title: Impaired CNS leptin action is implicated in depression associated with obesity.
abstract: Recent epidemiological studies indicate that obesity increases the incidence of depression. We examined the implication of leptin for obesity-associated depression. Leptin induced antidepressive behavior in normal mice in a forced swimming test (FST), and leptin-overexpressing transgenic mice with hyperleptinemia exhibited more antidepressive behavior in the FST than nontransgenic mice. In contrast, leptin-deficient ob/ob mice showed more severe depressive behavior in the FST than normal mice, and leptin administration substantially ameliorated this depressive behavior. Diet-induced obese (DIO) mice fed a high-fat diet showed more depressive behavior in the FST and in a sucrose preference test compared with mice fed a control diet (CD). In DIO mice, leptin induced neither antidepressive action nor increment of the number of c-Fos immunoreactive cells in the hippocampus. Diet substitution from high-fat diet to CD in DIO mice ameliorated the depressive behavior and restored leptin-induced antidepressive action. Brain-derived neurotrophic factor concentrations in the hippocampus were significantly lower in DIO mice than in CD mice. Leptin administration significantly increased hippocampal brain-derived neurotrophic factor concentrations in CD mice but not in DIO mice. The antidepressant activity of leptin in CD mice was significantly attenuated by treatment with K252a. These findings demonstrated that leptin induces an antidepressive state, and DIO mice, which exhibit severe depressive behavior, did not respond to leptin in both the FST and the biochemical changes in the hippocampus. Thus, depression associated with obesity is due, at least in part, to impaired leptin activity in the hippocampus.
authors.affiliation: Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Yamada
authors.forename: Goro
authors.initials: G
authors.lastname: Katsuura
authors.forename: Yukari
authors.initials: Y
authors.lastname: Ochi
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Toru
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001931:Brain Mapping; D019208:Brain-Derived Neurotrophic Factor / Q000008:administration & dosage / Q000378:metabolism; D002227:Carbazoles / Q000008:administration & dosage / Q000494:pharmacology; D003863:Depression / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D004041:Dietary Fats / Q000009:adverse effects; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D026121:Indole Alkaloids / Q000008:administration & dosage / Q000494:pharmacology; D007276:Injections, Intraventricular; D020738:Leptin / Q000008:administration & dosage / Q000097:blood / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009765:Obesity / Q000523:psychology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011897:Random Allocation; D020813:Receptor, trkB / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004041:Dietary Fats; D026121:Indole Alkaloids; D020738:Leptin; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D011994:Recombinant Proteins; C049985:staurosporine aglycone; D020813:Receptor, trkB