euthyroid Humans

“…Administered to hypothyroid rats, 3,5-T 2 prevented and even reversed the severe consequences typically induced by a high-fat diet, like weight gain, insulin resistance or hepatic steatosis [5,6,7]. The responsible mechanisms include improvement of the blood lipid profile through the stimulation of β-oxidation of free fatty acids (FFA) and mitochondrial uncoupling, as well as depression of gluconeogenesis in hepatocytes [5,8]. Therefore, 3,5-T 2 appears to act in a distinctively different mode compared to T 3 .…”

Translating Pharmacological Findings from Hypothyroid Rodents to Euthyroid Humans: Is There a Functional Role of Endogenous 3,5-T2?

“…Furthermore, administered in pharmacological doses, 3,5-T2 prevented rodents from weight gain from a high-fat diet (12) and restrained the development of insulin resistance (10). Possible discussed underlying mechanisms included the activation of thermogenesis (13), the prevention of fat accumulation in skeletal muscle as well as in the liver (10,14), and the enhancement of lipolysis (10,12,13), together resulting in remarkable antisteatotic effects under high-fat diet conditions.…”