GLP-1 elicits an intrinsic gut-liver metabolic signal to ameliorate diet-induced VLDL overproduction and insulin resistance

Rituraj Khound, Jennifer Taher, Christopher Baker, Khosrow Adeli, Qiaozhu Su

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Objective-Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. Approach and Results-By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a highfat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Conclusions-Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

Original languageEnglish (US)
Pages (from-to)2252-2259
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number12
DOIs
StatePublished - Jan 1 2017

Fingerprint

Glucagon-Like Peptide 1
VLDL Lipoproteins
Insulin Resistance
Diet
Liver
Obesity
Vagotomy
Hyperlipidemias
Hepatocytes
Stearoyl-CoA Desaturase
Sterol Regulatory Element Binding Protein 1
Lipids
Fatty Acid Synthases
Lipogenesis
Glucose Intolerance
Palmitic Acid
High Fat Diet
Nonesterified Fatty Acids
Energy Metabolism
Fats

Keywords

  • Glucagon-like peptide-1
  • Gut hormone
  • Hyperlipidemia
  • Insulin resistance
  • Obesity
  • Palmitic acid
  • Vagotomy
  • Very-low-density lipoprotein

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

GLP-1 elicits an intrinsic gut-liver metabolic signal to ameliorate diet-induced VLDL overproduction and insulin resistance. / Khound, Rituraj; Taher, Jennifer; Baker, Christopher; Adeli, Khosrow; Su, Qiaozhu.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 37, No. 12, 01.01.2017, p. 2252-2259.

Research output: Contribution to journalArticle

@article{fd56074e69e7414dafc41521c5a768a4,
title = "GLP-1 elicits an intrinsic gut-liver metabolic signal to ameliorate diet-induced VLDL overproduction and insulin resistance",
abstract = "Objective-Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. Approach and Results-By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a highfat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Conclusions-Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.",
keywords = "Glucagon-like peptide-1, Gut hormone, Hyperlipidemia, Insulin resistance, Obesity, Palmitic acid, Vagotomy, Very-low-density lipoprotein",
author = "Rituraj Khound and Jennifer Taher and Christopher Baker and Khosrow Adeli and Qiaozhu Su",
year = "2017",
month = "1",
day = "1",
doi = "10.1161/ATVBAHA.117.310251",
language = "English (US)",
volume = "37",
pages = "2252--2259",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "12",

}

TY - JOUR

T1 - GLP-1 elicits an intrinsic gut-liver metabolic signal to ameliorate diet-induced VLDL overproduction and insulin resistance

AU - Khound, Rituraj

AU - Taher, Jennifer

AU - Baker, Christopher

AU - Adeli, Khosrow

AU - Su, Qiaozhu

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Objective-Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. Approach and Results-By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a highfat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Conclusions-Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

AB - Objective-Perturbations in hepatic lipid and very-low-density lipoprotein (VLDL) metabolism are involved in the pathogenesis of obesity and hepatic insulin resistance. The objective of this study is to delineate the mechanism of subdiaphragmatic vagotomy in preventing obesity, hyperlipidemia, and insulin resistance. Approach and Results-By subjecting the complete subdiaphragmatic vagotomized mice to various nutritional conditions and investigating hepatic de novo lipogenesis pathway, we found that complete disruption of subdiaphragmatic vagal signaling resulted in a significant decrease of circulating VLDL-triglyceride compared with the mice obtained sham procedure. Vagotomy further prevented overproduction of VLDL-triglyceride induced by an acute fat load and a highfat diet-induced obesity, hyperlipidemia, hepatic steatosis, and glucose intolerance. Mechanistic studies revealed that plasma glucagon-like peptide-1 was significantly raised in the vagotomized mice, which was associated with significant reductions in mRNA and protein expression of SREBP-1c (sterol regulatory element-binding protein 1c), SCD-1 (stearoyl-CoA desaturase-1), and FASN (fatty acid synthase), as well as enhanced hepatic insulin sensitivity. In vitro, treating mouse primary hepatocytes with a glucagon-like peptide-1 receptor agonist, exendin-4, for 48 hours inhibited free fatty acid, palmitic acid treatment induced de novo lipid synthesis, and VLDL secretion from hepatocytes. Conclusions-Elevation of glucagon-like peptide-1 in vagotomized mice may prevent VLDL overproduction and insulin resistance induced by high-fat diet. These novel findings, for the first time, delineate an intrinsic gut-liver regulatory circuit that is mediated by glucagon-like peptide-1 in regulating hepatic energy metabolism.

KW - Glucagon-like peptide-1

KW - Gut hormone

KW - Hyperlipidemia

KW - Insulin resistance

KW - Obesity

KW - Palmitic acid

KW - Vagotomy

KW - Very-low-density lipoprotein

UR - http://www.scopus.com/inward/record.url?scp=85038221309&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85038221309&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.117.310251

DO - 10.1161/ATVBAHA.117.310251

M3 - Article

C2 - 29074588

AN - SCOPUS:85038221309

VL - 37

SP - 2252

EP - 2259

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 12

ER -