title: Transient receptor potential vanilloid type 1-dependent regulation of liver-related neurons in the paraventricular nucleus of the hypothalamus diminished in the type 1 diabetic mouse.
abstract: The paraventricular nucleus (PVN) of the hypothalamus controls the autonomic neural output to the liver, thereby participating in the regulation of hepatic glucose production (HGP); nevertheless, mechanisms controlling the activity of liver-related PVN neurons are not known. Transient receptor potential vanilloid type 1 (TRPV1) is involved in glucose homeostasis and colocalizes with liver-related PVN neurons; however, the functional role of TRPV1 regarding liver-related PVN neurons has to be elucidated. A retrograde viral tracer was used to identify liver-related neurons within the brain-liver circuit in control, type 1 diabetic, and insulin-treated mice. Our data indicate that TRPV1 regulates liver-related PVN neurons. This TRPV1-dependent excitation diminished in type 1 diabetic mice. In vivo and in vitro insulin restored TRPV1 activity in a phosphatidylinositol 3-kinase/protein kinase C-dependent manner and stimulated TRPV1 receptor trafficking to the plasma membrane. There was no difference in total TRPV1 protein expression; however, increased phosphorylation of TRPV1 receptors was observed in type 1 diabetic mice. Our data demonstrate that TRPV1 plays a pivotal role in the regulation of liver-related PVN neurons. Moreover, TRPV1-dependent excitation of liver-related PVN neurons diminishes in type 1 diabetes, thus indicating that the brain-liver autonomic circuitry is altered in type 1 diabetes and may contribute to the autonomic dysfunction of HGP.
authors.affiliation: Department of Physiology, Tulane University, School of Medicine, New Orleans, Louisiana, USA. azsombo@tulane.edu
authors.forename: Hong
authors.initials: H
authors.lastname: Gao
authors.forename: Kayoko
authors.initials: K
authors.lastname: Miyata
authors.forename: Muthu D
authors.initials: MD
authors.lastname: Bhaskaran
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Derbenev
authors.forename: Andrea
authors.initials: A
authors.lastname: Zsombok
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000378:metabolism*; D051379:Mice; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation / Q000187:drug effects; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse