Metabolic Control of Adipose Tissue Remodeling and Fibrosis

棕色和米色脂肪组织燃烧能量以产生热量，并因其减少肥胖和代谢疾病的能力而备受关注。衰老导致小鼠和人的米色脂肪发育受损，易患代谢功能障碍，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发育而来，对某些刺激做出反应，最明显的是冷暴露。这些脂肪祖细胞也可以在肥胖症的情况下发育成纤维化生成肌纤维母细胞样细胞。我们注意到年轻小鼠的beiging过程减少了脂肪组织祖细胞的纤维化特征。这种祖细胞表型中的纤维形成向脂肪形成的转变由棕色脂肪转录因子PRDM 16调节。衰老降低了脂肪细胞中PRDM 16的表达水平，导致米色脂肪发育丧失和纤维化反应加重。细胞培养研究显示，PRDM 16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。具体而言，表达PRDM 16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作用于祖细胞以阻断肌成纤维细胞编程并促进脂肪生成。BHB的这种活性依赖于解酮酶BDH 1，这表明BHB通过重新连接它们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推定细胞来源。总之，这些研究促进了脂肪祖细胞中的BHB-催化剂抑制纤维化并刺激米色脂肪形成承诺的假设。因此，提高BHB水平/信号传导可能潜在地靶向改善脂肪纤维化并恢复衰老期间的米色脂肪细胞发育。在这个项目中，我们将使用小鼠模型，遗传命运映射，单细胞RNA分析和生理评估的组合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研究了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，以响应冷暴露和致肥胖条件。具体目标2将阐明BHB-催化剂抑制纤维化反应和促进祖细胞成脂定型的机制。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，并评估其在年轻与老年动物中的差异活性。这项工作的完成将定义一种新的途径，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.