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.

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

Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasis, are tightly controlled by nutrient availability, and they control nutrient handling. In this paper, we focus on how nutrients control the expression and action of PPARs and how cellular signaling events regulate the action of PPARs in metabolically active tissues (e.g., liver, skeletal muscle, heart, and white adipose tissue). We address the structure and function of the PPARs, and their interaction with other nuclear receptors, including PPAR cross-talk. We further discuss the roles played by different kinase pathways, including the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK MAPK), AMP-activated protein kinase (AMPK), Akt/protein kinase B (Akt/PKB), and the NAD+-regulated protein deacetylase SIRT1, serving to control the activity of the PPARs themselves as well as that of a key nutrient-related PPAR coactivator, PPARγcoactivator-1α(PGC-1α). We also highlight how currently applied nutrigenomic strategies will increase our understanding on how nutrients regulate metabolic homeostasis through PPAR signaling.