Neuromodulation of orexin neurons reduces diet-induced adiposity.
Neuromodulation of orexin neurons reduces diet-induced adiposity.
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DOI：
10.1038/ijo.2017.276
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Kotz CM
中科院分区：
文献类型：
--
作者：
Zink AN;Bunney PE;Holm AA;Billington CJ;Kotz CM
食欲素水平低与人类和动物的肥胖和体力活动减少有关。设计师受体专门激活的设计师药物（DREADDs）选择性激活食欲素神经元在小鼠外侧下丘脑（LH），以测量对自发性身体活动（SPA）的影响。通过将AAV载体立体定位注射到杂合食欲素-Cre或C57/B6 J小鼠的尾侧LH中来实现DREADD靶向。在一组研究中，检查食欲素神经元的激发（病毒：AAV 2-EF 1a-DIO-hM 3Dq-mCherry），并且在光周期开始后3-4小时开始测试期。在检查食欲素神经元（病毒：AAV 2-hSyn-DIO-hM 4Di-mCherry）的抑制的研究中，在黑暗周期开始前15分钟开始测试。通过腹腔注射氯氮平N-氧化物（CNO; 1或5 mg/kg）或生理盐水，记录在开放视野室中移动所花费的时间，持续2 h。在单独的小鼠群组中的后续研究使用间接量热室（SableSystem™）平行地量化SPA与能量消耗（EE）和食物摄入的变化。驯化后，在约1周的过程中进行测试阶段（生理盐水和/或CNO），每天注射。测量SPA、EE、食物摄入、粪便和身体组成（EchoMRI™）的变化。另外的小鼠群组被喂食高脂肪饮食（HFD）并每天注射CNO长达10天，以评估食欲素活化以预防饮食诱导的肥胖的潜力。食欲素的激活导致雄性和雌性小鼠的SPA增加，并伴随着能量消耗的增加，而总体食物摄入量没有变化。当食欲素激活发生在高脂肪饮食的背景下，体重增加和肥胖显着减弱。当DREADDs抑制食欲素活性时，SPA降低。这些结果表明，食欲素神经元在介导身体活动中起关键作用，并提出了治疗肥胖的新的治疗靶点。
Low levels of orexin are associated with obesity and reduced physical activity in humans and animals. Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) selectively activated orexin neurons in mouse lateral hypothalamus (LH) to measure effects on spontaneous physical activity (SPA). DREADD targeting was achieved by stereotaxic injection of AAV vectors into caudal lateral LH of heterozygous orexin-Cre or C57/B6J mice. In one set of studies, excitation of orexin neurons was examined (virus: AAV2-EF1a-DIO-hM3Dq-mCherry), and test sessions began 3-4 h after light cycle onset. In a study examining the inhibition of orexin neurons (virus: AAV2-hSyn-DIO-hM4Di-mCherry), testing began 15 min prior to dark cycle onset. Clozapine n-oxide (CNO; 1 or 5 mg/kg) or saline was injected intraperitoneally and time spent moving in open field chambers was recorded for 2 h. Follow-up studies in separate mouse cohorts quantified SPA in parallel with changes in energy expenditure (EE) and chow intake using indirect calorimetry chambers (SableSystem™). Following acclimation, testing sessions (saline and/or CNO) took place over the course of ~1 week, with injections administered every day. Changes in SPA, EE, chow intake, fecal boli, and body composition (EchoMRI™) were measured. Additional mice cohorts were fed a high-fat diet (HFD) and injected with CNO daily up to 10 days to assess the potential for orexin activation to prevent diet-induced obesity. Activation of orexin resulted in increases in SPA in male and female mice, and was accompanied by increases in energy expenditure without changes in overall chow intake. When orexin activation occurred in the context of high fat diet, weight gain and adiposity were significantly attenuated. SPA was decreased when DREADDs were used to inhibit orexin activity. These results demonstrate that orexin neurons play a critical role in mediating physical activity and suggest a novel therapeutic target for treating obesity.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
影响因子：
--
作者：
Kotz, CM;Teske, JA;Wang, CF
通讯作者：
Wang, CF
影响因子：
2.5
作者：
Brownell, Sara E.;Conti, Bruno
通讯作者：
Conti, Bruno
影响因子：
2.9
作者：
Bunney PE;Zink AN;Holm AA;Billington CJ;Kotz CM
通讯作者：
Kotz CM
DOI：
10.1073/pnas.0811126106
发表时间：
2009-03-17
影响因子：
11.1
作者：
Matsuki, Taizo;Nomiyama, Mika;Sakurai, Takeshi
通讯作者：
Sakurai, Takeshi