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，并因其减少肥胖和代谢疾病的能力而受到广泛关注。衰老会导致小鼠和人类的米色脂肪发育受损，容易出现代谢功能障碍，并限制米色脂肪靶向治疗的潜力。米色脂肪细胞是由脂肪祖细胞响应某些刺激（尤其是寒冷暴露）而发育而来的。在肥胖的情况下，这些脂肪祖细胞还可以发育成产生纤维化的肌成纤维细胞样细胞。我们注意到，年轻小鼠的米色化过程减少了脂肪组织祖细胞的纤维化特征。祖细胞表型中这种从纤维形成到脂肪形成的转变受到棕色脂肪转录因子 PRDM16 的调节。衰老降低了脂肪细胞中 PRDM16 的表达水平，导致米色脂肪发育丧失和纤维化反应加剧。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祖细胞的纤维化活性。具体来说，表达 PRDM16 的脂肪细胞参与高水平的脂肪酸氧化并产生酮体 β-羟基丁酸 (BHB)。 BHB 作用于祖细胞，阻止肌成纤维细胞编程并促进脂肪生成。 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祖细胞。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。总而言之，这些研究提出了这样的假设：脂肪祖细胞中的 BHB 分解代谢可抑制纤维化并刺激米色脂肪形成。因此，提高 BHB 水平/信号传导可能有助于改善脂肪纤维化并恢复衰老过程中米色脂肪细胞的发育。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 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。具体目标 1 检查 BHB 代谢在调节米色、棕色和白色脂肪细胞分化以响应冷暴露和肥胖条件方面的体内生理作用。具体目标 2 将阐明 BHB 分解代谢抑制祖细胞纤维生成反应并促进脂肪生成的机制。具体目标 3 将确定脂肪组织中纤维脂肪生成祖细胞的身份，并评估它们在年轻和老年动物中的差异活性。这项工作的完成将定义一条将组织代谢活动与祖细胞命运控制联系起来的新途径，并提出减少代谢和/或纤维化疾病的新方法。