Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice
Hypothalamic REV-ERB nuclear receptors control diurnal food intake and leptin sensitivity in diet-induced obese mice
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DOI：
10.1172/jci140424
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发表时间：
2021-01-04
影响因子：
15.9
通讯作者：
Lazar, Mitchell A.
中科院分区：
文献类型：
--
作者：
Adlanmerini, Marine;Nguyen, Hoang C. B.;Lazar, Mitchell A.
当能量消耗超过能量摄入时，就会发生肥胖。下丘脑腹内侧核（VMH）、弓状核（ARC）和背内侧核（DMH）控制食物摄入和能量消耗。在这里，我们报告说，与女性相比，缺乏昼夜节律核受体REV-ERB α和β在结节下丘脑（HDKO小鼠）的雄性小鼠体重增加过度肥胖的高脂肪饮食，由于减少能量消耗和增加食物摄入量在轻阶段。此外，在HDKO小鼠中，禁食后的反跳性食物摄入显著增加。综合转录组学和顺反子分析显示，这种进食行为的中断是由于ARC中的REV-ERB依赖性瘦素信号传导受到干扰。事实上，在体内瘦素的敏感性受损的HMO小鼠在一个肥胖的饮食在昼夜的方式。因此，REV-ERB在饮食诱导的肥胖中下丘脑控制食物摄入和昼夜瘦素敏感性中起关键作用。
Obesity occurs when energy expenditure is outweighed by energy intake. Tuberal hypothalamic nuclei, including the arcuate nucleus (ARC), ventromedial nucleus (VMH), and dorsomedial nucleus (DMH), control food intake and energy expenditure. Here we report that, in contrast with females, male mice lacking circadian nuclear receptors REV-ERB alpha and -beta in the tuberal hypothalamus (HDKO mice) gained excessive weight on an obesogenic high-fat diet due to both decreased energy expenditure and increased food intake during the light phase. Moreover, rebound food intake after fasting was markedly increased in HDKO mice. Integrative transcriptomic and cistromic analyses revealed that such disruption in feeding behavior was due to perturbed REV-ERB-dependent leptin signaling in the ARC. Indeed, in vivo leptin sensitivity was impaired in HMO mice on an obesogenic diet in a diurnal manner. Thus, REV-ERBs play a crucial role in hypothalamic control of food intake and diurnal leptin sensitivity in diet-induced obesity.