Linking stress-associated brain and adipose functions

将压力相关的大脑和脂肪功能联系起来

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要急性强烈应激通过脑基质影响能量稳态的基本机制人们对这些过程的性别二态性知之甚少。环境压力会引发战斗或- 通过脑干中的蓝斑 (LC) 进行“逃跑或冻结”反应，蓝斑是脑干中主要的交感神经调节因子人类和动物触发能量代谢。 LC 神经支配棕色脂肪组织 (BAT) 表达高水平的 PAC1 神经肽 PACAP 受体（垂体腺苷酸环化酶激活肽）。 PACAP/PAC1 是各种压力源、恐惧、食欲、进食和能量的关键调节因子新陈代谢，并与人类创伤后应激障碍 (PTSD) 等压力相关疾病存在遗传关系。有趣的是，患有 PTSD 的女性血液中这种神经肽和大脑 PAC1 受体的水平很高以两性二态的方式调节动物的恐惧。测试 PAC1 在急性重症中的重要性为了研究压力和能量稳态，我们在小鼠中使用了压力增强恐惧学习（SEFL）行为模型。我们的初步数据表明，从 LC 上去除 PAC1 受体可增强 SEFL 表达、能量通过间接量热法测量评估新陈代谢，并增加解偶联等代谢基因女性 BAT 中的蛋白质 1 含量高于男性。因此，利用 PAC1 受体的生物学特性，我们的目标是建立一个以系统性和性别依赖性方式将急性强烈应激和能量代谢联系起来的机制框架通过LC方式。我们假设 LC 中的 PAC1 受体对于门控应激相关性很重要代谢信息和 BAT 以性别二态性方式发挥作用。目标 1 将测试 SEFL 介导的损失 LC-PAC1 对全身能量消耗和 BAT 功能的作用。为此，我们将测试病毒是否存在 cre-重组酶介导 PAC1 缺失的小鼠 LC 中 PAC1 缺失调节 SEFL 相关 BAT 中的能量消耗和产热基因的诱导以性别依赖性方式（通过转录分析、线粒体生物能学和组织脂肪分解）。目标 2 将测试 PAC1 是否表达 LC 神经元在 SEFL 下以性别二态方式直接投射到 BAT。为此，我们将使用逆行病毒追踪结合 LC 中 PAC1 的原位杂交来确定 LC 至 BAT 的投射细胞群。我们预测雌性小鼠将表现出能量消耗增强、BAT 生热作用和 LC 增加投射到 BAT。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烈压力和能量代谢联系起来，我们的研究将为未来的一些研究奠定重要基础工作。这将作为研究慢性应激中代谢的中枢交感神经控制的前提。相关病症，如创伤后应激障碍（PTSD），它们与代谢性疾病共存，并且在美国人口。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Sexually dimorphic role of diet and stress on behavior, energy metabolism, and the ventromedial hypothalamus.

饮食和压力对行为、能量代谢和腹内侧下丘脑的性别二态性作用。

DOI：
发表时间：
2023-11-17
期刊：
影响因子：
0
作者：
Shetty, Sanutha;Duesman, Samuel J;Patel, Sanil;Huyhn, Pacific;Shroff, Sanjana;Das, Anika;Chowhan, Disha;Sebra, Robert;Beaumont, Kristin;McAlpine, Cameron S;Rajbhandari, Prashant;Rajbhandari, Abha K
通讯作者：
Rajbhandari, Abha K