Central Serotonergic Pathways Regulating Energy Balance

调节能量平衡的中枢血清素通路

• 批准号: 7211479
• 负责人: Lora K Heisler
• 金额: $ 17.03万
• 依托单位: UNIVERSITY OF CAMBRIDGE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211479
• 关键词: ART protein; Abbreviations; Adverse effects; Affect; Agonist; Amphetamines; Animal Model; Appetite Depressants; Attenuated; Behavioral; Body Weight; Body Weight decreased; Body fat; Cardiopulmonary; Cells; Chronic; Clinical; Cocaine; Collaborations; Combined Modality Therapy; Control Groups; Data; Diabetes Mellitus; Diabetic mouse; Diet; Dose; Drug effect disorder; Eating; Endocrine; Energy Metabolism; Event; Fenfluramine; Genes; Genetic; Glucose; Histocytochemistry; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; Immunohistochemistry; In Situ Hybridization; Insulin Resistance; Label; Lateral Hypothalamic Area; Leptin; Literature; Measures; Mediating; Melanocortin 4 Receptor; Metabolic; Metabolic Clearance Rate; Methods; Modeling; Mus; Mutant Strains Mice; Neuraxis; Neurobiology; Neurons; Neuropeptides; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathway interactions; Peptides; Pharmaceutical Preparations; Phentermine; Physiological; Population; Prevention; Pro-Opiomelanocortin; Proteins; Purpose; Rate; Reporting; Research; Rodent; Role; Sapphire; Satiation; Series; Serotonin; Serotonin Agents; Structure of nucleus infundibularis hypothalami; Sympathomimetics; Techniques; Testing; Therapeutic Effect; Transcript; Transcriptional Regulation; Transgenic Mice; Transgenic Organisms; United States; United States Food and Drug Administration; alpha-Melanocyte stimulating hormone; blood glucose regulation; diabetic; dorsal motor nucleus; energy balance; glucose disposal; improved; insulin secretion; insulin sensitivity; melanocyte; mouse model; neuropeptide Y; obesity treatment; paraventricular nucleus; receptor; research study; reuptake; serotonin receptor

DESCRIPTION (provided by applicant): Elucidating the basic neurobiology of energy homeostasis is paramount in the prevention and treatment of obesity and type II diabetes. Drugs that increase the activity of central serotonin (5-hydroxytryptamine, 5-HT) have been widely used as appetite suppressants. However, these drugs often elicit unwanted side effects because they target multiple 5-HT pathways and receptors. A notable example is d-fenfluramine (d-Fen), a drug that blocks the reuptake of 5-HT and stimulates its release. In the mid-1990's, d-Fen was prescribed to millions of people in the United States for weight loss, frequently in combination with the sympathomimetic phentermine, but was withdrawn from clinical use in 1997 by the Food and Drug Administration due to reports of adverse cardiopulmonary events. The purpose of this proposal is to delineate the central nervous system (CNS) pathways through which drugs such as d-Fen selectively mediate their effects on food intake. We have strong preliminary data indicating that these drugs exert their effect on energy homeostasis by engaging melanocortin pathways. These central melanocortin pathways, through the melanocortin-4 receptors (MC4-Rs), have potent effects on metabolic-hormonal, neuroendocrine, and behavioral parameters associated with energy balance. In this proposal, we will assess whether 5-HT drugs selectively affect energy homeostasis through a necessary downstream activation of MC4-Rs. We propose a model of the mechanism of serotonergic drug action in which activation of specific serotonergic receptors increases the release of the endogenous MC4-R agonist alpha-melanocyte stimulating hormone (alpha-MSH) and inhibits the release of the endogenous antagonist agouti related peptide (AgRP). We will determine whether serotonergic diet drugs require functional downstream MC4-Rs to exert their effect. We offer a series of behavioral, physiological, genetic, and electrophysiological experiments to test components of our model. Data generated from this proposal have the potential to not only delineate the interaction between two key pathways regulating energy homeostasis, but to also identify a promising and very selective target for the prevention and treatment of obesity and type II diabetes.

描述（由申请人提供）：阐明能量稳态的基本神经生物学在预防和治疗肥胖症和II型糖尿病中至关重要。增加中枢5-羟色胺（5-hydroxytryptamine，5-HT）活性的药物被广泛用作食欲抑制剂。然而，这些药物通常会引起不必要的副作用，因为它们靶向多种5-HT途径和受体。一个值得注意的例子是d-芬氟拉明（d-Fen），一种阻止5-HT再摄取并刺激其释放的药物。在20世纪90年代中期，在美国，d-芬被处方给数百万人用于减肥，经常与拟交感神经药物芬特明联合使用，但由于不良心肺事件的报道，1997年被食品和药物管理局从临床使用中撤回。本提案的目的是描述中枢神经系统（CNS）途径，通过这些途径，药物如d-Fen选择性地介导其对食物摄入的影响。我们有强有力的初步数据表明，这些药物通过参与黑皮质素途径对能量稳态发挥作用。这些通过黑皮质素-4受体（MC 4-Rs）的中枢黑皮质素途径对与能量平衡相关的代谢-激素、神经内分泌和行为参数具有强效作用。在这个提议中，我们将评估5-HT药物是否通过必要的下游激活MC 4-Rs选择性地影响能量稳态。我们提出了一个模型的肾上腺素能药物的作用机制，其中特定的肾上腺素能受体的激活增加释放的内源性MC 4-R激动剂α-黑素细胞刺激激素（α-MSH），并抑制释放的内源性拮抗剂肾上腺素相关肽（AgRP）。我们将确定β-肾上腺素能减肥药是否需要功能性下游MC 4-R来发挥其作用。我们提供了一系列的行为，生理，遗传和电生理实验来测试我们的模型组件。从这一建议产生的数据不仅有可能描绘两个关键途径之间的相互作用调节能量稳态，但也确定了一个有前途的和非常有选择性的目标，预防和治疗肥胖症和II型糖尿病。

项目成果

Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism.

• DOI: 10.1016/j.cmet.2008.10.011
• 发表时间: 2008-12
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Kumar KG;Trevaskis JL;Lam DD;Sutton GM;Koza RA;Chouljenko VN;Kousoulas KG;Rogers PM;Kesterson RA;Thearle M;Ferrante AW Jr;Mynatt RL;Burris TP;Dong JZ;Halem HA;Culler MD;Heisler LK;Stephens JM;Butler AA
• 通讯作者: Butler AA

Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats.

反复性低血糖会增加大鼠下丘脑葡萄糖磷酸化活性。

• DOI: 10.1016/j.metabol.2010.05.009
• 发表时间: 2011
• 期刊: Metabolism: clinical and experimental
• 作者: Osundiji,MayowaA;Hurst,Paul;Moore,StephenP;Markkula,SPauliina;Yueh,ChenY;Swamy,Ashwini;Hoashi,Shu;Shaw,JillS;Riches,ChristineH;Heisler,LoraK;Evans,MarkL
• 通讯作者: Evans,MarkL

Distribution and neurochemical characterization of neurons within the nucleus of the solitary tract responsive to serotonin agonist-induced hypophagia.

• DOI: 10.1016/j.bbr.2008.07.039
• 发表时间: 2009-01-03
• 期刊: BEHAVIOURAL BRAIN RESEARCH
• 影响因子: 2.7
• 作者: Lam, Daniel D.;Zhou, Ligang;Vegge, Andreas;Xiu, Philip Y.;Christensen, Britt T.;Osundiji, Mayowa A.;Yueh, Chen-yu;Evans, Mark L.;Heisler, Lora K.
• 通讯作者: Heisler, Lora K.

Brain glucose sensors play a significant role in the regulation of pancreatic glucose-stimulated insulin secretion.

• DOI: 10.2337/db11-1050
• 发表时间: 2012-02
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Osundiji MA;Lam DD;Shaw J;Yueh CY;Markkula SP;Hurst P;Colliva C;Roda A;Heisler LK;Evans ML
• 通讯作者: Evans ML