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 对于肥胖症患者来说，减肥可以挽救生命。尽管很多肥胖者通过减肥 节食和运动，绝大多数人随着时间的推移会恢复减掉的体重。多种药物治疗已 已获得美国食品和药物管理局（FDA）批准用于帮助患者减肥。然而，在每个 在这种情况下，这些治疗的效果是暂时的，治疗停止后体重会恢复。这 意味着患者必须终生服用这些药物才能实现健康益处。在 除了终身药物治疗的经济成本外，患者还必须应对副作用和药物治疗 反抗。因此，对能够减轻体重的新医疗干预措施的需求仍然未得到满足 无需终生治疗。在本提案中，我们的目标是研究多巴胺功能如何随着动物的变化而改变。 体重增加。多巴胺功能的降低与肥胖有关，而减少多巴胺的药物 功能（如抗精神病药物）会导致体重增加。这引出了我们的中心假设： 肥胖会减少伏隔核（NAc）中多巴胺的释放，从而导致暴饮暴食和 体重增加。这一假设的推论是，增加多巴胺的释放会导致体重减轻。 事实上，直接刺激多巴胺神经元或服用增加多巴胺的药物 释放（如安非他明）导致体重减轻。然而，由于副作用和滥用倾向， 多巴胺能兴奋剂不是有用的治疗剂。因此，我们的首要目标是了解 当动物变得肥胖时，多巴胺功能发生细胞变化，为设计提供信息 神经调节方法可以永久逆转这些变化，从而实现持久的减肥效果，而无需生命- 长期服药。为了验证这一假设，我们建议比较体内多巴胺在细胞核中的释放 对照小鼠与肥胖小鼠的伏隔核（目标 1）。我们还将采用离体电生理学方法 确定肥胖小鼠多巴胺神经元活性变化的细胞机制（目标 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释放，以测试 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 推进调节食物寻找和摄入、告知和改善减肥的重要基础 肥胖症患者的结果。