title: Diet-induced obesity causes peripheral and central ghrelin resistance by promoting inflammation.
abstract: Ghrelin, a stomach-derived orexigenic peptide, transmits starvation signals to the hypothalamus via the vagus afferent nerve. Peripheral administration of ghrelin does not induce food intake in high fat diet (HFD)-induced obese mice. We investigated whether this ghrelin resistance was caused by dysfunction of the vagus afferent pathway. Administration (s.c.) of ghrelin did not induce food intake, suppression of oxygen consumption, electrical activity of the vagal afferent nerve, phosphorylation of ERK2 and AMP-activated protein kinase alpha in the nodose ganglion, or Fos expression in hypothalamic arcuate nucleus of mice fed a HFD for 12 weeks. Administration of anti-ghrelin IgG did not induce suppression of food intake in HFD-fed mice. Expression levels of ghrelin receptor mRNA in the nodose ganglion and hypothalamus of HFD-fed mice were reduced. Inflammatory responses, including upregulation of macrophage/microglia markers and inflammatory cytokines, occurred in the nodose ganglion and hypothalamus of HFD-fed mice. A HFD blunted ghrelin signaling in the nodose ganglion via a mechanism involving in situ activation of inflammation. These results indicate that ghrelin resistance in the obese state may be caused by dysregulation of ghrelin signaling via the vagal afferent.
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Farhana
authors.initials: F
authors.lastname: Naznin
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Toshinai
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: T M Zaved
authors.initials: TM
authors.lastname: Waise
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Cherl
authors.initials: C
authors.lastname: NamKoong
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Abu Saleh
authors.initials: AS
authors.lastname: Md Moin
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.affiliation: Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan Division of NeurologyRespirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, JapanDepartment of Sports and FitnessFaculty of Wellness, Shigakkan University, 55 Nakoyama, Yokone, Obu 474-8651, JapanAMED-CRESTAgency for Medical Research and Development, 1-7-1 Otemachi, Chiyoda-ku, Tokyo 100-0004, Japan nakazato@med.miyazaki-u.ac.jp.
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Nakazato
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D054439:Ghrelin / Q000008:administration & dosage / Q000097:blood / Q000502:physiology*; D007031:Hypothalamus / Q000503:physiopathology; D007249:Inflammation / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D020738:Leptin / Q000008:administration & dosage / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009620:Nodose Ganglion / Q000503:physiopathology; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000503:physiopathology*; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054440:Receptors, Ghrelin / Q000235:genetics; D015398:Signal Transduction
chemical_list: D054439:Ghrelin; D020738:Leptin; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D054440:Receptors, Ghrelin; D055372:AMP-Activated Protein Kinases
keywords: diet-induced obesity; ghrelin; inflammation; nodose ganglion; vagus nerve