title: Leptin receptor signaling in the hypothalamus regulates hepatic autonomic nerve activity via phosphatidylinositol 3-kinase and AMP-activated protein kinase.
abstract: Leptin action in the brain has emerged as an important regulator of liver function independently from its effects on food intake and body weight. The autonomic nervous system plays a key role in the regulation of physiological processes by leptin. Here, we used direct recording of nerve activity from sympathetic or vagal nerves subserving the liver to investigate how brain action of leptin controls hepatic autonomic nerve activity. Intracerebroventricular (ICV) administration of leptin activated hepatic sympathetic traffic in rats and mice in dose- and receptor-dependent manners. The hepatic sympatho-excitatory effects of leptin were also observed when leptin was microinjected directly into the arcuate nucleus (ARC), but not into the ventromedial hypothalamus (VMH). Moreover, using pharmacological and genetic approaches, we show that leptin-induced increase in hepatic sympathetic outflow depends on PI3K but not AMP-activated protein kinase (AMPK), STAT3, or ERK1/2. Interestingly, ICV leptin also increased hepatic vagal nerve activity in rats. We show that this response is reproduced by intra-ARC, but not intra-VMH, leptin administration and requires PI3K and AMPK. We conclude that central leptin signaling conveys the information to the liver through the sympathetic and parasympathetic branches of the autonomic nervous system. Our data also provide important insight into the molecular events underlying leptin's control of hepatic autonomic nerve activity by implicating PI3K and AMPK pathways.
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan, Department of Internal Medicine, and mtanida@kanazawa-med.ac.jp kamal-rahmouni@uiowa.edu.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tanida
authors.affiliation: College of Pharmacology, Hokuriku University, Kanazawa, Ishikawa 920-1180, Japan, and.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Pharmacology.
authors.forename: Donald A
authors.identifier: http://orcid.org/0000-0001-8742-4428
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Kurata
authors.affiliation: Department of Physiology II, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan.
authors.forename: Toshishige
authors.initials: T
authors.lastname: Shibamoto
authors.affiliation: Department of Pharmacology, Department of Internal Medicine, and Fraternal Order of Eagles Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242 mtanida@kanazawa-med.ac.jp kamal-rahmouni@uiowa.edu.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D020738:Leptin / Q000494:pharmacology; D008099:Liver / Q000294:innervation*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D054411:Receptors, Leptin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014630:Vagus Nerve / Q000502:physiology*
chemical_list: D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases
keywords: AMPK; PI3K; autonomic function; leptin; liver