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

8 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 high-fat 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
Pages (from-to)2252-2259
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume37
Issue number12
Early online date26 Oct 2017
DOIs
Publication statusPublished - 01 Dec 2017

Keywords

  • Animals
  • Biomarkers/blood
  • Blood Glucose/metabolism
  • Cells, Cultured
  • Diet, High-Fat
  • Disease Models, Animal
  • Fatty Acid Synthase, Type I/genetics
  • Fatty Liver/blood
  • Gene Expression Regulation
  • Glucagon-Like Peptide 1/metabolism
  • Hepatocytes/metabolism
  • Hyperlipidemias/blood
  • Incretins/pharmacology
  • Insulin/blood
  • Insulin Resistance
  • Intestines/drug effects
  • Lipoproteins, VLDL/metabolism
  • Liver/drug effects
  • Male
  • Mice, Inbred C57BL
  • Obesity/blood
  • Peptides/pharmacology
  • RNA, Messenger/genetics
  • Signal Transduction
  • Stearoyl-CoA Desaturase/genetics
  • Sterol Regulatory Element Binding Protein 1/genetics
  • Time Factors
  • Triglycerides/metabolism
  • Up-Regulation
  • Vagotomy
  • Vagus Nerve/physiopathology
  • Venoms/pharmacology

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