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

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 T 2 induced an increase in mitochondrial oxidation when palmitoyl-CoA (+104%), palmitoylcarnitine (+80%), or succinate (+30%) 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/β-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2 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. Copyright © 2009 the American Physiological Society.

3,5-Diiodo-L-thyronine rapidly enhances mitochondrialfatty acid oxidation rate and thermogenesis in rat skeletalmuscle: AMP-activated protein kinase involvement. Am J PhysiolEndocrinol Metab 296: E497–E502, 2009. First published December30, 2008; doi:10.1152/ajpendo.90642.2008.—Triiodothyronine regulatesenergy metabolism and thermogenesis. Among triiodothyroninederivatives, 3,5-diiodo-L-thyronine (T2) has been shown to exertmarked effects on energy metabolism by acting mainly at the mitochondriallevel. Here we investigated the capacity of T2 to affect bothskeletal muscle mitochondrial substrate oxidation and thermogenesiswithin 1 h after its injection into hypothyroid rats. Administration of T2induced an increase in mitochondrial oxidation when palmitoyl-CoA(104%), palmitoylcarnitine (80%), or succinate (30%) was used assubstrate, but it had no effect when pyruvate was used. T2 was able to 1)activate the AMPK-ACC-malonyl-CoA metabolic signaling pathwayknown to direct lipid partitioning toward oxidation and 2) increase theimporting of fatty acids into the mitochondrion. These results suggest thatT2 stimulates mitochondrial fatty acid oxidation by activating severalmetabolic pathways, such as the fatty acid import/-oxidation cycle/FADH2-linked respiratory pathways, where fatty acids are imported. T2also enhanced skeletal muscle mitochondrial thermogenesis by activatingpathways involved in the dissipation of the proton-motive force notassociated with ATP synthesis (“proton leak”), the effect being dependenton the presence of free fatty acids inside mitochondria. We conclude thatskeletal muscle is a target for T2, and we propose that, by activatingprocesses able to enhance mitochondrial fatty acid oxidation and thermogenesis,T2 could play a role in protecting skeletal muscle againstexcessive intramyocellular lipid storage, possibly allowing it to avoidfunctional disorders.