Abstract
MINOR (Mitogen-Inducible Nuclear Orphan Receptor) is one member of the NR4A3 nuclear orphan receptor family which are immediate early gene products involved in neuroendocrine regulation, neural differentiation, liver regeneration, cell apoptosis, and mitogenic and inflammatory stimulation in different cell types. We have found that MINOR can modulate insulin action and the glucose transport system in 3T3-L1 adipocytes; however, MINOR is highly expressed in skeletal muscle and its function in vivo is not well understood. To determine the role of MINOR in vivo, we have generated a mouse model that has the MINOR gene specifically expressed in the skeletal muscle using a muscle creatine kinase (MCK) promoter, and investigated whether the gene functions of MINOR would be linked to insulin action in vivo since skeletal muscle is one of the primary target tissues for insulin action. We demonstrate that these MCK-MINOR transgenic mice have reduced body weight due to a reduction of fat mass inside the body. Mice with MINOR overexpression also have improved insulin and glucose tolerances, reduced plasma levels of triglyceride, cholesterol and free fatty acid as well as enhanced expression of genes which are related to insulin action and its signaling pathways. Thus, MINOR functions in skeletal muscle act to improve insulin sensitivity and glucose intolerances and regulate insulin action and lipid and energy expenditure process.
Highlights
Type 2 diabetes is a disease caused by defects in insulin secretion combined with the presence of insulin resistance in peripheral target tissues which mainly include skeletal muscle, adipose tissue, and liver
Overexpression of MINOR was selectively performed in mouse skeletal muscle using the muscle creatine kinase (MCK) promoter
Other two members of the NR4A nuclear family, TR3 (NR4A1) and Nurr1 (NR4A2) expression levels showed no significant chances in skeletal muscle due to the overexpression of MINOR in this tissue (Figure 1C), suggesting that there are no functional compensations occurred among MINOR and other two nuclear receptor family members in skeletal muscle
Summary
Type 2 diabetes is a disease caused by defects in insulin secretion combined with the presence of insulin resistance in peripheral target tissues which mainly include skeletal muscle, adipose tissue, and liver. To better understand the molecular defects responsible for human insulin resistance, we previously assessed differential gene expression in human skeletal muscle biopsies from insulin-sensitive and -resistant individuals using cDNA microarray technology [1] These studies identified one of the differentially expressed genes that are members of the NR4A (NGFI-B) family of orphan nuclear receptors within the greater steroid/thyroid receptor superfamily, namely, MINOR (Mitogen-Inducible Nuclear Orphan Receptor). Based on homology within the DNA binding domain, there are two additional members of the NR4A (NGFI-B) family of orphan nuclear receptors, Nurr ( known as NR4A2, TINUR, and NOT) and Nur ( known as, NR4A1, NGFI-B, and TR3) These NR4A/NGFI-B proteins are immediate early response gene products that are involved in neuroendocrine regulation, neural differentiation, liver regeneration, cell apoptosis, and mitogenic and inflammatory stimulation in different cell types [3,4,5,6,7,8]
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