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: 10166840
• 负责人: Patrick Seale
• 金额: $ 46.81万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166840
• 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; Expression Profiling; 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; 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; 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以产生热量，并由于其减少肥胖症和代谢疾病的能力而引起了很多关注。衰老会导致小鼠和人的米色脂肪发育受损，易于代谢功能障碍，并限制了米色脂肪靶向疗法的潜力。米色脂肪细胞从脂肪祖细胞中发展，响应某些刺激，最著名的是冷暴露。在肥胖症的背景下，这些脂肪祖细胞也可以发展为纤维化产生肌纤维细胞样细胞。我们注意到，年轻小鼠的变化降低了脂肪组织祖细胞的纤维化谱。祖细胞表型中的这种纤维化向辅导性转移受棕色脂肪转录因子PRDM16的调节。衰老降低了脂肪细胞中PRDM16的表达水平，从而导致米色脂肪的发展损失和综合的纤维化反应。细胞培养研究表明，PRDM16通过出乎意料的旁分泌途径抑制脂肪祖细胞的纤维生成活性。具体而言，表达PRDM16的脂肪细胞具有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，以阻止肌纤维细胞编程和支持脂肪形成。 BHB的这种活性取决于酮酶BDH1，这表明BHB通过重新传播其代谢来调节祖细胞。最后，脂肪基质细胞的单细胞表达分析研究确定了衰老诱导的肌纤维细胞的假定细胞来源。总的来说，这些研究促进了脂肪祖细胞中BHB-catabolism的假设，可抑制纤维化并刺激米色脂肪生成剂量。因此，升高的BHB水平/信号传导可能有可能针对改善脂肪纤维化并在衰老过程中恢复米色脂肪细胞的发育。在该项目中，我们将使用小鼠模型，遗传脂肪图，单细胞RNA分析分析和物理评估的组合来研究酮代谢在调节脂肪组织重塑调节中的新作用。特定的目标1检查BHB代谢在调节中的体内生理作用，响应冷暴露和肥胖状况，米色，棕色和白色脂肪细胞分化。具体的目标2将阐明BHB-catabolism反映纤维源性反应并促进祖细胞中的脂肪性承诺的机制。具体目标3将确定脂肪组织中纤维辅助祖细胞的身份，并评估其在年轻动物与年龄动物中的差异活性。这项工作的完成将定义一种新的途径，该途径将组织代谢活性与祖细胞命运的控制联系起来，并提出了减少代谢和/或纤维化疾病的新方法。