GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein
Background/Objective: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabol...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822001594 |
| _version_ | 1817969237065465856 |
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| author | Simon Hoffman Danielle Alvares Khosrow Adeli |
| author_facet | Simon Hoffman Danielle Alvares Khosrow Adeli |
| author_sort | Simon Hoffman |
| collection | DOAJ |
| description | Background/Objective: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. Methods: Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. Results: GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. Conclusion: Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism. |
| first_indexed | 2024-04-13T20:18:47Z |
| format | Article |
| id | doaj.art-fbee2f4641c14897ab653913265336b3 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-04-13T20:18:47Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-fbee2f4641c14897ab653913265336b32022-12-22T02:31:38ZengElsevierMolecular Metabolism2212-87782022-11-0165101590GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal veinSimon Hoffman0Danielle Alvares1Khosrow Adeli2Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, CanadaMolecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, CanadaMolecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada; Corresponding author. Molecular Medicine, The Hospital for Sick Children, 555 University Ave, Atrium Room 3652, Toronto, ON M5G 1X8, Canada.Background/Objective: GLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. Methods: Syrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. Results: GLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. Conclusion: Our data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.http://www.sciencedirect.com/science/article/pii/S2212877822001594Glucagon-like peptide-1 (GLP-1)Portal veinVagus nerveNodose ganglionDyslipidemiaChylomicron |
| spellingShingle | Simon Hoffman Danielle Alvares Khosrow Adeli GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein Molecular Metabolism Glucagon-like peptide-1 (GLP-1) Portal vein Vagus nerve Nodose ganglion Dyslipidemia Chylomicron |
| title | GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| title_full | GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| title_fullStr | GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| title_full_unstemmed | GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| title_short | GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| title_sort | glp 1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein |
| topic | Glucagon-like peptide-1 (GLP-1) Portal vein Vagus nerve Nodose ganglion Dyslipidemia Chylomicron |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822001594 |
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