title: 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.
  
  
  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: 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.).
authors: Sarah
authors: S
authors: Farr
authors: 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.).
authors: Christopher
authors: C
authors: Baker
authors: 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.).
authors: Mark
authors: M
authors: Naples
authors: 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.).
authors: Jennifer
authors: J
authors: Taher
authors: 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.).
authors: Jahangir
authors: J
authors: Iqbal
authors: 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.).
authors: Mahmood
authors: M
authors: Hussain
authors: 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.
authors: Khosrow
authors: K
authors: Adeli
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D002914:Chylomicrons / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000294:innervation; D050356:Lipid Metabolism / Q000187:drug effects; D008074:Lipoproteins / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D002914:Chylomicrons; D000067757:Glucagon-Like Peptide-1 Receptor; D008074:Lipoproteins; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: apolipoprotein B-48; central nervous system; chylomicron; glucagon-like peptide-1