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Background: Canonical Wnt signaling is involved in many physiological and pathological states. As it regulates lipid metabolism and glucose homeostasis, its misregulation may lead to the development of diabetes and obesity. We have already reported that activation of the Wnt/b-catenin canonical signaling pathway increased insulin sensitivity and prevented lipid deposits in rat skeletal muscle through a reciprocal regulation of Wnt10b and the lipogenic factor SREBP-1c. Results: Here we have studied the role of Wnt/b-catenin canonical signaling in skeletal muscle of genetically obese and diabetic (ob/ob) mice and their control ob/+ mice. We showed that Wnt10b and SREBP-1c expressions were conversely regulated in cultured mouse myoblasts isolated from lean ob/+ or obese ob/ob mice. Activation of the Wnt/b-catenin pathway using Wnt10b overexpression or the selective GSK3 inhibitor 6-Bromo-indirubin-3'oxime (BIO) was sufficient to decrease lipogenic genes expression in cultured myoblasts isolated from control and obese mice. In vivo, we performed direct electrotransfection of Wnt10b cDNA or BIO injections in Tibialis Anterior (TA) muscles of ob/ob and ob/+ mice. Both up-regulated Wnt10b gene expression and down-regulated SREBP-1c expression. Canonical Wnt signaling increased slow Myosin Heavy Chain-I (MHC-I) oxidative fiber number as well as fast Myosin Heavy Chain-IIA (MHC-IIA) oxidative fiber number, while decreasing fast glycolytic fiber number in TA muscle. In addition, Wnt signaling increased mitochondrial oxidative metabolism and respiratory reserve capacity by 2- and 3-fold in myotubes cultured from ob/ob and ob/+ mice muscles respectively. Surprisingly, the activation of the Wnt pathway was sufficient to reduce hyperglycemia by 30% within 3 weeks in ob/ob mice. Conclusions: Our results show that activation of Wnt/b-catenin signaling in skeletal muscle induced a shift towards a more oxidative metabolism in myofibers, thus mimicking the effects of exercise training. Wnt10b could be a valuable candidate to develop therapeutic drugs for the treatment of obesity and/or type 2 diabetes.Competing Interest StatementThe authors have declared no competing interest.