title: A fatty acid-dependent hypothalamic-DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins.
abstract: The brain emerges as a regulator of hepatic triglyceride-rich very-low-density lipoproteins (VLDL-TG). The neurocircuitry involved as well as the ability of fatty acids to trigger a neuronal network to regulate VLDL-TG remain unknown. Here we demonstrate that infusion of oleic acid into the mediobasal hypothalamus (MBH) activates a MBH PKC-δ→KATP-channel signalling axis to suppress VLDL-TG secretion in rats. Both NMDA receptor-mediated transmissions in the dorsal vagal complex (DVC) and hepatic innervation are required for lowering VLDL-TG, illustrating a MBH-DVC-hepatic vagal neurocircuitry that mediates MBH fatty acid sensing. High-fat diet (HFD)-feeding elevates plasma TG and VLDL-TG secretion and abolishes MBH oleic acid sensing to lower VLDL-TG. Importantly, HFD-induced dysregulation is restored with direct activation of either MBH PKC-δ or KATP-channels via the hepatic vagus. Thus, targeting a fatty acid sensing-dependent hypothalamic-DVC neurocircuitry may have therapeutic potential to lower hepatic VLDL-TG and restore lipid homeostasis in obesity and diabetes.
authors.affiliation: Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Jessica T Y
authors.initials: JT
authors.lastname: Yue
authors.affiliation: 1] Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7 [2] Departments of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Mona A
authors.initials: MA
authors.lastname: Abraham
authors.affiliation: 1] Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7 [2] Departments of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Mary P
authors.initials: MP
authors.lastname: LaPierre
authors.affiliation: 1] Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7 [2] Departments of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Mighiu
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada T6G 2E1.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Light
authors.affiliation: Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7.
authors.forename: Beatrice M
authors.initials: BM
authors.lastname: Filippi
authors.affiliation: 1] Toronto General Research Institute and Department of Medicine, UHN, Toronto, Ontario, Canada M5G 1L7 [2] Departments of Physiology, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [3] Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8 [4] Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Lam
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000378:metabolism*; D008074:Lipoproteins / Q000378:metabolism*; D008079:Lipoproteins, VLDL; D008099:Liver / Q000294:innervation / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000502:physiology; D019301:Oleic Acid / Q000737:chemistry; D015221:Potassium Channels / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014280:Triglycerides / Q000378:metabolism*; D014630:Vagus Nerve / Q000502:physiology
chemical_list: D001055:Apolipoproteins B; D005227:Fatty Acids; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D015221:Potassium Channels; D014280:Triglycerides; C030087:lipoprotein triglyceride; C030106:very low density lipoprotein triglyceride; D049452:Green Fluorescent Proteins; D019301:Oleic Acid; D011493:Protein Kinase C