Metabolic Control of Adipose Tissue Remodeling and Fibrosis

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。衰老导致小鼠和人类米色脂肪发育受损，易导致代谢功能障碍，并限制了米色脂肪靶向治疗的潜力。米色脂肪细胞由脂肪祖细胞在某些刺激下发育而来，最明显的是冷暴露。在肥胖的情况下，这些脂肪祖细胞也可以发育成纤维化的肌成纤维细胞样细胞。我们注意到，年轻小鼠的北京过程减少了脂肪组织祖细胞的纤维化谱。祖细胞表型的纤维化向脂肪性转变是由棕色脂肪转录因子PRDM16调控的。衰老降低了脂肪细胞中PRDM16的表达水平，导致米色脂肪发育缺失和纤维化反应加重。细胞培养研究表明，PRDM16通过一种意想不到的旁分泌途径抑制脂肪祖细胞的成纤维活性。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-羟基丁酸酯（BHB）。BHB作用于祖细胞，阻断肌成纤维细胞编程，促进脂肪形成。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。总之，这些研究促进了脂肪祖细胞中bhb分解代谢抑制纤维化并刺激米色脂肪生成的假设。因此，提高BHB水平/信号可能潜在地靶向改善脂肪纤维化和恢复衰老过程中的米色脂肪细胞发育。在这个项目中，我们将使用小鼠模型、遗传命运图谱、单细胞RNA谱分析和生理评估相结合的方法来研究酮代谢在调节脂肪组织重塑中的新作用。特异性目的1研究bhb代谢在调节米色、棕色和白色脂肪细胞分化中的体内生理作用，以应对寒冷暴露和致肥条件。特异性目标2将阐明bhb分解代谢抑制纤维化反应和促进祖细胞脂肪生成的机制。特异性目标3将确定脂肪组织中纤维脂肪源性祖细胞的身份，并评估它们在幼龄和老年动物中的差异活性。这项工作的完成将定义一个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。

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.