Modulation of feeding behavior and metabolism by dynorphin
Modulation of feeding behavior and metabolism by dynorphin
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DOI：
10.1038/s41598-020-60518-0
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发表时间：
2020-03-02
影响因子：
4.6
通讯作者：
Zimmer, Andreas
中科院分区：
文献类型：
--
作者：
Ghule, Aishwarya;Racz, Ildiko;Zimmer, Andreas
神经元对不同饮食和喂养方案的代谢和行为反应的调节是一个重要的研究领域。在此，我们研究了阿片肽强啡肽是否调节摄食行为和代谢。将缺乏强啡肽肽（KO）的小鼠暴露于正常饮食（ND）或高脂饮食（HFD）12周。此外，小鼠具有时间限制（TR）或随意（AL）获取食物的能力。在整个12周的喂养计划中监测体重、摄食量和血糖水平。通过免疫组织化学分析脑样品以检测下丘脑肽的表达水平的变化。正如预期的那样，HFD或AL获得食物的动物比ND或TR获得的小鼠体重增加更多。出乎意料的是，与相应的WT组相比，TR HFD组的KO雌性动物以及AL ND或AL HFD组的KO雄性动物表现出显著增加的体重增量。基因型之间的卡路里摄入量仅略有不同：雌性ND AL组中存在显著差异，其中强啡肽KO小鼠比WT小鼠吃得更多。尽管TR喂养方案的雌性KO小鼠消耗的食物量与WT对照相似，但它们显示出显著更高的血糖水平。我们观察到KO小鼠下丘脑食欲肽神经肽Y（NPY）和食欲素-A的水平显着降低。这种降低在HFD组和AL条件下变得特别明显。WT小鼠腹侧苍白球中的κ阿片样受体（KOR）水平在HFD后高于ND喂养。我们假设，HFD增强强啡肽信号在这个享乐中心，以维持能量稳态，因此KO小鼠有一个更明显的表型在HFD条件下，由于缺乏它。我们的数据表明，强啡肽调节与TR喂养方案和HFD消费的代谢变化。我们的结论是，缺乏强啡肽的原因脱钩之间的能量摄入和体重增加的小鼠; KO小鼠维持HFD变得超重，尽管他们的正常食物摄入。因此，使用κ阿片受体激动剂治疗肥胖症可以被认为是一种潜在的治疗策略。
The neuronal regulation of metabolic and behavioral responses to different diets and feeding regimens is an important research area. Herein, we investigated if the opioid peptide dynorphin modulates feeding behavior and metabolism. Mice lacking dynorphin peptides (KO) were exposed to either a normal diet (ND) or a high-fat diet (HFD) for a period of 12 weeks. Additionally, mice had either time-restricted (TR) or ad libitum (AL) access to food. Body weight, food intake and blood glucose levels were monitored throughout the 12-week feeding schedule. Brain samples were analyzed by immunohistochemistry to detect changes in the expression levels of hypothalamic peptides. As expected, animals on HFD or having AL access to food gained more weight than mice on ND or having TR access. Unexpectedly, KO females on TR HFD as well as KO males on AL ND or AL HFD demonstrated a significantly increased body weight gain compared to the respective WT groups. The calorie intake differed only marginally between the genotypes: a significant difference was present in the female ND AL group, where dynorphin KO mice ate more than WT mice. Although female KO mice on a TR feeding regimen consumed a similar amount of food as WT controls, they displayed significantly higher levels of blood glucose. We observed significantly reduced levels of hypothalamic orexigenic peptides neuropeptide Y (NPY) and orexin-A in KO mice. This decrease became particularly pronounced in the HFD groups and under AL condition. The kappa opiod receptor (KOR) levels were higher after HFD compared to ND feeding in the ventral pallidum of WT mice. We hypothesize that HFD enhances dynorphin signaling in this hedonic center to maintain energy homeostasis, therefore KO mice have a more pronounced phenotype in the HFD condition due to the lack of it. Our data suggest that dynorphin modulates metabolic changes associated with TR feeding regimen and HFD consumption. We conclude that the lack of dynorphin causes uncoupling between energy intake and body weight gain in mice; KO mice maintained on HFD become overweight despite their normal food intake. Thus, using kappa opioid receptor agonists against obesity could be considered as a potential treatment strategy.