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Obesity-linked insulin resistance is mainly due to fatty acid overload in non-adipose tissues, particularly skeletal muscle and liver, where it results in high production of reactive oxygen species and mitochondrial dysfunction. Accumulating evidence indicates that resistance and endurance training alone and in combination can counteract the harmful effects of obesity increasing insulin sensitivity, thus preventing diabetes. This review focuses the mechanisms underlying the exercise role in opposing skeletal muscle insulin resistance-linked metabolic dysfunction. It is apparent that exercise acts through two mechanisms: (1) it stimulates glucose transport by activating an insulin-independent pathway and (2) it protects against mitochondrial dysfunction-induced insulin resistance by increasing muscle antioxidant defenses and mitochondrial biogenesis. However, antioxidant supplementation combined with endurance training increases glucose transport in insulin-resistant skeletal muscle in an additive fashion only when antioxidants that are able to increase the expression of antioxidant enzymes and/or the activity of components of the insulin signaling pathway are used.

At present, obesity is one of the most important public health problems in the world because it causes several diseases and reduces life expectancy. Although it is well known that insulin resistance plays a pivotal role in the development of type 2 diabetes mellitus (the more frequent disease in obese people) the link between obesity and insulin resistance is yet a matter of debate. One of the most deleterious effects of obesity is the deposition of lipids in non-adipose tissues when the capacity of adipose tissue is overwhelmed. During the last decade, reduced mitochondrial function has been considered as an important contributor to ‘toxic’ lipid metabolite accumulation and consequent insulin resistance. More recent reports suggest that mitochondrial dysfunction is not an early event in the development of insulin resistance, but rather a complication of the hyperlipidemia-induced reactive oxygen species (ROS) production in skeletal muscle, which might promote mitochondrial alterations, lipid accumulation and inhibition of insulin action. Here, we review the literature dealing with the mitochondria-centered mechanisms proposed to explain the onset of obesity-linked IR in skeletal muscle. We conclude that the different pathways leading to insulin resistance may act synergistically because ROS production by mitochondria and other sources can result in mitochondrial dysfunction, which in turn can further increase ROS production leading to the establishment of a harmful positive feedback loop.

The effects of thyroid state on liver mitochondrial protein mass was investigated in rats at 24 and 4 °C, as was oxidative phosphorylation using substrates which represent the final catabolic products of the metabolic fuels. In rats at 24 °C, a significant increase in mitochondrial protein mass (about +40%) was observed only in hyperthyroid animals, while a significant increase due to cold exposure was found in hypothyroid (+ 45%) and euthyroid (+ 35%) rats. In rats at 24 °C, hypothyroidism significantly decreased the oxidation of glutamate and palmitoyl carnitine but not of pyruvate, while hyperthyroidism only increased the oxidation of palmitoyl carnitine. On the other hand, exposure to cold significantly increased the oxidation of glutamate and pyruvate only in the presence of tri-iodothyronine. Our results underline not only the fact that a simple and single hypothesis for thyroid effects cannot be adopted, but also that any study concerning oxidative metabolism should be carried out using different substrates and involving different pathways of oxidation. Journal of Endocrinology (1991) 131, 67–73