INTERACTIONS OF LEPTIN AND CENTRAL SEROTONIN SYSTEMS

瘦素和中枢血清素系统的相互作用

• 批准号: 9276662
• 负责人: JOEL K. ELMQUIST
• 金额: $ 37.46万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-10 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276662
• 关键词: Address; Adverse effects; Affect; Agonist; Antidiabetic Drugs; Appetite Depressants; Body Weight; Body Weight decreased; Brain; Brain Stem; Comorbidity; Complex; Data; Diabetes Mellitus; Diet; Drug usage; Eating; Enterobacteria phage P1 Cre recombinase; FDA approved; Feeding behaviors; Fenfluramine; Funding; Glucose; Grant; Heart Valve Diseases; Hepatic; Homeobox; Homeostasis; Homologous Gene; Human; Hypothalamic structure; Impairment; Knockout Mice; Leptin; Liver; Location; Mediating; Mind; Molecular; Mus; Neurons; Nucleus solitarius; Obesity; Pathway interactions; Pharmaceutical Preparations; Pharmacogenetics; Pharmacology; Physiological; Play; Population; Pro-Opiomelanocortin; Process; Protein Isoforms; Pulmonary Hypertension; Role; Serotonergic System; Serotonin; Serotonin Receptor 5-HT2C; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Testing; Therapeutic; Viral Vector; Weight Gain; Weight-Loss Drugs; blood glucose regulation; combat; designer receptors exclusively activated by designer drugs; diabetic; dorsal motor nucleus; energy balance; experimental study; feeding; improved; insight; insulin sensitivity; interest; liver metabolism; mouse model; neural circuit; paraventricular nucleus; predictive modeling; prevent; public health relevance; reduced food intake; serotonin receptor

 DESCRIPTION (provided by applicant): The potent anti-obesity effects of serotonin 2C receptors (5-HT2CRs) were first demonstrated through the actions of the diet drug d-Fenfluramine (d-Fen, used in combination as Fen/Phen). While an effective anorexigenic agent, d-Fen also caused valvular heart disease and pulmonary hypertension, likely due to off- target effects. These unexpected side effects highlight the complexity of the central serotonin system. Recently, there has been renewed interest in the serotonin system due to the FDA approval of the new weight- loss drug, Lorcaserin (Belviq), which targets the 5-HT2CRs. However, it is still unclear which specific neuronal populations of the widely expressed 5-HT2CRs directly mediate the anti-obesity effects. In the previous grant period, we focused on defining the neurocircuitry involved in 5-HT2CRs signalling by reactivating 5-HT2CR expression in select neurons. Our findings suggest that the serotonin pathway is highly complex and that 5-HT2CRs have neuroanatomically and functionally distinct roles. While the roles of 5-HT2CRs in arcuate POMC neurons were extensively tested in the previous funding period, the current proposal will focus on functions of 5-HT2CRs in the brainstem (DMV/NTS) and in the paraventricular nucleus (PVH). We hypothesize that 5-HT and 5-HT drugs (including Lorcaserin) are able to act upon distinct populations of 5- HT2CR-expressing neurons to exert different but coordinated effects on energy and glucose homeostasis. In particular, 5-HT2CRs expressed by ARH POMC neurons mediate 5-HT's actions to suppress food intake and prevent body weight gain; 5-HT2CRs in PVH neurons, on the other hand, counteract these anorexigenic effects to promote feeding. In parallel, 5-HT acts via 5-HT2CRs in brainstem NTS/DMV neurons to enhance hepatic insulin sensitivity without influencing food intake and body weight. These questions are especially topical because in addition to Lorcaserin, other 5-HT2CR agonists are also being tested in humans to treat obesity, further reinforcing a need for mechanistic insights on how these compounds exert their effects.

 描述（由适用提供）：首先通过饮食药物D-Fenfluramine（D-Fen，用作FEN/PEN）的作用证明了5-羟色胺2C受体（5-HT2CR）的潜在抗肥胖作用。虽然D-Fen是有效的厌食剂，但也引起了瓣膜心脏病和肺动脉高压，可能是由于靶标作用引起的。这些意外的副作用突出了中央5-羟色胺系统的复杂性。最近，由于FDA批准了针对5-HT2CRS的新型体重损失药物Lorcaserin（Belviq），因此人们对5-羟色胺系统的兴趣重新引起了人们的兴趣。但是，尚不清楚广泛表达的5-HT2CR的哪些特定神经元直接介导了抗肥胖作用。在上一个赠款期间，我们专注于定义通过在某些神经元中重新激活5-HT2CR表达的5-HT2CR信号传导的神经记录。我们的发现表明，5-羟色胺途径是高度复杂的，并且5-HT2CR在神经解剖学和功能上具有不同的作用。尽管5-HT2CR在弧形POMC神经元中的作用在上一个资金期间进行了广泛的测试，但当前的建议将集中在脑干（DMV/NTS）和寄生核（PVH）中的5-HT2CR功能上。我们假设5-HT和5-HT药物（包括Lorcasein）能够对表达5-HT2CR的神经元的不同种群作用，从而对能量和葡萄糖稳态产生不同但协调的影响。特别是，ARH POMC神经元表达的5-HT2CR介导5-HT抑制食物摄入并防止体重增加的动作。另一方面，PVH神经元中的5-HT2CR抵消了这些厌食性作用以促进喂养。同时，5-HT在脑干NTS/DMV神经元中通过5-HT2CR起作用，以增强肝胰岛素敏感性，而不会影响食物摄入和体重。这些问题尤其是主题，因为除了洛凯辛外，其他5-HT2CR激动剂也在人类中进行了测试以治疗肥胖症，进一步加强了对这些化合物如何施加其作用的机械见解的需求。