Metabolic Control of Adipose Tissue Remodeling and Fibrosis

脂肪组织重塑和纤维化的代谢控制

• 批准号: 10418773
• 负责人: Patrick Seale
• 金额: $ 46.19万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418773
• 关键词: Adipocytes; Adipose tissue; Aging; Anatomy; Animals; Attention; Brown Fat; Cardiometabolic Disease; Catabolism; Cell Culture Techniques; Cell Differentiation process; Cell physiology; Cells; Competence; Connective Tissue; Cytoskeletal Modeling; Cytoskeleton; Development; Disease; Enzymes; Exposure to; Fatty Acids; Fatty acid glycerol esters; Fibrosis; Genes; Genetic; Hydroxybutyrates; Impairment; Ketone Bodies; Ketones; Link; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic dysfunction; Metabolism; Multipotent Stem Cells; Mus; Myofibroblast; Obesity; Paracrine Communication; Pathway interactions; Persons; Phenotype; Physiological; Play; Population; Population Heterogeneity; Process; Production; RNA; Role; Signal Pathway; Signal Transduction; Source; Stimulus; Stromal Cells; System; Testing; Thermogenesis; Tissues; Tracer; Transcription Coactivator; Work; adipocyte differentiation; aged; beta-Hydroxybutyrate; fatty acid oxidation; fibrogenesis; hypoxia inducible factor 1; in vivo; interstitial; lipid biosynthesis; metabolic profile; metabolomics; mouse model; novel; novel strategies; obesity treatment; obesogenic; paracrine; progenitor; programs; response; single cell analysis; single-cell RNA sequencing; stable isotope; stem cells; targeted treatment; transcription factor

Brown and beige adipose tissues burn energy for heat production and have garnered much attention because of their capacity to reduce obesity and metabolic disease. Aging leads to an impairment in beige fat development in mice and people, predisposing to metabolic dysfunction and limiting the potential of beige fat-targeted therapeutics. Beige fat cells develop from adipose progenitor cells in response to certain stimuli, most notably cold exposure. These adipose progenitor cells can also develop into fibrosis-generating myofibroblast-like cells in the context of obesity. We noted that the beiging process in young mice reduced the fibrosis profile of adipose tissue progenitor cells. This fibrogenic-to-adipogenic shift in progenitor phenotype was regulated by the brown fat transcription factor PRDM16. Aging reduced the expression levels of PRDM16 in adipocytes, leading to a loss of beige fat development and an aggravated fibrosis response. Cell culture studies revealed that PRDM16 suppresses the fibrogenic activity of adipose progenitor cells via an unexpected paracrine pathway. Specifically, PRDM16-expressing adipocytes engage high levels of fatty acid oxidation and produce the ketone body β-hydroxybutyrate (BHB). BHB acts on progenitor cells to block myofibroblast programing and facilitate adipogenesis. This activity of BHB depended on the ketolytic enzyme BDH1, suggesting that BHB regulates progenitor cells by re-wiring their metabolism. Finally, single cell expression profiling studies of adipose stromal cells identified a putative cellular source of aging-induced myofibroblasts. Altogether, these studies promote the hypothesis that BHB-catabolism in adipose progenitor cells suppresses fibrosis and stimulates beige adipogenic commitment. Therefore, raising BHB levels/signaling could potentially be targeted to ameliorate adipose fibrosis and restore beige adipocyte development during aging. In this project, we will use a combination of mouse models, genetic fate mapping, single cell RNA profiling analyses, and physiological assessments to investigate the novel role of ketone metabolism in regulating adipose tissue remodeling. Specific Aim 1 examines the in vivo physiological role of BHB-metabolism in regulating beige, brown and white fat cell differentiation in response to cold exposure and obesogenic conditions. Specific Aim 2 will elucidate the mechanisms by which BHB-catabolism represses fibrogenic responses and promotes adipogenic commitment in progenitor cells. Specific Aim 3 will determine the identity of fibro-adipogenic progenitors in adipose tissue and assess their differential activity in young vs. aged animals. Completion of this work will define a novel pathway that links tissue metabolic activity with control of progenitor fate and suggest new approaches to reduce metabolic and/or fibrotic disease.

棕色和米色脂肪组织燃烧能量产生热量，因其能够减少肥胖和代谢性疾病而引起了人们的极大关注。衰老导致小鼠和人的米色脂肪发育受损，容易出现代谢障碍，限制了米色脂肪靶向治疗的潜力。米色脂肪细胞由脂肪前体细胞发育而来，对某些刺激做出反应，最明显的是寒冷暴露。在肥胖的情况下，这些脂肪前体细胞也可以发育成纤维生成肌成纤维细胞样细胞。我们注意到，幼鼠的褐变过程减少了脂肪组织前体细胞的纤维化特征。这种成纤维细胞向成脂细胞的转变是由棕色脂肪转录因子PRDM16调节的。衰老降低了脂肪细胞中PRDM16的表达水平，导致米色脂肪发育的丧失和加重的纤维化反应。细胞培养研究表明，PRDM16通过意想不到的旁分泌途径抑制脂肪前体细胞的纤维化活性。具体地说，表达PRDM16的脂肪细胞进行高水平的脂肪酸氧化，并产生酮体β-羟丁酸盐(BHb)。BHB作用于祖细胞，阻断肌成纤维细胞的编程，促进脂肪生成。BHB的这种活性依赖于酮解酶BDH1，这表明BHB通过重新连接祖细胞的代谢来调节它们。最后，脂肪基质细胞的单细胞表达谱研究确定了衰老诱导的肌成纤维细胞的假定细胞来源。总之，这些研究支持这样的假设，即脂肪前体细胞中的BHB分解代谢抑制纤维化并刺激米色成脂承诺。因此，提高BHB水平/信号可能成为改善脂肪纤维化和恢复衰老过程中米色脂肪细胞发育的潜在靶点。在这个项目中，我们将结合小鼠模型、遗传命运图谱、单细胞RNA图谱分析和生理评估来研究酮代谢在调节脂肪组织重塑中的新作用。特定目的1检测体内BHB代谢在调节米色、棕色和白色脂肪细胞分化中的生理作用，以响应寒冷暴露和肥胖条件。具体目标2将阐明BHB分解代谢抑制成纤维反应和促进祖细胞成脂承诺的机制。具体目标3将确定脂肪组织中纤维成脂前体细胞的身份，并评估它们在幼年动物和老年动物中的不同活动。这项工作的完成将定义一条新的途径，将组织代谢活动与祖细胞命运的控制联系起来，并提出减少代谢和/或纤维化疾病的新方法。