Linking stress-associated brain and adipose functions

将压力相关的大脑和脂肪功能联系起来

• 批准号: 10698084
• 负责人: Abha K Rajbhandari
• 金额: $ 21.13万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10698084
• 关键词: Ablation; Acute; Adipose tissue; Affect; Anatomy; Animals; Area; Behavior; Behavioral; Behavioral Model; Bioenergetics; Biology; Blood; Brain; Brain Stem; Brown Fat; COVID-19 pandemic; Cells; Central Nervous System; Chemicals; Chronic stress; Data; Desire for food; Disease; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Experimental Designs; Female; Freezing; Fright; Future; Gatekeeping; Genes; Genetic Polymorphism; Homeostasis; Human; In Situ Hybridization; Indirect Calorimetry; Intake; Learning; Link; Lipolysis; LoxP-flanked allele; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mus; Nature; Neurons; Neuropeptide Receptor; Neuropeptides; Oxygen; PACAPR-1 protein; Peptides; Physiological; Pituitary Gland; Population; Process; Respiration; Rodent; Rodent Model; Role; Sex Differences; Societies; Stress; Systems Biology; Techniques; Testing; Thermogenesis; Tissues; Transcript; Viral; Water consumption; Woman; Work; acute stress; adenylate; biological adaptation to stress; comorbidity; environmental stressor; feeding; fighting; food consumption; knock-down; locus ceruleus structure; loss of function; mad itch virus; male; molecular targeted therapies; mouse model; nerve supply; novel; novel strategies; pituitary adenylate cyclase activating polypeptide; post-traumatic stress; programs; response; retrograde transport; sex; sexual dimorphism; stress related disorder; stressor; tool; transcriptomics; translational model; uncoupling protein 1; Ablation; Acute; Adipose tissue; Affect; Anatomy; Animals; Area; Behavior; Behavioral; Behavioral Model; Bioenergetics; Biology; Blood; Brain; Brain Stem; Brown Fat; COVID-19 pandemic; Cells; Central Nervous System; Chemicals; Chronic stress; Data; Desire for food; Disease; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Experimental Designs; Female; Freezing; Fright; Future; Gatekeeping; Genes; Genetic Polymorphism; Homeostasis; Human; In Situ Hybridization; Indirect Calorimetry; Intake; Learning; Link; Lipolysis; LoxP-flanked allele; Measurement; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mus; Nature; Neurons; Neuropeptide Receptor; Neuropeptides; Oxygen; PACAPR-1 protein; Peptides; Physiological; Pituitary Gland; Population; Process; Respiration; Rodent; Rodent Model; Role; Sex Differences; Societies; Stress; Systems Biology; Techniques; Testing; Thermogenesis; Tissues; Transcript; Viral; Water consumption; Woman; Work; acute stress; adenylate; biological adaptation to stress; comorbidity; environmental stressor; feeding; fighting; food consumption; knock-down; locus ceruleus structure; loss of function; mad itch virus; male; molecular targeted therapies; mouse model; nerve supply; novel; novel strategies; pituitary adenylate cyclase activating polypeptide; post-traumatic stress; programs; response; retrograde transport; sex; sexual dimorphism; stress related disorder; stressor; tool; transcriptomics; translational model; uncoupling protein 1

PROJECT SUMMARY/ABSTRACT The fundamental mechanisms by which acute intense stress affects energy homeostasis via brain substrates and sexual dimorphism of these processes are poorly understood. Environmental stressors induce fight-or- flight-or-freeze response via the locus coeruleus (LC) in the brainstem, a major sympathetic regulator in humans and animals that triggers energy metabolism. LC innervates the brown adipose tissue (BAT) and expresses high levels of PAC1 receptor for the neuropeptide PACAP (pituitary adenylate cyclase activating peptide). PACAP/PAC1 are critical regulators of stressors of all kinds, fear, appetite, feeding, and energy metabolism and genetically linked to stress-related disorders like post-traumatic stress (PTSD) in humans. Intriguingly, women with PTSD showing high blood levels of this neuropeptide and brain PAC1 receptors regulate fear in a sexually dimorphic manner in animals. To test the importance of PAC1 in acute intense stress and energy homeostasis, we used the stress-enhanced fear learning (SEFL) behavioral model in mice. Our preliminary data show that ablation of PAC1 receptors from the LC enhances SEFL expression, energy metabolism as assessed by indirect calorimetry measurement, and increases metabolic genes like uncoupling protein 1 in BAT in females than males. Thus, harnessing on the biology of PAC1 receptors, we aim to lay a mechanistic framework linking acute intense stress and energy metabolism in a systematic and sex-dependent manner via the LC. We hypothesize that PAC1 receptors in the LC are important for gating stress-associated metabolic information and BAT functions in a sexually dimorphic manner. Aim 1 will test a SEFL mediated loss of function of LC-PAC1 on whole body energy expenditure and on BAT functions. For this, we will test if viral cre-recombinase mediated PAC1 deletion from LC in mice with floxed PAC1 regulates SEFL-associated energy expenditure and induction of thermogenic genes in BAT in a sex-dependent manner (via transcript analysis, mitochondrial bioenergetics, and tissue lipolysis). Aim 2 will test if PAC1 expressing LC neurons project directly to BAT in a sexually dimorphic manner under SEFL. For this, we will use retrograde viral tracing to determine LC to BAT projecting cell populations combined with in situ hybridization for PAC1 in LC. We predict that female mice will show enhanced energy expenditure, BAT thermogenesis and increased LC projection to BAT. Overall, using state-of-the-art tools and techniques and rigorous systems biology approach of linking acute intense stress and energy metabolism, our studies will lay crucial groundwork for several future work. This will serve as a premise for studying central sympathetic control of metabolism in chronic stress- related conditions such as PTSD that are comorbid with metabolic diseases and increasingly prevalent in the US populations.

项目摘要/摘要 急性强烈压力通过脑底物影响能量稳态的基本机制 这些过程的性二态性知之甚少。环境压力源引起战斗或 通过脑干中的基因座（LC）飞行或冻结响应，这是一个主要的交感神经调节器 触发能量代谢的人类和动物。 LC支配棕色脂肪组织（BAT）和 表达高水平的PAC1受体的神经肽PACAP（垂体腺苷酸环化酶激活 肽）。 PACAP/PAC1是各种压力源的关键调节因子，恐惧，食欲，喂养和能量 代谢和遗传与与压力相关的疾病（如人类的创伤后应激（PTSD））有关。 有趣的是，患有PTSD的女性表现出该神经肽和脑PAC1受体的高血液水平 在动物中以性二态性方式调节恐惧。测试PAC1在急性激烈中的重要性 压力和能量稳态，我们在小鼠中使用了强烈的恐惧学习（SEFL）行为模型。 我们的初步数据表明，LC中PAC1受体的消融增强了SEFL表达，能量 通过间接量热法测量评估的代谢，并增加了新陈代谢基因（例如解偶联） 女性中的蛋白质1比男性。因此，利用PAC1受体的生物学，我们旨在放置一个 机械框架将急性强烈压力和能量代谢连接到系统性和性别依赖性 通过LC的方式。我们假设LC中的PAC1受体对于与门控应力相关很重要 代谢信息和蝙蝠以性二态性的方式发挥作用。 AIM 1将测试SEFL介导的损失 LC-PAC1在全身能量消耗和BAT功能上的功能。为此，我们将测试是否病毒 Cre-recombinase介导的PAC1从LC中介导的PAC1小鼠调节SEFL相关的小鼠 以性别依赖性方式以BAT的能量消耗和热基因诱导（通过转录本 分析，线粒体生物能和组织脂解）。 AIM 2将测试PAC1是否表达LC神经元 在SEFL下直接以性二态性方式进行击球。为此，我们将使用逆行病毒跟踪 为了确定LC的LC投影细胞群，并结合LC中PAC1的原位杂交。我们 预测雌性小鼠将表现出增强的能量消耗，蝙蝠的热发生和LC增加 投射蝙蝠。总体而言，使用最先进的工具和技术以及严格的系统生物学方法 将急性强调和能量代谢联系起来，我们的研究将为几个未来奠定重要的基础 工作。这将是研究慢性应激中代谢中心同情控制中心同情的前提。 与代谢性疾病合并的PTSD等相关条件，并且在 美国人口。