PDF(Pubmed)
Abstract：
OBJECTIVE: Hypothalamic signals potently stimulate energy expenditure by engaging peripheral mechanisms to restore energy homeostasis. Previous studies have identified several critical hypothalamic sites (e.g. preoptic area (POA) and ventromedial hypothalamic nucleus (VMN)) that could be part of an interconnected neurocircuit that controls tissue thermogenesis and essential for body weight control. However, the key neurocircuit that can stimulate energy expenditure has not yet been established.
METHODS: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips.
RESULTS: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons\' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons\' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue.
CONCLUSIONS: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.
METHODS: Here, we investigated the downstream mechanisms by which VMN neurons stimulate adipose tissue thermogenesis. We manipulated subsets of VMN neurons acutely as well as chronically and studied its effect on tissue thermogenesis and body weight control, using Sf1Cre and Adcyap1Cre mice and measured physiological parameters under both high-fat diet and standard chow diet conditions. To determine the node efferent to these VMN neurons, that is involved in modulating energy expenditure, we employed electrophysiology and optogenetics experiments combined with measurements using tissue-implantable temperature microchips.
RESULTS: Activation of the VMN neurons that express the steroidogenic factor 1 (Sf1; VMNSf1 neurons) reduced body weight, adiposity and increased energy expenditure in diet-induced obese mice. This function is likely mediated, at least in part, by the release of the pituitary adenylate cyclase-activating polypeptide (PACAP; encoded by the Adcyap1 gene) by the VMN neurons, since we previously demonstrated that PACAP, at the VMN, plays a key role in energy expenditure control. Thus, we then shifted focus to the subpopulation of VMNSf1 neurons that contain the neuropeptide PACAP (VMNPACAP neurons). Since the VMN neurons do not directly project to the peripheral tissues, we traced the location of the VMNPACAP neurons\' efferents. We identified that VMNPACAP neurons project to and activate neurons in the caudal regions of the POA whereby these projections stimulate tissue thermogenesis in brown and beige adipose tissue. We demonstrated that selective activation of caudal POA projections from VMNPACAP neurons induces tissue thermogenesis, most potently in negative energy balance and activating these projections lead to some similar, but mostly unique, patterns of gene expression in brown and beige tissue. Finally, we demonstrated that the activation of the VMNPACAP neurons\' efferents that lie at the caudal POA are necessary for inducing tissue thermogenesis in brown and beige adipose tissue.
CONCLUSIONS: These data indicate that VMNPACAP connections with the caudal POA neurons impact adipose tissue function and are important for induction of tissue thermogenesis. Our data suggests that the VMNPACAP → caudal POA neurocircuit and its components are critical for controlling energy balance by activating energy expenditure and body weight control.
摘要：
目的：下丘脑信号通过参与外周机制有效刺激能量消耗以恢复能量稳态。先前的研究已经确定了几个关键的下丘脑部位（例如视前区（POA）和腹内侧下丘脑核（VMN）），这些部位可能是控制组织产热的互连神经回路的一部分，对于控制体重至关重要。然而,可以刺激能量消耗的关键神经回路尚未建立。
方法：这里，我们研究了VMN神经元刺激脂肪组织产热的下游机制。我们对VMN神经元的子集进行了急性和慢性操作，并研究了其对组织产热和体重控制的影响。使用Sf1Cre和Adcyap1Cre小鼠，并在高脂饮食和标准饮食条件下测量生理参数。为了确定这些VMN神经元的传出节点，参与调节能量消耗，我们采用了电生理学和光遗传学实验,并结合了使用组织植入温度微芯片的测量.
结果：表达类固醇生成因子1（Sf1；VMNSf1神经元）的VMN神经元的激活降低了体重，饮食诱导的肥胖小鼠肥胖和能量消耗增加。这种功能可能是介导的，至少在某种程度上,通过VMN神经元释放垂体腺苷酸环化酶激活多肽（PACAP；由Adcyap1基因编码），因为我们之前证明了PACAP，在VMN,在能源消耗控制中起着关键作用。因此，然后,我们将焦点转移到含有神经肽PACAP(VMNPACAP神经元)的VMNSf1神经元亚群上.由于VMN神经元不直接投射到外周组织，我们追踪了VMNPACAP神经元的位置。我们确定VMNPACAP神经元投射并激活POA尾部区域的神经元，从而这些投射刺激棕色和米色脂肪组织中的组织产热。我们证明了从VMNPACAP神经元选择性激活尾部POA投射诱导组织产热,最有效的负能量平衡和激活这些预测导致一些类似的，但大多是独一无二的，棕色和米色组织中的基因表达模式。最后,我们证明，位于尾部POA的VMNPACAP神经元的激活对于诱导棕色和米色脂肪组织中的组织产热是必需的。
结论：这些数据表明VMNPACAP与尾端POA神经元的连接影响脂肪组织功能，并对诱导组织产热很重要。我们的数据表明，VMNPACAP→尾部POA神经回路及其组件对于通过激活能量消耗和控制体重来控制能量平衡至关重要。
方法：这里，我们研究了VMN神经元刺激脂肪组织产热的下游机制。我们对VMN神经元的子集进行了急性和慢性操作，并研究了其对组织产热和体重控制的影响。使用Sf1Cre和Adcyap1Cre小鼠，并在高脂饮食和标准饮食条件下测量生理参数。为了确定这些VMN神经元的传出节点，参与调节能量消耗，我们采用了电生理学和光遗传学实验,并结合了使用组织植入温度微芯片的测量.
结果：表达类固醇生成因子1（Sf1；VMNSf1神经元）的VMN神经元的激活降低了体重，饮食诱导的肥胖小鼠肥胖和能量消耗增加。这种功能可能是介导的，至少在某种程度上,通过VMN神经元释放垂体腺苷酸环化酶激活多肽（PACAP；由Adcyap1基因编码），因为我们之前证明了PACAP，在VMN,在能源消耗控制中起着关键作用。因此，然后,我们将焦点转移到含有神经肽PACAP(VMNPACAP神经元)的VMNSf1神经元亚群上.由于VMN神经元不直接投射到外周组织，我们追踪了VMNPACAP神经元的位置。我们确定VMNPACAP神经元投射并激活POA尾部区域的神经元，从而这些投射刺激棕色和米色脂肪组织中的组织产热。我们证明了从VMNPACAP神经元选择性激活尾部POA投射诱导组织产热,最有效的负能量平衡和激活这些预测导致一些类似的，但大多是独一无二的，棕色和米色组织中的基因表达模式。最后,我们证明，位于尾部POA的VMNPACAP神经元的激活对于诱导棕色和米色脂肪组织中的组织产热是必需的。
结论：这些数据表明VMNPACAP与尾端POA神经元的连接影响脂肪组织功能，并对诱导组织产热很重要。我们的数据表明，VMNPACAP→尾部POA神经回路及其组件对于通过激活能量消耗和控制体重来控制能量平衡至关重要。
