Leptin in the VMH and energy balance

瘦素在 VMH 和能量平衡中的作用

• 批准号: 10706486
• 负责人: Ruth B Harris
• 金额: $ 39万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706486
• 关键词: Ablation; Adipose tissue; Affect; Anatomy; Animals; Area; Body Weight decreased; Body fat; Brain; Cell Nucleus; Cells; Cholecystokinin; Cholera Toxin; Chronic; Chronic Disease; Data; Development; Diet; Dose; Eating; Energy Intake; Energy Metabolism; Failure; Fatty acid glycerol esters; Feedback; Feeding behaviors; Food; High Fat Diet; Hormones; Human; Hypothalamic structure; Impairment; In Situ Hybridization; Individual; Infusion procedures; Intake; Investigation; Lateral; Leptin; Liquid substance; Literature; Maintenance; Mediating; Modeling; Mus; Neurons; Neuropeptides; Nucleus solitarius; Obesity; Pathologic; Pathway interactions; Peripheral; Phenotype; Physiological; Physiological Processes; Prosencephalon; Rattus; Receptor Activation; Regulation; Research; Risk; Satiation; Signal Transduction; Structure of nucleus infundibularis hypothalami; Structure of paraventricular nucleus of thalamus; Synapses; System; Testing; Tracer; Viral; Weight; Weight Gain; diet-induced obesity; energy balance; experimental study; feeding; hindbrain; information processing; insight; leptin receptor; neural; neural network; neurochemistry; obesogenic; parabrachial nucleus; paraventricular nucleus; pharmacologic; prevent; receptor; response; synergism

Leptin was identified as a potential feedback signal in the regulation of energy balance in 1994, but little progress has been made in using leptin to prevent or reverse human obesity. This may be due to a failure to fully understand the central mechanisms by which leptin can control food intake which can only be evaluated when they are functioning normally. Control of energy balance is often investigated in models in which components of the system have been genetically modified, the animal has been fed an obesogenic diet or pharmacologic doses of leptin are used to investigate an endogenous physiologic system. Preliminary data using threshold doses of leptin in normal weight animals demonstrate the presence of a leptin sensitive pathway that inhibits food intake when circulating leptin concentrations rise above basal levels as a signal of positive energy balance. We have demonstrated that activation of leptin receptors in the hindbrain nucleus of the solitary tract (NTS) lowers the threshold for activation of hypothalamic leptin receptors through a neural network. This effect is most dramatic in the dorsomedial ventromedial nucleus of the hypothalamus (VMHdm), where there is a 3-fold increase in leptin receptor activation. Additional experiments demonstrated that loss of NTS leptin-receptor expressing cells raised the threshold for a hypothalamic response to leptin and that loss of leptin receptor expressing cells in the VMHdm abolished weight loss caused by hindbrain infusions of leptin. Based on these data and evidence that hypothalamic leptin suppresses food intake by amplifying the response to peripheral satiety signals, we hypothesize that small increases in circulating leptin amplify the response to peripheral satiety signals through a circuit in which NTS leptin enhances VMHdm leptin sensitivity. This application will establish the function and anatomy of the hypothesized network. The first Aim will test whether activation of VMHdm leptin receptors amplifies the response to peripheral satiety signals. The second Aim will test whether these receptors protect against diet-induced obesity. The third Aim will use tract tracing to identify the organization of the proposed neural network and in situ hybridization to identify the neurochemical phenotype of leptin receptor-expressing neurons in the NTS and VMHdm. Successful completion of these Aims will provide new information on the synergy between long-term signals of energy balance and peripheral short-term satiety signals as an integral component of a network that facilitates precise control of energy balance.

瘦素于1994年被确定为调节能量平衡的潜在反馈信号， 但在利用瘦素预防或逆转人类肥胖方面进展甚微。这可能 是由于未能完全理解瘦素控制食物的核心机制 摄入量只有在正常运作时才能评估。能量控制 平衡通常在模型中进行研究，其中系统的组成部分已被遗传 修改后，动物被喂食致肥胖饮食或使用药理学剂量的瘦素 研究内源性生理系统。使用阈剂量的初步数据 正常体重动物的瘦素表明存在瘦素敏感途径 当循环瘦素浓度高于基础水平时，抑制食物摄入，这是一个信号 正能量平衡。我们已经证明瘦素受体的激活 后脑孤束核（NTS）降低下丘脑激活的阈值 通过神经网络的瘦素受体。这种效应在背内侧最为显着 下丘脑腹内侧核 (VMHdm)，其中瘦素增加 3 倍 受体激活。额外的实验表明 NTS 瘦素受体的丧失 表达细胞提高了下丘脑对瘦素的反应阈值以及瘦素的损失 VMHdm 中的受体表达细胞消除了后脑输注引起的体重减轻 瘦素。根据这些数据和证据，下丘脑瘦素通过以下方式抑制食物摄入： 放大对周围饱腹感信号的反应，我们假设小幅增加 循环瘦素通过一个电路放大对外周饱腹感信号的反应，其中 NTS 瘦素增强 VMHdm 瘦素敏感性。该应用程序将建立功能并 假设网络的剖析。第一个目标将测试是否激活VMHdm 瘦素受体放大对外周饱腹感信号的反应。第二个目标将测试 这些受体是否可以预防饮食引起的肥胖。第三个目标将使用道 追踪以确定所提出的神经网络的组织并进行原位杂交 识别 NTS 中表达瘦素受体的神经元的神经化学表型， VMHdm。这些目标的成功完成将为协同作用提供新的信息 能量平衡的长期信号和外围短期饱腹感信号之间的关系 网络的组成部分，有助于精确控制能量平衡。