BDNF and TrkB-containing neuronal circuits mediating energy balance

描述（由研究者提供）：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。这是令人不安的，因为美国近30%的人口肥胖，64%的人口超重。脑源性神经营养因子（BDNF）及其受体TrkB的研究为肥胖研究提供了一条新的、有前景的途径。它们在发育和成熟的大脑中介导神经元的存活、分化、功能和可塑性。脑特异性靶向Bdnf基因的小鼠所表现出的显著肥胖突出了该信号通路在能量平衡紊乱病因学中的相关性。突变体表现出嗜食行为，并成为高瘦素血症、高胰岛素血症和高血糖症，表明这种神经营养因子是一种重要的食物摄入调节剂，通过中枢神经系统中未知的介质起作用。人类研究也显示了TrkB基因的基因改变与嗜食行为和肥胖之间的联系。本提案概述了旨在确定促进成年动物BDNF/TrkB信号通路饱腹效应的分子和细胞机制的研究。为此，我们将评估能量信号对大脑不同食欲调节区域BDNF和TrkB的表达和活性的影响。此外，Bdnf基因将在成年动物中以特定位点的方式靶向与这些过程相关的下丘脑和尾侧后脑核。将评估这些操作对能量摄入和消耗的影响。最后，由于BDNF已成为突触可塑性的重要促进者，我们将研究下丘脑中被认为影响能量稳态的突触可塑性相关过程是否需要BDNF。总之，这些研究将区分BDNF的发育作用与成熟大脑中影响体重的作用。这一分析将有助于阐明肥胖疾病的发病机制和干预的关键时期。此外，它们将使我们更接近治疗肥胖及其相关综合征的新策略。

DESCRIPTION (provided by investigator): Obesity is a risk factor for the development of type 2 diabetes, cardiovascular disease and other afflictions. This is troubling as close to 30% of the population in the United States is obese and 64% is overweight. The study of brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, provides a new and promising avenue in obesity research. They mediate neuronal survival, differentiation, function and plasticity in the developing and mature brain. The relevance of this signaling pathway in the etiology of energy balance disorders is highlighted by the dramatic obesity exhibited by mice with brain-specific targeting of the Bdnf gene. Mutants display hyperphagic behavior and become hyperleptinemic, hyperinsulinemic and hyperglycemic, indicating that this neurotrophin is an essential regulator of food intake acting through as yet unknown mediators in the central nervous system. Human studies also show links between genetic alterations in the TrkB gene and hyperphagic behavior and obesity. This proposal outlines studies designed to ascertain the molecular and cellular mechanisms facilitating the satiety effects of the BDNF/TrkB signaling pathway in the adult animal. For this, the effects of energy signals on the expression and activity of BDNF and TrkB in distinct appetite-modulating regions of the brain will be evaluated. Moreover, the Bdnf gene will be targeted in adult animals in a site-specific manner in hypothalamic and caudal hindbrain nuclei associated with these processes. The impact of these manipulations on energy intake and expenditure will be evaluated. Finally, as BDNF has emerged as a prominent facilitator of synaptic plasticity, we will investigate whether it is required for synaptic plasticity- related processes in the hypothalamus thought to influence energy homeostasis. Together, these studies will distinguish developmental roles of BDNF from ones in the mature brain that influence body weight. This analysis will help clarify disease mechanisms and critical periods of intervention for obesity disorders. Moreover, they will bring us closer to novel strategies for the treatment of obesity and its associated syndromes.