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.

摘要 减肥可以挽救肥胖症患者的生命。虽然许多肥胖的人减肥， 饮食和锻炼，绝大多数人会随着时间的推移恢复体重。多种药物治疗有 美国食品和药物管理局（FDA）批准，以帮助患者减肥。然而，在每个 在这种情况下，这些治疗的效果是暂时的，当治疗停止时体重会恢复。这 意味着患者必须终生服用这些药物，以实现其健康益处。在 除了终身药物治疗的经济成本外，患者还必须与副作用和药物治疗作斗争。 阻力因此，对于产生体重减轻的新的医学干预仍然存在未满足的需求。 没有终身治疗。在这个提议中，我们的目标是研究多巴胺功能是如何改变的， 增加体重。多巴胺功能的降低与肥胖有关，而降低多巴胺的药物 功能（如抗精神病药物）导致体重增加。这就引出了我们的核心假设， 肥胖会减少多巴胺在脑桥核（NAc）的释放，这会导致暴饮暴食， 体重增加.这一假设的一个推论是，促进多巴胺的释放将导致体重减轻。 事实上，无论是直接刺激多巴胺神经元，还是给予增加多巴胺的药物， 释放（如安非他明）会导致体重减轻。然而，由于副作用和滥用责任， 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，多巴胺功能的细胞变化， 神经调节方法，以永久扭转这些变化，以推动持久的减肥没有生命- 长期服药为了验证这一假设，我们建议在体内比较多巴胺释放的核 对照小鼠与肥胖小鼠的差异（目的1）。我们还将采用离体电生理方法， 确定肥胖小鼠多巴胺神经元活性变化的细胞机制（目的2）。 最后，我们将利用多巴胺神经元的神经可塑性来长期促进多巴胺的释放， 这是否会导致食物摄入量和体重的长期减少（目标3）。这项研究将提供一个 关键的基础，以推动努力调节食物寻求和摄入，以告知和改善减肥 肥胖症患者的结果。