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

瘦素水平对禁食反应的动态变化是众所周知的，而这些反应在肥胖和糖尿病等代谢性疾病中被钝化。瘦素通过大脑中的瘦素受体来调节许多神经元功能，包括神经元活动、神经发生、轴突生长和突触强度。最近越来越多的研究也强调了瘦素水平在神经退行性疾病（如阿尔茨海默病）、学习和记忆缺陷、药物滥用、精神疾病（如抑郁症）和神经性疼痛等脑部疾病的发病或进展中的作用。瘦素被认为是一种内感受性信号，其动态变化的精确调控是维持中枢和外周神经系统正常神经元功能的核心。

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.