Metabolic Changes: Connecting temperature sensing neurons to sympathetic adipose tissue stimulation

瘦素水平响应于禁食的动态变化是众所周知的，并且这些反应在代谢疾病如肥胖和糖尿病中是迟钝的。瘦素通过脑中的瘦素受体来调节许多神经元功能，包括神经元活性、神经发生、轴突生长和突触强度。越来越多的近期研究也强调了瘦素水平对于脑疾病如神经变性疾病（例如阿尔茨海默病）、学习和记忆缺陷、物质滥用、精神疾病（例如抑郁症）和神经性疼痛的发作或进展的作用。 循环瘦素（也被认为是内感受信号）的动态变化的精确调节是维持中枢和外周神经系统中正常神经元功能的核心。 其他人先前的工作表明，脂肪组织的交感神经激活抑制瘦素的产生和分泌。然而，参与交感神经调节的神经元群体的确切性质尚未完全了解。此外，交感神经通路如何与其他通路（如热和能量需求感觉信号）相互作用，有时会促进相反的作用，以增加或减少能量消耗，这在很大程度上仍然是未知的。我们以前的工作表明，下丘脑中不同的瘦素靶位点参与了热和能量需要的感觉信号，通过交感脂肪组织激活来调节能量消耗。然而，脂肪组织交感神经激活控制瘦素水平和代谢功能的必要性和充分性尚未直接研究。 该R 01应用使用小鼠作为模型，并将研究大脑如何通过节前和节后交感神经与选择的白色（WAT）和棕色脂肪组织（BAT）储库通信，以调节瘦素水平，并阐明它们与下丘脑、脑干和小脑中的热和能量需要感觉回路的相互作用。神经节前脊髓和交感神经节在各种生理条件下，如高温与低温和禁食与进食。它将通过结合可能是该领域首次提出的尖端技术来识别这两种类型脂肪组织的新型兴奋性和抑制性神经回路，例如免疫标记使能的溶剂清除器官三维成像（iDISCO），以允许对包括整个脊髓主干在内的外周回路进行令人印象深刻的详细可视化，以及在投射到BAT和/或WAT的节后神经元中使用仅由设计药物激活的刺激性和抑制性设计受体（DREADD），以评估这些脂肪组织贮库对环境温度或营养状态变化的生理反应的必要性和充分性。

Dynamic changes in leptin levels in response to fasting are well known, and these responses are blunted in metabolic diseases such as obesity and diabetes. Leptin acts via leptin receptors in the brain to modulate many neuronal functions, including neuronal activity, neurogenesis, axonal growth, and synaptic strength. An increasing number of recent studies also highlight a role of leptin levels for the onset or progression of brain disorders like neurodegenerative disease (e.g. Alzheimer’s disease), learning and memory deficits, substance abuse, mental illness (e.g. depression) and neuropathic pain. The precise regulation of the dynamic changes in circulating leptin, which is also considered an interoceptive signal, are at the core to maintain normal neuronal function in both the central and peripheral nervous systems. Previous work from others has shown that sympathetic activation of adipose tissue suppresses the production and secretion of leptin. However, the precise nature of the neuronal populations involved in the sympathetic regulation are not completely understood. Also, it remains largely unknown how the sympathetic pathways interact with other pathways like thermo and energy-need sensory signals, that sometimes promote opposing effects to increase or decrease energy expenditure. Our previous work demonstrates that distinct leptin target sites in the hypothalamus are involved in thermo and energy need sensory signals via sympathetic adipose tissue activation to regulate energy expenditure. Yet, the necessity and sufficiency of adipose tissue sympathetic activation to control leptin levels and metabolic function has not been directly studied. This R01 application uses the mouse as a model, and will investigate how the brain communicates with select white (WAT) and brown adipose tissue (BAT) depots via pre- and post-ganglionic sympathetic nerves to regulate leptin levels and to elucidate their interactions with thermo- and energy need sensory circuits in the hypothalamus, brainstem, preganglionic spinal cord and sympathetic ganglia in a variety of physiological conditions such as high versus low temperature and fasting versus feeding. It will identify novel excitatory and inhibitory neural circuits to these two types of adipose tissue through incorporating cutting-edge techniques proposed perhaps for the first time in this field, such as immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) to allow impressive detailed visualization of peripheral circuits including the entire trunk of the spinal cord, and the use of stimulatory and inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in postganglionic neurons projecting to BAT and/or WAT to assess necessity and sufficiency of these adipose tissue depots for the physiological responses to changes in ambient temperature or the nutritional status.