Dopaminergic control of obesity in mice

多巴胺能控制小鼠肥胖

• 批准号: 10718973
• 负责人: Alexxai V Kravitz
• 金额: $ 51.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-25 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718973
• 关键词: Amphetamines; Animals; Antipsychotic Agents; Body Weight; Body Weight decreased; Brain; Chronic; Clinical Treatment; Cross-Sectional Studies; Deep Brain Stimulation; Disease; Dopamine; Eating; Electrophysiology (science); Fiber; Financial cost; Focused Ultrasound; Food; Foundations; Goals; Health Benefit; High Prevalence; Hyperphagia; Intake; Intervention; Life; Link; Medical; Meta-Analysis; Methods; Mus; Neuronal Plasticity; Neurons; Neurotransmitters; Nucleus Accumbens; Obese Mice; Obesity; Outcome; Patients; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacotherapy; Photometry; Physiological; Physiology; Protocols documentation; Public Health; Research; Resistance; Rest; Role; Signal Transduction; Stimulant; Synapses; System; Testing; Therapeutic; Time; Transcranial magnetic stimulation; United States Food and Drug Administration; Ventral Tegmental Area; Weight; Weight Gain; Weight-Loss Drugs; Work; abuse liability; design; diet and exercise; dopamine system; dopaminergic neuron; feeding; food consumption; improved; in vivo; mesolimbic system; neuronal circuitry; neuroregulation; novel; obese patients; obesity treatment; optical sensor; patch clamp; pharmacologic; reduced food intake; side effect; tool; treatment effect

Abstract Losing weight can be life saving for people with obesity. Although many people with obesity lose weight with diet and exercise, the vast majority regain this lost weight over time. Multiple pharmacological treatments have been approved by the US Food and Drug Administration (FDA) to help patients lose weight. However, in each case the effect of these treatments is temporary, and weight is regained when the treatment is stopped. This means that patients must take these medications for the rest of their lives to realize their health benefits. In addition to the financial cost of life-long medication, patients must contend with side effects and medication resistance. As such, there remains an unmet need for new medical interventions that produce weight loss without lifelong treatment. In this proposal we aim to investigate how dopamine function is altered as animals gain weight. Reductions in dopamine function have been linked to obesity, and drugs that decrease dopamine function (such as antipsychotic medications) cause weight gain. This leads to our central hypothesis that obesity reduces dopamine release in the nucleus accumbens (NAc), which causes overeating and weight gain. A corollary of this hypothesis is that boosting dopamine release would lead to weight loss. Indeed, either direct stimulation of dopamine neurons or administration of drugs that increase dopamine release (such as amphetamine) cause weight loss. However, due to side effects and abuse liability, dopaminergic stimulants are not useful therapeutics. For this reason, our primary Aim is to understand the cellular changes in dopamine function that occur as animals become obese, to inform the design of neuromodulation approaches to permanently reverse these changes to drive lasting weight loss without life- long medication. To test this hypothesis, we propose to compare in vivo dopamine release in the nucleus accumbens of control vs. obese mice (Aim 1). We will also employ ex vivo electrophysiological approaches to determine the cellular mechanisms underlying changes in dopamine neuron activity in obese mice (Aim 2). And finally, we will engage neuroplasticity in dopamine neurons to chronically boost dopamine release, to test whether this causes long-lasting reductions in food intake and body weight (Aim 3). This research will provide a critical foundation to advance efforts for modulating food seeking and intake, to inform and improve weight loss outcomes in people with obesity.

抽象的 减肥可能是肥胖者的生命。虽然许多肥胖症患者减肥 饮食和运动，绝大多数人会随着时间的流逝而恢复这种体重减轻。多种药理治疗有 已获得美国食品药品监督管理局（FDA）的批准，以帮助患者减肥。但是，每个 病例这些治疗的作用是暂时的，当治疗停止时，重量会恢复。这 这意味着患者必须在余生中服用这些药物才能实现自己的健康益处。在 除了终身药物的经济成本外，患者必须与副作用和药物抗衡 反抗。因此，对产生减肥的新医疗干预措施的需求仍未满足 没有终身治疗。在此提案中，我们旨在研究多巴胺功能如何改变作为动物 体重增加。多巴胺功能的降低与肥胖有关，减少多巴胺的药物 功能（例如抗精神病药）会导致体重增加。这导致了我们的中心假设 肥胖可减少伏隔核（NAC）中的多巴胺释放，这会导致暴饮暴食和 体重增加。这一假设的推论是，增强多巴胺释放将导致体重减轻。 实际上，要么直接刺激多巴胺神经元或增加多巴胺的药物 释放（例如苯丙胺）会导致体重减轻。但是，由于副作用和虐待责任， 多巴胺能兴奋剂不是有用的治疗剂。因此，我们的主要目的是了解 当动物变得肥胖时发生的多巴胺功能的细胞变化，以告知设计 神经调节方法是永久扭转这些变化以驱动持久的体重减轻而没有生命的方法 - 长药。为了检验这一假设，我们建议比较核中体内多巴胺的释放 控制控制与肥胖小鼠（AIM 1）。我们还将采用体内电生理方法 确定肥胖小鼠多巴胺神经元活性变化的细胞机制（AIM 2）。 最后，我们将使多巴胺神经元中的神经可塑性与长期增强多巴胺的释放，以测试 这是否会导致食物摄入和体重的长期减少（AIM 3）。这项研究将提供 关键的基础，以促进调节食物寻求和摄入量的努力，以告知和改善体重减轻 肥胖者的结果。