GLP-1 receptor agonism ameliorates hepatic VLDL overproduction and de novo lipogenesis in insulin resistance

Abstract

Background/objectivesFasting dyslipidemia is commonly observed in insulin resistant states and mechanistically linked to hepatic overproduction of very low density lipoprotein (VLDL). Recently, the incretin hormone glucagon-like peptide-1 (GLP-1) has been implicated in ameliorating dyslipidemia associated with insulin resistance and reducing hepatic lipid stores. Given that hepatic VLDL production is a key determinant of circulating lipid levels, we investigated the role of both peripheral and central GLP-1 receptor (GLP-1R) agonism in regulation of VLDL production.MethodsThe fructose-fed Syrian golden hamster was employed as a model of diet-induced insulin resistance and VLDL overproduction. Hamsters were treated with the GLP-1R agonist exendin-4 by intraperitoneal (ip) injection for peripheral studies or by intracerebroventricular (ICV) administration into the 3rd ventricle for central studies. Peripheral studies were repeated in vagotomised hamsters.ResultsShort term (7–10 day) peripheral exendin-4 enhanced satiety and also prevented fructose-induced fasting dyslipidemia and hyperinsulinemia. These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma. The observed changes in fasting dyslipidemia could be partially explained by reduced respiratory exchange ratio (RER) thereby indicating a switch in energy utilization from carbohydrate to lipid. Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation. Despite these observations, GLP-1R activity could not be detected in primary hamster hepatocytes, thus leading to the investigation of a potential brain–liver axis functioning to regulate lipid metabolism. Short term (4 day) central administration of exendin-4 decreased body weight and food consumption and further prevented fructose-induced hypertriglyceridemia. Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling.ConclusionExendin-4 prevents fructose-induced dyslipidemia and hepatic VLDL overproduction in insulin resistance through an indirect mechanism involving altered energy utilization, decreased hepatic lipid synthesis and also requires an intact parasympathetic signaling pathway.

Antiobesity efficacy of GLP‐1 receptor agonist liraglutide is associated with peripheral tissue‐specific modulation of lipid metabolic regulators

“…First, our results demonstrated that liraglutide induced a decrease in caloric intake, body weight gain and the plasma levels of triglycerides and very low‐density lipoproteins (VLDL) in a diet‐independent manner. These results ratify findings from recent studies using different GLP‐1 analogues . It has been demonstrated that the peripheral and central administration of GLP‐1 analogues leads to neuronal activity in several hypothalamic sites, resulting in satiety factors .…”

“…These results ratify findings from recent studies using different GLP-1 analogues [29,30,43]. It has been demonstrated that the peripheral and central administration of GLP-1 analogues leads to neuronal activity in several hypothalamic sites, resulting in satiety factors [16,20,43].…”

Exenatide improves both hepatic and adipose tissue insulin resistance: A dynamic positron emission tomography study

“…(16) Moreover, studies in mice have shown that EX improves both hepatic (Hep-IR) and adipose tissue (Adippo-IR) IR by reducing hyperglycemia and very-low-density lipoprotein (VLDL) secretion, by inhibiting lipolysis and fatty acid overflow to the liver, and by enhancing TG hydrolysis and fatty acid oxidation. (6,(17)(18)(19) In humans, long-term treatment with liraglutide decreased hepatic de novo lipogenesis, (7,15) and EX reduced hepatic lipoprotein secretion. (8) Several studies have failed to demonstrate a significant effect of GLP-1-RAs on adipose tissue lipolysis.…”

Lesser yam (dioscorea esculenta) based cookies improves lipid profile in overweight/obese adults with an ad libitum diet via glucagon like peptide 1

“…In this study, we showed that fasting GLP-1 concentration was negatively correlated with the changes in LDL and cholesterol level. This suggested that increase production of GLP-1 in overweight and obese individuals was protective towards dyslipidaemia and cardiovascular diseases (Taher et al, 2014). The relationship between fasting GLP-1 concentration and lipid metabolism has also been suggested by Wadden et al (2003).…”