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Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells
A Bolado-Carrancio1, J A Riancho2, J Sainz3
1Department of Molecular Biology, University of Cantabria, IDIVAL, Santander, Spain.
Abstract:
NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.
Insights
Nuclear receptor NR5A2 activation enhances glucose uptake and utilization in muscle cells. This metabolic shift improves blood glucose levels and insulin sensitivity, offering potential therapeutic benefits.
Area of Science:
- Molecular Endocrinology
- Metabolic Regulation
- Skeletal Muscle Physiology
Background:
- Nuclear receptor subfamily 5 group A member 2 (NR5A2) regulates key metabolic pathways.
- NR5A2 ligands, like DLPC, show promise in treating liver steatosis and improving insulin sensitivity.
- Skeletal muscle plays a critical role in systemic glucose homeostasis.
Purpose of the Study:
- To investigate the impact of NR5A2 activation on skeletal muscle metabolism.
- To determine if NR5A2 influences glucose and fatty acid metabolism in muscle cells.
- To elucidate the potential mechanisms underlying NR5A2's effects on insulin sensitivity.
Main Methods:
- Utilized C2C12 mouse skeletal muscle cell cultures.
- Treated cells with DLPC, a specific NR5A2 ligand.
- Analyzed gene expression, glucose uptake, and fatty acid oxidation.
Main Results:
- DLPC treatment increased expression of GLUT4 and genes involved in glycolysis and glycogen metabolism.
- NR5A2 activation led to enhanced glucose uptake in C2C12 cells.
- Fatty acid oxidation was reduced by NR5A2 activation, particularly under high-glucose conditions.
Conclusions:
- NR5A2 activation promotes a shift towards glucose utilization in skeletal muscle.
- Enhanced glucose uptake by muscle cells may contribute to improved blood glucose control.
- NR5A2 represents a potential therapeutic target for enhancing insulin sensitivity.
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