Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shougoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Endocrinology. 2011 Jul;152(7):2634-43. doi: 10.1210/en.2011-0004. Epub 2011 Apr 26.
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.
最近的流行病学研究表明肥胖会增加抑郁症的发病率。我们研究了瘦素对肥胖相关抑郁症的影响。瘦素在强迫游泳试验（FST）中诱导正常小鼠产生抗抑郁行为，而高瘦素血症的瘦素过表达转基因小鼠在 FST 中表现出比非转基因小鼠更多的抗抑郁行为。相比之下，瘦素缺乏型 ob/ob 小鼠在 FST 中表现出比正常小鼠更严重的抑郁行为，而给予瘦素治疗则显著改善了这种抑郁行为。饮食诱导肥胖（DIO）小鼠喂食高脂肪饮食，在 FST 和蔗糖偏好测试中表现出比喂食对照饮食（CD）的小鼠更严重的抑郁行为。在 DIO 小鼠中，瘦素既没有诱导抗抑郁作用，也没有增加海马中 c-Fos 免疫反应细胞的数量。将 DIO 小鼠的饮食从高脂肪饮食改为 CD 饮食可改善其抑郁行为并恢复瘦素诱导的抗抑郁作用。DIO 小鼠海马中的脑源性神经营养因子浓度明显低于 CD 小鼠。瘦素治疗显著增加了 CD 小鼠海马中的脑源性神经营养因子浓度，但对 DIO 小鼠没有影响。K252a 处理显著减弱了瘦素在 CD 小鼠中的抗抑郁活性。这些发现表明，瘦素可诱导抗抑郁状态，而表现出严重抑郁行为的 DIO 小鼠在 FST 和海马生化变化中对瘦素均无反应。因此，与肥胖相关的抑郁症至少部分是由于海马中瘦素活性受损所致。
