Impaired CNS leptin action is implicated in depression associated with obesity

Nobuko Yamada, Goro Katsuura, Yukari Ochi, Ken Ebihara, Toru Kusakabe, Kiminori Hosoda, Kazuwa Nakao

Research output: Contribution to journalArticlepeer-review

205 Citations (Scopus)


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/obmice showed more severe depressive behavior in the FST than normal mice, andleptin 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 isdue, at least in part, to impaired leptin activity in the hippocampus.

Original languageEnglish
Pages (from-to)2634-2643
Number of pages10
Issue number7
Publication statusPublished - 2011 Jul

ASJC Scopus subject areas

  • Endocrinology


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