Orexin and serotonin interactions to promote physical activity and prevent obesity

食欲素和血清素相互作用促进身体活动和预防肥胖

• 批准号: 10376722
• 负责人: Charles J. Billington
• 金额: --
• 依托单位: MINNEAPOLIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376722
• 关键词: Acute; Affect; Animal Model; Animals; Antidepressive Agents; Area; Body Weight; Body Weight decreased; Brain; Brown Fat; Calories; Cells; Chemicals; Chronic; Clinical; Data; Disease; Drug Targeting; Effectiveness; Energy Metabolism; Equipment; Exercise; Expenditure; Goals; Health; Human; Hypothalamic structure; Individual; Injury; Knowledge; Laboratories; Lateral; Length; Location; Measures; Mediating; Methods; Monitor; Mus; Nerve; Neurons; Neuropeptides; Neurotransmitters; Obesity; Outcome; Output; Pharmaceutical Preparations; Physical activity; Play; Population; Property; Role; Serotonin; Serotonin Agents; Site; Study models; Testing; Thermogenesis; Thinness; Veterans; Weight; Weight Gain; Work; addiction; base; comorbidity; compare effectiveness; designer receptors exclusively activated by designer drugs; dorsal raphe nucleus; hypocretin; individual variation; individualized medicine; new technology; novel therapeutics; obesity prevention; obesity treatment; orexin A; precision medicine; prevent; receptor; response; serotonin receptor; targeted treatment; therapy development; therapy duration; treatment strategy; weight gain prevention

The overall goal of this proposal is to identify strategies that target the orexin brain network that regulates spontaneous physical activity, and the associated caloric expenditure. This energy expenditure is referred to as non-exercise activity thermogenesis (NEAT), and we propose that this can be exploited to develop new therapies for weight gain prevention and weight loss in those unable to exercise. The specific objectives are to determine which sub-population of orexin neurons are associated with the most robust effect on NEAT; whether therapy length influence the effectiveness of this targeted NEAT therapy; and finally, whether serotonin in a specific brain area, the dorsal raphe nucleus (DRN), modulates the calories produced by this targeted NEAT therapy. The significance is the potential to discover a new therapy for Veterans needing to lose weight or for preventing weight gain in Veterans with limited options for formal exercise, thus reducing the burden of obesity and associated co-morbidities. Drugs targeting orexin and serotonin receptors are already clinically available, providing proof-of-concept that these drugs could be successfully manipulated for human health. The novelty lies in the idea to create a therapy based on promotion of NEAT; our newly established methods to study brain networks using Designer Receptors Exclusively activated by Designer Drugs (DREADDs); our animal models for studying orexin, a neuropeptide that significantly increases NEAT; and newly obtained equipment for allowing sophisticated quantification of NEAT.

这项提案的总体目标是确定针对食欲素大脑网络的策略， 调节自发的身体活动和相关的热量消耗。这种能量 消耗被称为非运动活动产热（NEAT），我们建议， 可以用来开发新的治疗方法，用于预防体重增加和减肥， 锻炼身体具体目标是确定食欲素神经元的哪个亚群是 与对NEAT最稳健的影响相关;治疗时间是否影响 这种有针对性的NEAT疗法;最后，无论是在特定的大脑区域，中缝背核， 细胞核（DRN）调节这种靶向NEAT疗法产生的卡路里。和手段改革的重大意义 为需要减肥或预防体重的退伍军人发现新疗法的潜力 增加退伍军人的正式锻炼选择有限，从而减少肥胖的负担， 相关合并症。针对食欲素和血清素受体的药物已经在临床上 提供了概念验证，这些药物可以成功地用于人类 健康新颖之处在于创造一种基于促进NEAT的治疗方法的想法;我们的新 建立了研究大脑网络的方法，使用设计者受体， 设计药物（DREADDs）;我们研究食欲素的动物模型，食欲素是一种神经肽， 增加NEAT;和新获得的设备，允许复杂的量化NEAT。

项目成果

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice.

• DOI: 10.1016/j.nlm.2017.10.014
• 发表时间: 2017-12
• 期刊: Neurobiology of learning and memory
• 影响因子: 2.7
• 作者: Mavanji V;Butterick TA;Duffy CM;Nixon JP;Billington CJ;Kotz CM
• 通讯作者: Kotz CM

Discovery of Arylsulfonamides as Dual Orexin Receptor Agonists.

• DOI: 10.1021/acs.jmedchem.1c00841
• 发表时间: 2021-06-24
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhang D;Perrey DA;Decker AM;Langston TL;Mavanji V;Harris DL;Kotz CM;Zhang Y
• 通讯作者: Zhang Y

Orexin, serotonin, and energy balance.

• DOI: 10.1002/wsbm.1536
• 发表时间: 2022-01
• 期刊: WIREs mechanisms of disease
• 影响因子: 3.1

Neuromodulation of orexin neurons reduces diet-induced adiposity.

• DOI: 10.1038/ijo.2017.276
• 发表时间: 2018-04
• 期刊: International journal of obesity (2005)
• 作者: Zink AN;Bunney PE;Holm AA;Billington CJ;Kotz CM
• 通讯作者: Kotz CM