期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 37, 期 12, 页码 2252-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.117.310251
关键词
glucagon-like peptide-1; gut hormone; hyperlipidemia; insulin resistance; obesity; palmitic acid; vagotomy; very-low-density lipoprotein
资金
- US Department of Agriculture (USDA)/National Institute of Food and Agriculture (NIFA)
- Heart and Stroke Foundation Canada
- Natural Sciences and Engineering Research Council of Canada (NSERC)
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. Visual Overview-An online visual overview is available for this article.
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