Dissecting the thermogenic adipose niche

剖析产热脂肪生态位

• 批准号: 10504460
• 负责人: Yu-Hua Tseng
• 金额: $ 73.96万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504460
• 关键词: Adipocytes; Adipose tissue; Adult; Afferent Neurons; Agonist; Animals; Anterior; Biopsy; Brown Fat; Calcium; Capsaicin; Cardiometabolic Disease; Cardiovascular Diseases; Cations; Cell Communication; Cells; Cervical; Coculture Techniques; Complex; Conditioned Culture Media; Data; Databases; Development; Diabetes Mellitus; Economic Burden; Energy Metabolism; Etiology; Fatty acid glycerol esters; Flow Cytometry; Functional disorder; Genes; Health; Heterogeneity; House mice; Human; Image; Impairment; In Vitro; Individual; Ion Channel; Knowledge; Lead; Ligands; Link; Low Prevalence; Maps; Measures; Medical Economics; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; Neck; Nociception; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; PPAR gamma; Pathology; Physiologic Thermoregulation; Physiological; Platelet-Derived Growth Factor alpha Receptor; Play; Population; Proliferating; Receptor Signaling; Regulation; Research; Rodent; Role; Scheme; Shapes; Signal Induction; Signal Transduction; Site; Small Nuclear RNA; Stimulus; System; TRP channel; Temperature; Testing; Tetanus Helper Peptide; Therapeutic; Triglycerides; United States; Vascular Smooth Muscle; adipocyte differentiation; base; cell type; computerized tools; improved; insight; intercellular communication; lipid biosynthesis; loss of function; member; metabolic phenotype; mouse model; novel; novel therapeutic intervention; obesity prevention; optogenetics; receptor; release of sequestered calcium ion into cytoplasm; response; single-cell RNA sequencing; stem cells; transcriptome; transcriptomics; volunteer

Project Summary/Abstract Adipose tissue plays a critical role in the regulation of whole-body energy metabolism, and adipose dysfunction directly links to the etiology of several commonly seen metabolic diseases, such as type 2 diabetes mellitus and cardiovascular diseases. There are several different adipose depots dispersed throughout the body. White adipose tissue (WAT) is the primary site of the triglyceride storehouse. In contrast, thermogenic fat, which consists of classical brown adipose tissue (BAT) and inducible beige/brite fat, is specialized for thermogenic energy expenditure. In humans, individuals with detectable BAT have a significantly lower prevalence of cardiometabolic diseases, pointing to the metabolic benefits and therapeutic promise of BAT. Thermogenic adipose tissue can rapidly respond to environmental challenges by modulating cellular compositions and cell- to-cell interactions. Such adaptation is key to maintaining metabolic health. Intercellular communications within the thermogenic adipose niche orchestrate adipose tissue development and play an essential role in adipose tissue turnover, expansion, and remodeling in response to external stimuli. To dissect the complex cellular makeup of thermogenic fat, we performed single-cell RNA-sequencing analysis of BAT from mice housed at different temperatures. The results revealed a high degree of heterogeneity of thermogenic adipose niche and showed cold exposure induced dynamic changes of cellular composition in BAT. Importantly, we identified a novel population of adipose progenitor cells (APCs), which was derived from the vascular smooth muscle (VSM) lineage and uniquely expressed Trpv1 (transient receptor potential cation channel subfamily V member 1). Lineage tracing studies demonstrated that the Trpv1-expressing VSM-APCs could proliferate and differentiate into highly thermogenic adipocytes in response to cold stimulation. Work in progress showed that impaired adipogenic differentiation of Trpv1-expressing APCs resulted in reduced expression of thermogenic genes in BAT and WAT, suggesting an important role of these cells in thermoregulation. Additional preliminary data showed that the Trpv1-expressing APCs could respond to local signals and differentiate into thermogenic adipocytes. These exciting findings have led us to propose a model involving intercellular communications in which interplays between the APCs and inductive signals shapes adipocyte differentiation and function. In this proposal, we will test this hypothesis by determining the physiological role of the Trpv1-expressing APCs in metabolic regulation, identifying the endogenous and exogenous stimuli of Trpv1-positive APCs, and mapping the cellular interactome of the thermogenic adipose niche using computational tools and spatial transcriptomic analysis. Successful completion of the proposed studies will provide new insight into the role of intercellular communications in the regulation of adipose tissue development and function.

项目概要/摘要 脂肪组织在调节全身能量代谢和脂肪功能障碍中发挥着关键作用 与 2 型糖尿病等几种常见代谢性疾病的病因直接相关 和心血管疾病。有几种不同的脂肪库分布在全身各处。白色的 脂肪组织（WAT）是甘油三酯仓库的主要场所。相比之下，产热脂肪， 由经典棕色脂肪组织 (BAT) 和可诱导米色/棕色脂肪组成，专门用于产热 能量消耗。在人类中，具有可检测到的 BAT 的个体的患病率显着降低 心脏代谢疾病，指出 BAT 的代谢益处和治疗前景。产热 脂肪组织可以通过调节细胞组成和细胞因子来快速应对环境挑战。 与细胞的相互作用。这种适应是维持代谢健康的关键。细胞间通讯 生热脂肪生态位协调脂肪组织发育并在脂肪形成中发挥重要作用 响应外部刺激的组织更新、扩张和重塑。剖析复杂的细胞 为了研究产热脂肪的组成，我们对饲养在 不同的温度。结果揭示了生热脂肪生态位的高度异质性和 显示冷暴露诱导 BAT 细胞组成的动态变化。重要的是，我们确定了一个 新型脂肪祖细胞 (APC) 群体，源自血管平滑肌 (VSM)谱系和独特表达的Trpv1（瞬时受体电位阳离子通道亚家族V成员 1）。谱系追踪研究表明，表达 Trpv1 的 VSM-APC 可以增殖并 响应冷刺激分化成高产热脂肪细胞。正在进行的工作表明 表达 Trpv1 的 APC 的成脂分化受损导致生热表达减少 BAT 和 WAT 中的基因，表明这些细胞在体温调节中发挥着重要作用。附加初步 数据显示，表达Trpv1的APC可以响应局部信号并分化为产热细胞 脂肪细胞。这些令人兴奋的发现促使我们提出了一个涉及细胞间通讯的模型 APC 和感应信号之间的相互作用塑造脂肪细胞的分化和功能。在这个 提案中，我们将通过确定表达 Trpv1 的 APC 的生理作用来检验这一假设。 代谢调节，识别 Trpv1 阳性 APC 的内源性和外源性刺激，并绘制图谱 使用计算工具和空间转录组学研究生热脂肪生态位的细胞相互作用组 分析。拟议研究的成功完成将为细胞间质的作用提供新的见解 脂肪组织发育和功能调节中的通讯。