Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes.
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are relatively new pharmacological agents used to normalize glucose level in type 2 diabetes. Recently, GLP- RAs have been approved for the treatment of obesity to reduce body weight in non-diabetic patients. The extra-pancreatic effects of GLP-1RAs as well as molecular mechanism of action are still poorly understood. Thus the study was aimed to verify the hypothesis that the mechanism of action of the GLP-1RAs involves mitochondria and that GLP-1RAs administration can improve mitochondrial functions.
For this purpose preadipocytes CHUBS7 were differentiated to mature adipocytes and then stimulated with GLP-1RA, exendin-4 100 nM for 24 h. Oxygen consumption rates, mitochondrial membrane potential, intracellular ATP (adenosine triphosphate) level, SIRT1 and SIRT3 gene expression and histone deacetylases activity were measured.
Exendin-4 was found to uncouple mitochondrial electron transport from ATP synthesis, slightly decreasing mitochondrial membrane potential in mature adipocytes. Routine respiration and uncoupled oxygen consumption rates were higher in exendin-4 treated adipocytes than in non-treated cells. ATP level remained unchanged. Exendin-4 enhanced SIRT1 and SIRT3 genes expression. Histone deacetylases activity in nuclear fraction was not affected by exendin-4, although the activity of histone deacetylases class III was increased. All the effects on mitochondrial bioenergetics induced by exendin-4 were abolished by addition of glucagon-like peptide 1 receptor antagonist.
In conclusion, exendin-4 activates sirtuins pathway and increases energy expenditure in human adipocytes. Our results suggest another mechanism that may be responsible for body weight reduction observed in patients using GLP-1RAs.
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