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Arterioscler Thromb Vasc Biol. 2015 May;35(5):1092-100. doi: 10.1161/ATVBAHA.114.304873. Epub 2015 Feb 12.

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

Author information

1
From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (S.F., J.T., K.A.); Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (S.F., C.B., M.N., J.T., K.A.); and Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY (J.I., M.H.).
2
From the Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada (S.F., J.T., K.A.); Molecular Structure and Function Program, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada (S.F., C.B., M.N., J.T., K.A.); and Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY (J.I., M.H.). khosrow.adeli@sickkids.ca.

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.

KEYWORDS:

apolipoprotein B-48; central nervous system; chylomicron; glucagon-like peptide-1

Comment in

PMID:
25675997
DOI:
10.1161/ATVBAHA.114.304873
[Indexed for MEDLINE]

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