Novel Roles of GLP-1 and GLP-2 in the Regulation of Hepatic Lipid/Lipoprotein Homeostasis and the Involvement of BAT Activation
type: CreativeWork
description: Major complications of insulin resistance and type 2 diabetes (T2D) include the development of non-alcoholic fatty liver disease (NAFLD) and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very low density lipoprotein (VLDL) production. Recent studies have implicated neuronal signalling in the control of hepatic lipid metabolism and VLDL production. The gut derived hormones glucagon-like peptide (GLP)-1 and GLP-2 have been shown to signal through neuronal pathways and display postprandial hypolipidemic and hyperlipidemic actions respectively. Furthermore, activation of brown adipose tissue (BAT) through the sympathetic nervous system also displays hypolipidemic actions and has recently been shown to be activated by GLP-1. We hypothesized that GLP-1 and GLP-2 will play opposing roles by decreasing and increasing VLDL production and NAFLD respectively. We further hypothesized that the effects of GLP-1 in modulating lipid metabolism occur through the activation of BAT. Using the Syrian Golden hamster, we showed that the GLP-1 receptor (GLP-1R) agonist exendin-4 decreased body weight, fasting dyslipidemia and VLDL overproduction by enhancing lipid utilization and decreasing hepatic de novo lipogenesis. These effects occurred through a vagal signalling pathway and were independent of changes in food consumption. To assess the involvement of BAT in the hypolipidemic actions of GLP-1, we first characterized the hamster as a novel and effective model of BAT activation. Î˛3-adrenergic receptor (Î˛3-AR) agonism activated hamster BAT, induced browning of WAT and prevented diet-induced NAFLD. The hypolipidemic actions of GLP-1R agonism were partially mediated by BAT as shown in hamsters that underwent BAT removal. Conversely, the sister peptide GLP-2 increased VLDL production and hepatic steatosis in hamsters and mice. Interestingly, GLP-2R knockout (KO) mice were protected against diet-induced dyslipidemia but displayed enhanced hepatic lipid…
abstract: Major complications of insulin resistance and type 2 diabetes (T2D) include the development of non-alcoholic fatty liver disease (NAFLD) and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very low density lipoprotein (VLDL) production. Recent studies have implicated neuronal signalling in the control of hepatic lipid metabolism and VLDL production. The gut derived hormones glucagon-like peptide (GLP)-1 and GLP-2 have been shown to signal through neuronal pathways and display postprandial hypolipidemic and hyperlipidemic actions respectively. Furthermore, activation of brown adipose tissue (BAT) through the sympathetic nervous system also displays hypolipidemic actions and has recently been shown to be activated by GLP-1. We hypothesized that GLP-1 and GLP-2 will play opposing roles by decreasing and increasing VLDL production and NAFLD respectively. We further hypothesized that the effects of GLP-1 in modulating lipid metabolism occur through the activation of BAT. Using the Syrian Golden hamster, we showed that the GLP-1 receptor (GLP-1R) agonist exendin-4 decreased body weight, fasting dyslipidemia and VLDL overproduction by enhancing lipid utilization and decreasing hepatic de novo lipogenesis. These effects occurred through a vagal signalling pathway and were independent of changes in food consumption. To assess the involvement of BAT in the hypolipidemic actions of GLP-1, we first characterized the hamster as a novel and effective model of BAT activation. Î˛3-adrenergic receptor (Î˛3-AR) agonism activated hamster BAT, induced browning of WAT and prevented diet-induced NAFLD. The hypolipidemic actions of GLP-1R agonism were partially mediated by BAT as shown in hamsters that underwent BAT removal. Conversely, the sister peptide GLP-2 increased VLDL production and hepatic steatosis in hamsters and mice. Interestingly, GLP-2R knockout (KO) mice were protected against diet-induced dyslipidemia but displayed enhanced hepatic lipid…
author: Taher, Jennifer
keywords: Brown Adipose Tissue, Diabetes, Dyslipidemia, Fatty Liver, Glucagon-like peptide, Lipoproteins
date published: 2017-11
date modified: 2026-07-27T21:28:13Z
provider: University of Toronto
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Toronto

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property ID: Handle
value: http://hdl.handle.net/1807/93032