Sarah Farr1, Christopher Baker1, Mark Naples1, Jennifer Taher1, Jahangir Iqbal1, Mahmood Hussain1, Khosrow Adeli2. 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.
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: Miriam Jacome-Sosa; Elizabeth J Parks; Richard S Bruno; Esra Tasali; Gary F Lewis; Barbara O Schneeman; Tia M Rains Journal: Adv Nutr Date: 2016-03-15 Impact factor: 8.701
Authors: Maritza J Romero; Rudolf Lucas; Huijuan Dou; Supriya Sridhar; Istvan Czikora; Eby M Mosieri; Ferenc G Rick; Norman L Block; Subbaramiah Sridhar; David Fulton; Neal L Weintraub; Zsolt Bagi; Andrew V Schally Journal: Proc Natl Acad Sci U S A Date: 2016-02-01 Impact factor: 11.205