Zhang Ni, Yang Liang, Guo Lanting, Bi Sheng
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, China.
Front Mol Neurosci. 2018 May 29;11:179. doi: 10.3389/fnmol.2018.00179. eCollection 2018.
Previous reports have shown that running wheel activity or voluntary exercise prevents hyperphagia and obesity in various animal models of obesity, but such effects seem only minimal in obese animals lacking leptin or leptin receptors. The mechanisms underlying this ineffectiveness remain unclear. Here, we identified the action of neuronal activation in the dorsomedial hypothalamus (DMH) in modulating physical activity, food intake and body weight using leptin receptor mutant obese Zucker (, ZF) and Koletsky (, SHROB) rats. Ad lib-fed SHROB rats with locked running wheels became hyperphagic and gained body weight rapidly. These alterations were not ameliorated in ad lib-fed SHROB rats with voluntary access to running wheels, but the body weight of SHROB rats with running wheel access was significantly decreased when they were pair-fed to the amounts consumed by lean controls. Determinations of hypothalamic gene expression revealed that sedentary ad lib-fed SHROB rats had increased expression of neuropeptide Y () and decreased expression of pro-opiomelanocortin () in the arcuate nucleus (ARC). Both ARC and expression were further altered under running and pair-fed conditions, indicating that both genes are appropriately regulated in response to increased energy demands or alterations caused by running activity and food restriction. Strikingly, c-Fos immunohistochemistry revealed that while voluntary running activity elevated the number of c-Fos positive cells in the DMH (particularly in the ventral and caudal subregions) of intact rats, such activation was not observed in ZF rats. Using adeno-associated virus (AAV)-mediated expression of the designer receptors hM3D(Gq) in the ventral and caudal DMH of ZF rats, we found that chemogenetic stimulation of neurons in these DMH subregions via injection of the designer drug clozapine N-oxide (CNO) significantly increased their running activity and reduced their food intake and body weight. Together, these results demonstrate that activation of ventral and caudal DMH neurons promotes physical activity and decreases food intake and body weight and suggest that intact DMH neural signaling is likely crucial for exercise-induced reductions of food intake and body weight in obese rats lacking leptin receptors.
先前的报告表明，在各种肥胖动物模型中，跑轮活动或自愿运动可预防食欲亢进和肥胖，但在缺乏瘦素或瘦素受体的肥胖动物中，这种作用似乎微乎其微。这种无效性背后的机制仍不清楚。在这里，我们利用瘦素受体突变的肥胖 Zucker（ZF）和 Koletsky（SHROB）大鼠，确定了下丘脑背内侧核（DMH）中神经元激活在调节身体活动、食物摄入和体重方面的作用。随意进食且跑轮锁定的 SHROB 大鼠变得食欲亢进，并迅速增重。在可自愿使用跑轮的随意进食 SHROB 大鼠中，这些改变并未得到改善，但当将有跑轮使用机会的 SHROB 大鼠配对喂食至瘦素对照组的食量时，其体重显著下降。下丘脑基因表达的测定显示，久坐且随意进食的 SHROB 大鼠弓状核（ARC）中神经肽 Y（NPY）的表达增加，促阿片黑素皮质素（POMC）的表达减少。在跑步和配对喂食条件下，ARC 中的 NPY 和 POMC 表达均进一步改变，表明这两个基因都能根据能量需求增加或跑步活动和食物限制引起的改变进行适当调节。引人注目的是，c-Fos 免疫组织化学显示，虽然自愿跑步活动增加了正常大鼠 DMH（特别是腹侧和尾侧亚区）中 c-Fos 阳性细胞的数量，但在 ZF 大鼠中未观察到这种激活。通过腺相关病毒（AAV）介导在 ZF 大鼠的腹侧和尾侧 DMH 中表达设计受体 hM3D(Gq)，我们发现通过注射设计药物氯氮平 N-氧化物（CNO）对这些 DMH 亚区的神经元进行化学遗传刺激，可显著增加它们的跑步活动，并减少它们的食物摄入量和体重。总之，这些结果表明，腹侧和尾侧 DMH 神经元的激活促进身体活动，减少食物摄入量和体重，并表明完整的 DMH 神经信号可能对缺乏瘦素受体的肥胖大鼠运动诱导的食物摄入量和体重减少至关重要。
