The Role of BDNF in VMH astrocytes influencing energy and glucose homeostasis

 描述（由申请人提供）：肥胖是2型糖尿病、心血管疾病和其他疾病发展的危险因素。我们以前的研究发现脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）在控制食物摄入和体重的中枢神经回路中具有重要作用。与此一致，在成年下丘脑腹内侧（VMH）中具有全局中枢（BDNF 2L/2LCk-cre）或选择性BDNF耗尽的小鼠表现出过度进食、肥胖和代谢紊乱。脑源性神经营养因子功能的减弱也与人类的贪食行为和严重肥胖有关。这些发现具有重要的临床意义，因为干扰BDNF信号传导的BdnfVal 66 Met变体在美国人中非常普遍。在这里，我们建议调查是否BDNF调节星形胶质细胞的结构可塑性和功能，以增加兴奋性驱动的VMH，饱腹感中心的神经元。在已知的能量平衡中心中，BDNF在VMH中最丰富，在那里它起着必要的饱腹感作用。支持性证据包括：i）能量状态对BDNF及其受体TrkB在VMH中表达的强烈影响，ii）通过选择性地删除成年小鼠VMH中的BDNF引起的暴食和肥胖，iii）在BDNF 2L/2LCk-cre小鼠中VMH中兴奋性突触密度降低和兴奋性突触后电流频率降低。BDNF对VMH神经元兴奋性影响的细胞和分子机制仍有待充分阐明。BDNF是神经元可塑性的动态调节剂，并改变星形胶质细胞的形态和介导钙信号。这些是显著的影响，因为胶质细胞形态的变化与突触接触重塑相关。此外，突触周星形胶质细胞对谷氨酸的清除在维持谷氨酸稳态和形成突触电流方面很重要。BDNF对星形胶质细胞的这些作用已经在几个脑区被确定，但在进食回路中没有。事实上，星形胶质细胞-神经元相互作用在下丘脑摄食回路和能量平衡调节中的作用仍然是一个研究领域。它值得检查的下丘脑回路，包括那些涉及VMH的突触连接的动态变化，被认为有助于食欲控制。作为了解VMH中星形胶质细胞如何影响摄食回路的第一步，我们建议检查能量状态和BDNF对该细胞群体的影响。研究包括检查能量状态和BDNF对VMH星形胶质细胞结构可塑性，谷氨酸摄取动力学和翻译mRNA的动态变化的影响，使用最先进的解剖学，电生理学和分子方法。计划中的研究将阐明涉及VMH中神经胶质-神经元通信的新机制，该机制调节进食回路和饱腹感的活动，从而确定治疗肥胖症的治疗策略的新靶点。

 DESCRIPTION (provided by applicant): Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. Our previous studies identified a novel and critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controllig food intake and body weight. In agreement, mice with global central (BDNF2L/2LCk-cre) or selective BDNF depletion in the adult ventromedial hypothalamus (VMH) exhibit excessive feeding, obesity and metabolic disturbances. Diminished BDNF function has also been associated with hyperphagic behavior and severe obesity in humans. These findings have significant clinical implications as the BdnfVal66Met variant, which interferes with BDNF signaling, is highly prevalent among Americans. Here, we propose investigating whether BDNF regulates astrocyte structural plasticity and function to increase the excitatory drive of anorexigenic neurons in the VMH, a satiety center. Among known energy balance centers, BDNF is most abundant in the VMH, where it plays a required satiety role. Supportive evidence includes: i) robust effects of energy status on expression of BDNF and its receptor, TrkB, in the VMH, ii) the hyperphagia and obesity elicited by selectively deleting Bdnf in the VMH of adult mice iii) reduced density of excitatory synapses and decreased frequency of excitatory post synaptic currents in the VMH inBDNF2L/2LCk-cre mice. The cellular and molecular mechanisms underlying the effects of BDNF on neuronal excitability in the VMH remain to be fully elucidated. BDNF is a dynamic regulator of neuronal plasticity and alters morphology and mediates calcium signaling in astrocytes. These are significant effects as changes in glial morphology are associated with synaptic contact remodeling. Moreover, glutamate clearance by perisynaptic astrocytes is important in maintaining glutamate homeostasis and shaping synaptic currents. These effects of BDNF on astrocytes have been identified in several brain regions, but not in feeding circuits. Indeed, the role of astrocyte-neuron interactions in hypothalamic feeding circuits and the regulation of energy balance remains a vastly under studied research area. It warrants examination as dynamic changes in synaptic connectivity of hypothalamic circuits, including those involving the VMH, are thought to contribute to appetite control. As a first step t understand how astrocytes in the VMH influence feeding circuits, we propose examining the effect of energy status and BDNF on this cell population. Studies comprise examination of effects of energy status and BDNF on structural plasticity, glutamate uptake kinetics and dynamic changes in translating mRNAs in VMH astrocytes using cutting edge anatomical, electrophysiological and molecular approaches. The planned studies will elucidate novel mechanisms involving glial-neuron communication in the VMH that regulate activity of feeding circuits and satiety and thereby identify new targets for therapeutic strategies to treat obesity.