Constitutive expression of SOCS-3 in skeletal muscle induces obesity in mice

Abstract

Type 1 or type 2 diabetes is a metabolic syndrome characterized by chronic hyperglycemia. The World Health Organization estimates that there are more than 180 millions of diabetic people worldwide and this number should double by 2030. The prevalence of diabetes strongly increases in all countries and nowadays its development is considered epidemic. Type 2 diabetes or non-insulin-dependent diabetes represents 95% of diabetic patients. Most of the time, it is associated with obesity. Type 2 diabetes occurs when insulin-sensitive tissues become insulin-resistant and pancreatic β-cells secrete less insulin. SOCS (Suppressor Of Cytokine Signaling) proteins have been discovered because of their negative feedback loop on cytokine signaling but they are also important inhibitors of the insulin signaling pathway (SOCS-3 in particular). Insulin actually induces SOCS-3 expression, which then interacts with the insulin receptor. SOCS-3 prevents the interaction between the receptor and its substrates, which decreases the upstream signal. Therefore SOCS-3 could play an important role in the development of insulin resistance. Liver, skeletal muscle and adipose tissue are the main target-tissue of insulin. It was shown in vitro that SOCS-3 inhibits insulin signaling in these tissues. However, SOCS-3 role in vivo and the mechanisms involved in the process are not fully understood yet. Furthermore we do not have a clear picture of the exact role of each tissue in the development of insulin resistance. The aims of this study are 1) to find out if constitutive expression of SOCS-3 in skeletal muscle could induce insulin resistance and type 2 diabetes, 2) to analyze the underlying molecular mechanisms. To do this, we have generated transgenic mice, which constitutively express SOCS-3 specifically in skeletal muscle (MLC/SOCS-3 mice). We have analyzed the phenotype of the transgenic mice compared to their wild type littermates and we have performed a molecular analysis of the muscles. Interestingly, MLC/SOCS-3 mice have more adipose tissue, result of an increase in the size of the adipocytes. Food intake is the same in the transgenic mice compared to the wild type littermate. However, we found a decrease in energy expenditure for the transgenic mice, which could be due, at least in part, to a decrease of physical activity. Transgenic mice have a normal glucose tolerance and no hyperglycemia. So MLC/SOCS-3 mice do not develop type 2 diabetes. Insulin tolerance is nevertheless reduced and this correlates with the degree of obesity of the transgenic mice. Molecular analysis of skeletal muscle did not show any decrease in insulin signaling in the muscle of MLC/SOCS-3 mice. However, we observed a decrease in SOCS-2 expression, another isoform of the SOCS family. SOCS-2 is a potential insulin inhibitor and so this decrease in SOCS-2 expression could compensate the increase in SOCS-3 expression and in this manner insulin signaling would not be disturbed. In conclusion, this study shows new evidence for the role of SOCS-3 in insulin resistance, as well as its possible involvement in muscle physiology. We have shown that, if constitutive expression of SOCS-3 in the skeletal muscle does not lead to type 2 diabetes, this induces an increase in adipose tissue, which is due in part to a decrease in physical activity. Molecular mechanisms for the role of SOCS-3 in physical activity remain to be defined.