OBJECTIVE High-fat diets (HFDs) are known to induce insulin resistance. Previously, we showed that 3,5-diiodothyronine (T2), concomitantly administered to rats on a 4-week HFD, prevented gain in body weight and adipose mass. Here we investigated whether and how T2 prevented HFD-induced insulin resistance. RESEARCH DESIGN AND METHODS We investigated the biochemical targets of T2 related to lipid and glucose homeostasis over time using various techniques, including genomic and proteomic profiling, immunoblotting, transient transfection, and enzyme activity analysis. RESULTS Here we show that, in rats, HFD feeding induced insulin resistance (as expected), whereas T2 administration prevented its onset. T2 did so by rapidly stimulating hepatic fatty acid oxidation, decreasing hepatic triglyceride levels, and improving the serum lipid profile, while at the same time sparing skeletal muscle from fat accumulation. At the mechanistic level, 1) transfection studies show that T2 does not act via thyroid hormone receptor β; 2) AMP-activated protein kinase is not involved in triggering the effects of T2; 3) in HFD rats, T2 rapidly increases hepatic nuclear sirtuin 1 (SIRT1) activity; 4) in an in vitro assay, T2 directly activates SIRT1; and 5) the SIRT1 targets peroxisome proliferator–activated receptor (PPAR)-γ coactivator (PGC-1α) and sterol regulatory element–binding protein (SREBP)-1c are deacetylated with concomitant upregulation of genes involved in mitochondrial biogenesis and downregulation of lipogenic genes, and PPARα/δ-induced genes are upregulated, whereas genes involved in hepatic gluconeogenesis are downregulated. Proteomic analysis of the hepatic protein profile supported these changes. CONCLUSIONS T2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and, finally, prevention of diet-induced insulin resistance.

Thyroid hormones (THs) are produced by the thyroid gland and converted in peripheral organs by deiodinases. THs regulate cell functions through two distinct mechanisms: genomic (nuclear) and nongenomic (non-nuclear). Many TH effects are mediated by the genomic pathway – a mechanism that requires TH activation of nuclear thyroid hormone receptors. The overall nongenomic processes, emerging as important accessory mechanisms in TH actions, have been observed at the plasma membrane, in the cytoplasm and cytoskeleton, and in organelles. Some products of peripheral TH metabolism (besides triiodo-l-thyronine), now termed ‘nonclassical THs’, were previously considered as inactive breakdown products. However, several reports have recently shown that they may have relevant biological effects. The recent accumulation of knowledge on how classical and nonclassical THs modulate the activity of membrane receptors, components of the mitochondrial respiratory chain, kinases and deacetylases, opened the door to the discovery of new pathways through which they act. We reviewed the current state-of-the-art on the actions of the nonclassical THs, discussing the role that these endogenous TH metabolites may have in the modulation of thyroid-related effects in organisms with differing complexity, ranging from nonmammals to humans.

Evidence indicates that many forms of fructose-induced metabolic disturbance are associated with oxidative stress and mitochondrial dysfunction. Mitochondria are prominent targets of oxidative damage; however, it is not clear whether mitochondrial DNA (mtDNA) damage and/or its lack of repair are events involved in metabolic disease resulting from a fructose-rich diet. In the present study, we evaluated the degree of oxidative damage to liver mtDNA and its repair, in addition to the state of oxidative stress and antioxidant defense in the liver of rats fed a high-fructose diet. We used male rats feeding on a high-fructose or control diet for eight weeks. Our results showed an increase in mtDNA damage in the liver of rats fed a high-fructose diet and this damage, as evaluated by the expression of DNA polymerase γ, was not repaired; in addition, the mtDNA copy number was found to be significantly reduced. A reduction in the mtDNA copy number is indicative of impaired mitochondrial biogenesis, as is the finding of a reduction in the expression of genes involved in mitochondrial biogenesis. In conclusion, a fructose-rich diet leads to mitochondrial and mtDNA damage, which consequently may have a role in liver dysfunction and metabolic diseases.

The worldwide prevalence of obesity‐associated pathologies, including type 2 diabetes, requires thorough investigation of mechanisms and interventions. Recent studies have highlighted thyroid hormone analogs and derivatives as potential agents able to counteract such pathologies. In this study, in rats receiving a high‐fat diet (HFD), we analyzed the effects of a 4‐wk daily administration of a naturally occurring iodothyronine, 3,5‐diiodo‐L‐thyronine (T2), on the gastrocnemius muscle metabolic/structural phenotype and insulin signaling. The HFD‐induced increases in muscle levels of fatty acid translocase (3‐fold; P <0.05) and TGs (2‐fold, P <0.05) were prevented by T2 (each; P <0.05 vs. HFD). T2 increased insulin‐stimulated Akt phosphorylation levels (~2.5‐fold; P <0.05 vs. HFD). T2 induced these effects while sparing muscle mass and without cardiac hypertrophy. T2 increased the muscle contents of fast/glycolytic fibers (2‐fold; P <0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3‐fold; P <0.05 vs. HFD). Adipocyte differentiation‐related protein was predominantly present within the slow/oxidative fibers in HFD‐T2. In T2‐treated rats ( vs. HFD), glycolytic enzymes and associated components were up‐regulated (proteomic analysis, significance limit: 2‐fold; P <0.05), as was phosphofructokinase activity (by 1.3‐fold; P <0.05), supporting the metabolic shift toward a more glycolytic phenotype. These results highlight T2 as a potential therapeutic approach to the treatment of diet‐induced metabolic dysfunctions.—Moreno, M., Silvestri, E., De Matteis, R., de Lange, P., Lombardi, A., Glinni, D., Senese, R., Cioffi, F., Salzano, A. M., Scaloni, A., Lanni, A., Goglia, F. 3,5‐Diiodo‐L‐thyronine prevents high‐fat diet‐induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations. FASEB J. 25, 3312–3324 (2011). www.fasebj.org