The synthetic glucagon-like peptide-1 receptor agonist liraglutide affects the kinetics of pro-inflammatory kinases and improves insulin sensitivity of 3T3-L1 adipocytes

Abstract Background Obesity is the main risk factor of latent inflammation, which leads to insulin resistance (IR) which can transform to type 2 diabetes mellitus (T2DM). Today several groups of drugs are used to correct T2DM and its complications. The most perspective treatment is the use of glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide, that affect the insulin exocytosis in pancreatic β-cells. The metabolic pathways in these cells are well studied, but liraglutide's effects on other insulin-sensitive tissues, such as adipose tissue, remain unclear. Purpose We wanted to investigate the effect of the synthetic analogue of GLP-1 liraglutide on insulin sensitivity and on inflammatory and mitogenic signaling pathways in 3T3-L1 adipocytes. Methods We studied the effects of liraglutide on the kinetics of inflammatory and mitogenic pathways and insulin sensitivity in 3T3-L1 adipocytes, which were differentiated according to standard protocol with insulin, IBMX and dexamethasone. IR was induced by treatment with 1mM free fatty acids for 24 hours. Activities of insulin, mitogenic and inflammatory signaling pathways were analyzed by Western blotting with phospho-specific antibodies. Insulin sensitivity was also assessed by insulin-stimulated [3H]-deoxyglucose uptake analysis. Results We have showed that liraglutide promotes the decrease in expression of kinases JNK and ERK. So, under these results, we had a hypothesis that liraglutide changes cAMP-dependent regulation of transcription. In order to check it we have used the inhibitor of adenylyl cyclase (SQ22536) to see whether there will be any effects of liraglutide. As we suspected there was no effect, so our hypothesis of the liraglutide-stimulated activation of cAMP-dependent pathway was confirmed. In the model of IR adipocytes liraglutide promotes the increase of total amount of IRS and Akt and increased phosphorylation of pAkt-T308. When SQ22536 was added there was no effect of liraglutide on insulin sensitivity. Conclusion These results suggest the action of liraglutide in 3T3-L1 adipocytes via transcriptional regulation and insulin sensitivity control. According to our hypothesis, GLP-1 analogue liraglutide can influence systemic insulin sensitivity via regulation of adipose tissue metabolism. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation