Central Nervous System Regulation of Intestinal Lipoprotein Metabolism by Glucagon-Like Peptide-1 via a Brain-Gut Axis.

Abstract

OBJECTIVE:

Intestinal overproduction of atherogenic chylomicron particles postprandially is an important component of diabetic dyslipidemia in insulin-resistant states. In addition to enhancing insulin secretion, peripheral glucagon-like peptide-1 (GLP-1) receptor stimulation has the added benefit of reducing this chylomicron overproduction in patients with type 2 diabetes mellitus. Given the presence of central GLP-1 receptors and GLP-1-producing neurons, we assessed whether central GLP-1 exerts an integral layer of neuronal control during the production of these potentially atherogenic particles.

APPROACH AND RESULTS:

Postprandial production of triglyceride-rich lipoproteins was assessed in Syrian hamsters administered a single intracerebroventricular injection of the GLP-1 receptor agonist exendin-4. Intracerebroventricular exendin-4 reduced triglyceride-rich lipoprotein-triglyceride and -apolipoprotein B48 accumulation relative to vehicle-treated controls. This was mirrored by intracerebroventricular MK-0626, an inhibitor of endogenous GLP-1 degradation, and prevented by central exendin9-39, a GLP-1 receptor antagonist. The effects of intracerebroventricular exendin-4 were also lost during peripheral adrenergic receptor and central melanocortin-4 receptor inhibition, achieved using intravenous propranolol and phentolamine and intracerebroventricular HS014, respectively. However, central exendin9-39 did not preclude the effects of peripheral exendin-4 treatment on chylomicron output.

CONCLUSIONS:

Central GLP-1 is a novel regulator of chylomicron production via melanocortin-4 receptors. Our findings point to the relative importance of central accessibility of GLP-1-based therapies and compel further studies examining the status of this brain-gut axis in the development of diabetic dyslipidemia and chylomicron overproduction.

• Authors: Sarah Farr, Christopher Baker, Mark Naples, Jennifer Taher, Jahangir Iqbal, Mahmood Hussain, Khosrow Adeli
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 35 Issue 5 Pg. 1092-100 (May 2015) ISSN: 1524-4636 [Electronic] United States
• PMID: 25675997 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 American Heart Association, Inc.

Chemical References

• Chylomicrons
• Glucagon-Like Peptide-1 Receptor
• Lipoproteins
• Peptides
• Receptors, Glucagon
• Venoms
• Glucagon-Like Peptide 1
• Exenatide

Topics

• Animals
• Central Nervous System (drug effects, metabolism)
• Chylomicrons (drug effects, metabolism)
• Cricetinae
• Diabetes Mellitus, Type 2 (metabolism, physiopathology)
• Disease Models, Animal
• Exenatide
• Glucagon-Like Peptide 1 (metabolism)
• Glucagon-Like Peptide-1 Receptor
• Intestinal Mucosa (metabolism)
• Intestines (innervation)
• Lipid Metabolism (drug effects)
• Lipoproteins (drug effects, metabolism)
• Peptides (pharmacology)
• Random Allocation
• Receptors, Glucagon (metabolism)
• Venoms (pharmacology)