High-fat feeding impairs nutrient sensing and gut brain integration in the caudomedial nucleus of the solitary tract in mice.
High-fat feeding impairs nutrient sensing and gut brain integration in the caudomedial nucleus of the solitary tract in mice.
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DOI：
10.1371/journal.pone.0118888
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Blouet C
中科院分区：
文献类型：
--
作者：
Cavanaugh AR;Schwartz GJ;Blouet C
高血压性肥胖的部分特征是进食量的增加导致每日能量摄入量增加，但进食量调节回路活动受损的机制，特别是聚集在后脑孤束尾侧核(CmNTS)的调节回路活动受损的机制仍鲜为人知。在这篇文章中，我们评估了高脂肪(HF)喂养和饮食诱导肥胖(DIO)在控制膳食大小方面对cmNTS营养感知和代谢整合的影响。对标准饲料、低脂(LF)饲料或HF饲料喂养2周或6个月的小鼠，植入针对cmNTS的双侧脑管。通过行为室和进食模式分析评估单独或与ip CCK联合注射CmNTS L亮氨酸后大鼠的摄食行为。通过蛋白质印迹、免疫荧光和对氨基酸感应mTORC1通路(哺乳动物雷帕霉素复合体1的靶标)的药物抑制，评估了与摄食反应有关的分子机制。我们发现，喂食HF可钝化L-亮氨酸给药的厌食效应。在饲喂HF的小鼠的中枢神经系统中，L亮氨酸传感器P70 S6激酶1的基线活性增加，而L亮氨酸诱导的这一通路的激活受到抑制，这表明饲喂HF与CNNTS、mTOR营养和激素感觉的损害有关。有趣的是，mTORC1抑制剂雷帕霉素的急性致食欲作用在服用HF的小鼠中得到了保留，支持了HF诱导基线cmNTS mTORC1活性增加是L亮氨酸感觉缺陷的基础的断言。最后，取消了CCK和CNNTS L亮氨酸对DIO小鼠的协同抑食作用。这些结果表明，饲喂HF导致了cmNTS营养感知和代谢整合在调节膳食大小方面的损害。
Hyperphagic obesity is characterized in part by a specific increase in meal size that contributes to increased daily energy intake, but the mechanisms underlying impaired activity of meal size regulatory circuits, particularly those converging at the caudomedial nucleus of the solitary tract in the hindbrain (cmNTS), remain poorly understood. In this paper, we assessed the consequences of high-fat (HF) feeding and diet-induced obesity (DIO) on cmNTS nutrient sensing and metabolic integration in the control of meal size. Mice maintained on a standard chow diet, low-fat (LF) diet or HF diet for 2 weeks or 6 months were implanted with a bilateral brain cannula targeting the cmNTS. Feeding behavior was assessed using behavioral chambers and meal-pattern analysis following cmNTS L-leucine injections alone or together with ip CCK. Molecular mechanisms implicated in the feeding responses were assessed using western blot, immunofluorescence and pharmacological inhibition of the amino acid sensing mTORC1 pathway (mammalian target of rapamycin complex 1). We found that HF feeding blunts the anorectic consequences of cmNTS L-leucine administration. Increased baseline activity of the L-leucine sensor P70 S6 kinase 1 and impaired L-leucine-induced activation of this pathway in the cmNTS of HF-fed mice indicate that HF feeding is associated with an impairment in cmNTS mTOR nutritional and hormonal sensing. Interestingly, the acute orexigenic effect of the mTORC1 inhibitor rapamycin was preserved in HF-fed mice, supporting the assertion that HF-induced increase in baseline cmNTS mTORC1 activity underlies the defect in L-leucine sensing. Last, the synergistic feeding-suppressive effect of CCK and cmNTS L-leucine was abrogated in DIO mice. These results indicate that HF feeding leads to an impairment in cmNTS nutrient sensing and metabolic integration in the regulation of meal size.
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影响因子：
64.8
作者：
Wu, Qi;Clark, Michael S.;Palmiter, Richard D.
通讯作者：
Palmiter, Richard D.
影响因子：
29
作者：
Blouet C;Schwartz GJ
通讯作者：
Schwartz GJ
DOI：
10.1152/ajpregu.00604.2003
发表时间：
2004-07-01
影响因子：
2.8
作者：
Blevins, JE;Schwartz, MW;Baskin, DG
通讯作者：
Baskin, DG
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
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作者：
Duca, F. A.;Swartz, T. D.;Covasa, M.
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