Neural mechanisms in high fat diet impairment of brown adipose tissue activity

高脂肪饮食损害棕色脂肪组织活性的神经机制

• 批准号: 10327308
• 负责人: CHRISTOPHER J MADDEN
• 金额: $ 42.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327308
• 关键词: Address; Adipose tissue; Adult; Affect; Anatomy; Anesthesia procedures; Animals; Area; Attention; Biological; Body Weight; Body Weight decreased; Brain; Brown Fat; Characteristics; Data; Diet; Dietary Component; Dorsal; Dynorphins; Electron Transport; Electrophysiology (science); Energy Intake; Energy Metabolism; Failure; Fatty acid glycerol esters; Fever; Glutamates; High Fat Diet; Human; Hypothalamic structure; Impairment; In Vitro; Lateral; Maintenance; Mediating; Metabolic; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Nerve; Neural Pathways; Neuromodulator; Neurons; Nucleus solitarius; Obesity; Opioid; Opioid Antagonist; Output; Oxides; Pathway interactions; Play; Positioning Attribute; Preoptic Areas; Process; Production; Rattus; Receptor Activation; Regulation; Research; Research Project Grants; Role; Series; Signal Transduction; Signaling Molecule; Skin; Skin Temperature; Spinal; Stimulus; Synaptic Transmission; Testing; Therapeutic; Thermogenesis; Thermoreceptors; Tissues; Vanilloid; Weight Gain; Work; antagonist; design; designer receptors exclusively activated by designer drugs; dietary; dietary control; dorsal horn; energy balance; experimental study; fat burning; fatty acid metabolism; improved; in vivo; insight; interest; kappa opioid receptors; lipid metabolism; mortality; neural circuit; neural model; neuromechanism; neurophysiology; norbinaltorphimine; novel; novel therapeutic intervention; obese person; parabrachial nucleus; pre-prodynorphin; prevent; receptor; uncoupling protein 1

Project Summary The sympathetic activation of brown adipose tissue (BAT) increases the metabolism of fatty acids within this tissue. Due to the presence of uncoupling protein-1 in the mitochondria of BAT the electrochemical gradient generated by the electron transport chain is dissipated in the absence of the production of ATP. This process which is unique to BAT (as well as inducible forms of BAT, “beige” adipose tissue) in essence metabolizes fat to produce heat. The obvious implications of this “fat burning” process for energy balance and body weight regulation have led to intense interest in the biological mechanisms governing this process. The activity of the sympathetic nerves innervating BAT is the principal regulator of this process. Our research has defined the fundamental neural pathways through which thermal and febrile stimuli elicit changes in the sympathetic outflow to BAT. However, relatively little is known about the neural circuits involved in the metabolic influences on BAT and how dietary components (such as the fat content of the diet) influence these regulatory circuits. In the proposed research project, we will perform an extensive series of in vivo and in vitro electrophysiological, anatomical, neuropharmacological, and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) experiments to address specific aims that will provide new insights into the neural mechanisms responsible for the impairment of BAT activation during high fat diet (HFD) and the specific contribution of this impairment to HFD- induced weight gain. The first aim will determine the role of transient receptor potential vanilloid type 1 (TRPV1) in NTS in the impairment of BAT activation during maintenance on a high fat diet. The second aim will define the downstream projection target of the NTS that is responsible for inhibition of sympathetic output to BAT during HFD. The third aim will define the role of preprodynorphin neurons in the lateral parabrachial nucleus and kappa opioid receptor activation in the preoptic area in the impairment of BAT activation during HFD. The forth aim will define the output projection target and neurophysiological characteristics of kappa opioid receptor containing neurons of the preoptic area.

项目摘要 棕色脂肪组织（BAT）的交感神经激活增加了 脂肪酸由于解偶联蛋白-1存在于线粒体中， BAT中，由电子传递链产生的电化学梯度消散在 缺乏ATP的生产。这一过程是BAT独有的（以及可诱导的 BAT的形式，"米色"脂肪组织）本质上代谢脂肪以产生热量。明显的 这种"脂肪燃烧"过程对能量平衡和体重调节的影响导致了 对控制这一过程的生物学机制的浓厚兴趣。的活性 支配BAT的交感神经是该过程的主要调节器。我们的研究 定义了基本的神经通路，通过这些通路，热刺激和发热刺激引起 交感神经流出到BAT的变化。然而，对神经系统的了解相对较少。 参与代谢对BAT的影响以及饮食成分（如 饮食中的脂肪含量）影响这些调节回路。 在拟议的研究项目中，我们将进行一系列广泛的体内和体内研究。 体外电生理学、解剖学、神经药理学和设计受体 专门由设计药物激活（DREADDs）实验，以解决特定的目标， 将为BAT受损的神经机制提供新的见解 高脂饮食（HFD）期间的激活以及这种损伤对HFD的具体贡献- 诱导体重增加。第一个目标是确定瞬时受体电位香草酸的作用 NTS中的1型（TRPV1）在维持高脂饮食期间BAT激活受损中的作用 饮食.第二个目标将确定负责的NTS的下游投影目标 用于抑制HFD期间交感神经输出至BAT。第三个目标将确定 臂旁外侧核前强啡肽原神经元与κ阿片受体 在HFD期间BAT激活受损中的视前区激活。第四个目标将 明确κ阿片的输出投射靶点和神经生理学特征 视前区的含受体神经元。

项目成果

A blood-to-brain delivery system to treat obesity.

• DOI: 10.1038/s42255-021-00463-y
• 发表时间: 2021-10
• 期刊: Nature metabolism
• 影响因子: 20.8
• 作者: Mota CMD;Madden CJ
• 通讯作者: Madden CJ

A Foundation for the Neural Control of Viral Fever.

病毒发烧的神经控制基础。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Madden,ChristopherJ;Mota,ClarissaM
• 通讯作者: Mota,ClarissaM

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.

• DOI: 10.1172/jci.insight.122058
• 发表时间: 2019-03
• 期刊: JCI insight
• 影响因子: 8
• 作者: Runping Wang;Yongjun Lu;M. Cicha;Madhu V Singh;C. Benson;C. Madden;M. Chapleau;F. Abboud

Mediobasal hypothalamic neurons contribute to the control of brown adipose tissue sympathetic nerve activity and cutaneous vasoconstriction.

下丘脑中部神经元有助于控制棕色脂肪组织交感神经活动和皮肤血管收缩。

• DOI: 10.1016/j.jtherbio.2023.103551
• 发表时间: 2023
• 期刊: Journal of thermal biology
• 影响因子: 2.7
• 作者: Mota,ClarissaMD;Madden,ChristopherJ
• 通讯作者: Madden,ChristopherJ

Neural circuits mediating circulating interleukin-1β-evoked fever in the absence of prostaglandin E2 production.

• DOI: 10.1016/j.bbi.2022.04.008
• 发表时间: 2022-07
• 期刊: Brain, behavior, and immunity