Photoperiodic Control of Obesity

光周期控制肥胖

• 批准号: 8121640
• 负责人: Timothy Jon Bartness
• 金额: $ 48.95万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8121640
• 关键词: Action Potentials; Activities of Daily Living; Acute; Address; Adipose tissue; Adrenergic Receptor; Affect; Agonist; Animals; Area; Body fat; Brain; Brown Fat; Capsaicin; Chronic; Collaborations; Data; Denervation; Drug or chemical Tissue Distribution; Employee Strikes; Engineering; Enzymes; Esthesia; Exhibits; Exposure to; Fasting; Fatty acid glycerol esters; Feedback; Fiber; Food deprivation (experimental); Hamsters; Health; Herpesvirus 1; Human; Hypertension; Individual; Infusion procedures; Injection of therapeutic agent; Label; Leptin; Lipase; Lipectomy; Lipids; Lipolysis; Maps; Measures; Mediating; Melanocortin 4 Receptor; Melatonin; Messenger RNA; Methods; Microinjections; Modeling; Nerve; Nerve Fibers; Nervous system structure; Neurons; Neuropeptide Receptor; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Operative Surgical Procedures; Pattern; Peripheral; Phosphorylation; Photoperiod; Procedures; Process; Prostaglandins E; Reporter; Risk; Risk Factors; Rodent; Role; Sensory; Severities; Siberian Hamster; Simplexvirus; Site; Spinal Ganglia; Stimulus; Suid Herpesvirus 1; Sympathetic Nervous System; Temperature; Testing; Thermogenesis; Time; Tissues; Tracer; Travel; Triglycerides; Variant; Viral; Visceral; adverse outcome; afferent nerve; base; food restriction; improved; in vivo; interdisciplinary approach; nerve supply; neurochemistry; novel; perilipin A; receptor; relating to nervous system; response; sensory feedback; sterol esterase; subcutaneous; uncoupling protein 1

Siberian hamsters develop a naturally-occurring, photoperiod-induced obesity in long summer days (LDs) and that is reversed by short winter days (SDs). The LD-induced obesity is reversed by SNS stimulation of WAT and these and other data show that stimulation of WAT SNS drive is the principal initiator of lipolysis. Using a retrograde transneuronal viral tract tracer, the pseudorabies virus (PRV), the origins of the sympathetic nervous system (SNS) outflow from brain to white and brown adipose tissue (WAT and BAT) have been defined. Using an anterograde transneuronal viral tract tracer, the H129 strain of the herpes simplex virus-1, the central sensory circuits from WAT have been defined. Emphasize here is on LD obesity reversal via the SNS, but the manipulations are largely independent of SDs thereby having greater relevance to human obesity reversal. How does WAT SNS and sensory innervation coordinate the control of fat pad-specific WAT lipolysis and BAT thermogenesis? In Aim 1, tests for convergence of brain SNS outflow projections to different WAT/BAT pads are done using multiple PRV variants. The role of central melanocortin-4 receptors (MC4-Rs) in WAT lipolysis/BAT thermogenesis is tested by injecting MC4-R agonist into brain sites of WAT/ BAT SNS outflow neurons co-localized with MC4-Rs. Whether MC4-R-induced increased WAT SNS drive/lipolysis is modifiable is tested by sympathectomizing WAT pads to induce increased SNS drive by the remaining WAT pads. In Aim 2, neuroanatomical tests for SNS-sensory feedback loops subserving lipolysis are done using PRV (SNS) and H129 (sensory) injected into the same WAT pads and is tested functionally by measuring WAT sensory nerve electrophysiological activity in response to lipolysis-associated factors. The role of sensory nerve feedback for appropriate WAT SNS drive/lipolysis is tested by selectively sensory denervating WAT pads followed by lipolytic challenges. These studies will provide new and critical data regarding the control of lipolysis and thermogenesis in obesity reversal.

西伯利亚仓鼠在漫长的夏季（LD）中会自然发生光周期诱导的肥胖，而在短暂的冬季（SD）中则相反。 LD 引起的肥胖可通过 WAT 的 SNS 刺激来逆转，这些数据和其他数据表明，WAT SNS 驱动的刺激是脂肪分解的主要引发剂。使用逆行跨神经元病毒道示踪剂伪狂犬病病毒（PRV），交感神经系统（SNS）从大脑流出到白色和棕色脂肪组织（WAT和BAT）的起源已经被确定。使用顺行跨神经元病毒道示踪剂，即单纯疱疹病毒 H129 株，WAT 的中枢感觉回路已被定义。这里强调的是通过 SNS 逆转 LD 肥胖，但操作很大程度上独立于 SD，因此与人类肥胖逆转具有更大的相关性。 WAT SNS 和感觉神经支配如何协调脂肪垫特异性 WAT 脂肪分解和 BAT 产热的控制？在目标 1 中，使用多个 PRV 变体完成大脑 SNS 流出投影到不同 WAT/BAT 垫的收敛测试。通过将 MC4-R 激动剂注射到与 MC4-Rs 共定位的 WAT/BAT SNS 流出神经元的大脑部位来测试中枢黑皮质素-4 受体 (MC4-Rs) 在 WAT 脂肪分解/BAT 生热作用中的作用。通过交感神经切除WAT垫以通过剩余的WAT垫诱导增加的SNS驱动来测试MC4-R诱导的增加的WAT SNS驱动/脂肪分解是否是可修改的。在目标 2 中，通过将 PRV (SNS) 和 H129（感觉）注射到相同的 WAT 垫中，对促进脂肪分解的 SNS 感觉反馈回路进行神经解剖学测试，并通过测量 WAT 感觉神经电生理活动对脂肪分解相关因素的反应进行功能测试。感觉神经反馈对于适当的 WAT SNS 驱动/脂肪分解的作用是通过选择性感觉去神经化 WAT 垫然后进行脂肪分解挑战来测试的。这些研究将提供有关肥胖逆转中脂肪分解和产热控制的新的关键数据。