Wu Shaw-Wen, Xu Baoji
Department of Neuroscience, the Scripps Research Institute, Jupiter, FL 33458.
Department of Neuroscience, the Scripps Research Institute, Jupiter, FL 33458
eNeuro. 2022 Apr 6;9(2). doi: 10.1523/ENEURO.0009-22.2022. Print 2022 Mar-Apr.
Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), are implicit in causing obesity. Mutations that reduce BDNF and TrkB expression are associated with obesity in humans and mice. Recently, it was reported that gene deletion in the neurons of the paraventricular hypothalamus (PVH) caused positive energy balance and severe obesity in the form of hyperphagia, impaired adaptive thermogenesis, and decreased energy expenditure. Thus, we hypothesize that activation of these neurons will have the opposite effect and provide an opportunity for long-lasting obesity treatment. To specifically activate BDNF-expressing PVH (PVH) neurons, we injected Cre-dependent adeno-associated virus (AAV) expressing the excitatory DREADD hM3Dq bilaterally into the PVH of knock-in mice and then administered clozapine-N-oxide (CNO). Using this technique, we demonstrated that acute activation of these neurons rapidly decreased normal nocturnal feeding and fasting-induced feeding in male and female mice. At thermoneutral temperatures, acute activation also rapidly increased adaptive thermogenesis, increased core body temperature, increased locomotion, increased energy expenditure, and decreased respiratory exchange ratio (RER) in male and female mice. These observations indicate that acute stimulation of PVH neurons promotes negative energy balance and weight loss. However, the rapid decrease in RER after activation of PVH neurons was followed by a delayed and prolonged increase in RER that remained elevated for 3 d in female mice. Thus, although acute activation of PVH neurons promotes negative energy balance in the short term, long-term effects of activation include sexually dimorphic overcompensatory mechanisms that may promote positive energy balance in female mice.
脑源性神经营养因子（BDNF）及其受体原肌球蛋白受体激酶B（TrkB）与肥胖的发生有关。降低BDNF和TrkB表达的突变与人类和小鼠的肥胖相关。最近，有报道称室旁下丘脑（PVH）神经元中的基因缺失导致正能量平衡和严重肥胖，表现为食欲亢进、适应性产热受损和能量消耗减少。因此，我们假设激活这些神经元将产生相反的效果，并为长期治疗肥胖提供机会。为了特异性激活表达BDNF的PVH神经元，我们将表达兴奋性DREADD hM3Dq的Cre依赖性腺相关病毒（AAV）双侧注射到敲入小鼠的PVH中，然后给予氯氮平N-氧化物（CNO）。使用该技术，我们证明了急性激活这些神经元可迅速减少雄性和雌性小鼠的正常夜间进食和禁食诱导的进食。在热中性温度下，急性激活还可迅速增加雄性和雌性小鼠的适应性产热、升高核心体温、增加活动、增加能量消耗并降低呼吸交换率（RER）。这些观察结果表明，急性刺激PVH神经元可促进负能量平衡和体重减轻。然而，PVH神经元激活后RER迅速下降，随后出现延迟且持续时间较长的RER升高，在雌性小鼠中这种升高持续3天。因此，尽管急性激活PVH神经元在短期内促进负能量平衡，但激活的长期影响包括性别差异的过度补偿机制，这可能会促进雌性小鼠的正能量平衡。
