Hassan Ahmed M, Mancano Giulia, Kashofer Karl, Liebisch Gerhard, Farzi Aitak, Zenz Geraldine, Claus Sandrine P, Holzer Peter
Research Unit of Translational Neurogastroenterology, Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria.
Department of Food and Nutritional Sciences, University of Reading, Reading, UK.
Nutr Neurosci. 2022 Feb;25(2):299-312. doi: 10.1080/1028415X.2020.1751508. Epub 2020 Apr 15.
Imbalanced nutrition and obesity are risk factors for depression, a relationship that in rodents can be modeled by depression-like behavior in response to high-fat diet (HFD). In this work, we examined the role of the intestinal microbiota and the adipocytokine leptin as potential mediators of the effects of HFD to induce anhedonia-like behavior and reduce self-care in mice. Male mice were fed a control diet or HFD (60 kJ% from fat) for a period of 4 weeks, after which behavioral tests and molecular analyses (gut microbiome composition, intestinal metabolome, fecal fatty acids, plasma hormone levels) were performed. The role of the intestinal microbiota was addressed by selective depletion of gut bacteria with a combination of non-absorbable antibiotics, while the implication of leptin was examined by the use of leptin-deficient mice. Antibiotic treatment reduced the HFD-induced weight gain and adiposity and prevented HFD-induced anhedonia-like behavior and self-care reduction. These effects were associated with a decrease in fecal fatty acids and intestinal microbiota-related metabolites including short-chain fatty acids, glucose and amino acids. Gut microbiota depletion suppressed the HFD-induced rise of plasma leptin, and the circulating leptin levels correlated with the anhedonia-like behavior and reduced self-care caused by HFD. The anhedonic effect of HFD was absent in leptin-deficient mice although these animals gained more weight and adiposity in response to HFD than wild-type mice. The results indicate that anhedonia-like behavior induced by HFD in mice depends on the intestinal microbiome and involves leptin as a signaling hormone.
营养失衡和肥胖是抑郁症的风险因素，在啮齿动物中，这种关系可以通过对高脂饮食（HFD）产生的类似抑郁行为来模拟。在这项研究中，我们研究了肠道微生物群和脂肪细胞因子瘦素作为高脂饮食诱导小鼠快感缺失样行为和自我护理能力下降的潜在介导因素的作用。雄性小鼠喂食对照饮食或高脂饮食（脂肪提供60 kJ%的能量）4周，之后进行行为测试和分子分析（肠道微生物群组成、肠道代谢组、粪便脂肪酸、血浆激素水平）。通过使用不可吸收抗生素联合选择性清除肠道细菌来研究肠道微生物群的作用，同时通过使用瘦素缺乏小鼠来研究瘦素的影响。抗生素治疗减少了高脂饮食诱导的体重增加和肥胖，并预防了高脂饮食诱导的快感缺失样行为和自我护理能力下降。这些作用与粪便脂肪酸和肠道微生物群相关代谢物（包括短链脂肪酸、葡萄糖和氨基酸）的减少有关。肠道微生物群的清除抑制了高脂饮食诱导的血浆瘦素升高，并且循环瘦素水平与高脂饮食引起的快感缺失样行为和自我护理能力下降相关。瘦素缺乏小鼠没有出现高脂饮食的快感缺失效应，尽管这些动物对高脂饮食的反应比野生型小鼠体重增加和肥胖更明显。结果表明，高脂饮食在小鼠中诱导的快感缺失样行为取决于肠道微生物群，并且涉及瘦素作为一种信号激素。
