Central administration of coagonist of GLP-1 and glucagon receptors improves dyslipidemia

Coagonists of Glucagon-like peptide-1 (GLP-1) and glucagon receptors are under clinical investigation for treatment of obesity associated with diabetes. In addition to their role in glucose homeostasis, GLP-1 and glucagon modulate lipid metabolism. In this study, we have investigated the role of central GLP-1 receptor (GLP-1R) and glucagon receptor (GCGR) activation in regulation of lipid metabolism in cholesterol-fed hamsters. Hamsters were treated with coagonist alone (0.3 μg) or in combination with either GLP-1R antagonist (0.15 μg) or GCGR antagonist (0.3 μg) for 4 weeks by intracerebroventricular route (icv). A pair-fed control to coagonist was included in the experiment. In a separate experiment, vagotomized hamsters were treated with coagonist (0.3 μg) for four weeks. At the end of the treatment, plasma and hepatic lipids, bile homeostasis, and hepatic gene expression were determined. Coagonist treatment caused a reduction in plasma and liver lipids, and reduced triglyceride absorption from intestine. Also, hepatic triglyceride secretion, bile flow, and biliary cholesterol excretion were increased by the coagonist treatment. Coagonist treatment exhibited increased energy expenditure and reduced the expression of SREBP-1C, HMG-CoA reductase, SCD-1, FAS and ACC in liver. Increase in the expression of LDLR, ACOX1, CPT-1, PPAR-α, CYP7A1, ABCA1 and ABCB11 was also observed in liver. The effect of coagonist on lipids was partially blocked by either GLP-1R or GCGR antagonist. Coadministration of GLP-1R antagonist blocked the effect of coagonist on bile flow, while effect of coagonist on biliary cholesterol was blocked by co-administration of GCGR antagonist. Coagonist did not affect lipid metabolism in vagotomized hamsters. It appears that central administration of coagonist reduces dyslipidemia by activation of GLP-1R and GCGR, independent of its anorectic effect.