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

Taher J, Baker CL, Cuizon C, Masoudpour H, Zhang R, Farr S, Naples M, Bourdon C, Pausova Z, Adeli K - Mol Metab (2014)

Bottom Line: These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma.Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation.Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling.

View Article: PubMed Central - PubMed

Affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.

ABSTRACT

Background/objectives: Fasting 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.

Methods: The 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.

Results: Short 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.

Conclusion: Exendin-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.

No MeSH data available.


Related in: MedlinePlus

Peripheral exendin-4 does not alter liver or fat pad weight in an intervention treatment strategy. Hamsters underwent the intervention study and plasma and tissue was collected from vehicle and exendin-4 hamsters after a 5 h fast. (A) Liver and (B) epididymal fat pad weight. (C) Plasma AST and (D) ALT following a 5 h fast. n = 5–7. Analyzed by Student's unpaired t-test.
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dfig1: Peripheral exendin-4 does not alter liver or fat pad weight in an intervention treatment strategy. Hamsters underwent the intervention study and plasma and tissue was collected from vehicle and exendin-4 hamsters after a 5 h fast. (A) Liver and (B) epididymal fat pad weight. (C) Plasma AST and (D) ALT following a 5 h fast. n = 5–7. Analyzed by Student's unpaired t-test.


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

Taher J, Baker CL, Cuizon C, Masoudpour H, Zhang R, Farr S, Naples M, Bourdon C, Pausova Z, Adeli K - Mol Metab (2014)

Peripheral exendin-4 does not alter liver or fat pad weight in an intervention treatment strategy. Hamsters underwent the intervention study and plasma and tissue was collected from vehicle and exendin-4 hamsters after a 5 h fast. (A) Liver and (B) epididymal fat pad weight. (C) Plasma AST and (D) ALT following a 5 h fast. n = 5–7. Analyzed by Student's unpaired t-test.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4264039&req=5

dfig1: Peripheral exendin-4 does not alter liver or fat pad weight in an intervention treatment strategy. Hamsters underwent the intervention study and plasma and tissue was collected from vehicle and exendin-4 hamsters after a 5 h fast. (A) Liver and (B) epididymal fat pad weight. (C) Plasma AST and (D) ALT following a 5 h fast. n = 5–7. Analyzed by Student's unpaired t-test.
Bottom Line: These changes were accompanied by decreased fasting plasma glucose levels, reduced hepatic lipid content and decreased levels of VLDL-TG and -apoB100 in plasma.Additionally, exendin-4 reduced mRNA markers associated with hepatic de novo lipogenesis and inflammation.Additionally, the peripheral lipid-lowering effects of exendin-4 were negated in vagotomised hamsters implicating the involvement of parasympathetic signaling.

View Article: PubMed Central - PubMed

Affiliation: Molecular Structure and Function, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada.

ABSTRACT

Background/objectives: Fasting 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.

Methods: The 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.

Results: Short 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.

Conclusion: Exendin-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.

No MeSH data available.


Related in: MedlinePlus