Bahn Young Jae, Wang Yanling, Dagur Pradeep, Scott Nicholas, Cero Cheryl, Long Kelly T, Nguyen Nhuquynh, Cypess Aaron M, Rane Sushil G
Diabetes, Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, MD, USA.
Flow Cytometry Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD, USA.
Mol Metab. 2024 Dec;90:102054. doi: 10.1016/j.molmet.2024.102054. Epub 2024 Oct 24.
Adipose tissue depots vary markedly in their ability to store and metabolize triglycerides, undergo beige adipogenesis and susceptibility to metabolic disease. The molecular mechanisms that underlie such heterogeneity are not entirely clear. Previously, we showed that TGF-β signaling suppresses beige adipogenesis via repressing the recruitment of dedicated beige progenitors. Here, we find that TGF-β signals dynamically regulate the balance between adipose tissue fibrosis and beige adipogenesis.
We investigated adipose tissue depot-specific differences in activation of TGF-β signaling in response to dietary challenge. RNA-seq and fluorescence activated cell sorting was performed to identify and characterize cells responding to changes in TGF-β signaling status. Mouse models, pharmacological strategies and human adipose tissue analyses were performed to further define the influence of TGF-β signaling on fibrosis and functional beige adipogenesis.
Elevated basal and high-fat diet inducible activation of TGF-β/Smad3 signaling was observed in the visceral adipose tissue depot. Activation of TGF-β/Smad3 signaling was associated with increased adipose tissue fibrosis. RNA-seq combined with fluorescence-activated cell sorting of stromal vascular fraction of epididymal white adipose tissue depot resulted in identification of TGF-β/Smad3 regulated ITGA5+ fibrogenic progenitors. TGF-β/Smad3 signal inhibition, genetically or pharmacologically, reduced fibrosis and increased functional beige adipogenesis. TGF-β/Smad3 antagonized the beneficial effects of PPARγ whereas TGF-β receptor 1 inhibition synergized with actions of rosiglitazone, a PPARγ agonist, to dampen fibrosis and promote beige adipogenesis. Positive correlation between TGF-β activation and ITGA5 was observed in human adipose tissue, with visceral adipose tissue depots exhibiting higher fibrosis potential than subcutaneous or brown adipose tissue depots.
Basal and high-fat diet inducible activation of TGF-β underlies the heterogeneity of adipose tissue depots. TGF-β/Smad3 activation promotes adipose tissue fibrosis and suppresses beige progenitors. Together, these dual mechanisms preclude functional beige adipogenesis. Controlled inhibition of TβRI signaling and concomitant PPARγ stimulation can suppress adipose tissue fibrosis and promote beige adipogenesis to improve metabolism.
脂肪组织库在储存和代谢甘油三酯、发生米色脂肪生成以及对代谢疾病的易感性方面存在显著差异。造成这种异质性的分子机制尚不完全清楚。此前，我们发现转化生长因子-β（TGF-β）信号通过抑制特定米色祖细胞的募集来抑制米色脂肪生成。在此，我们发现TGF-β信号动态调节脂肪组织纤维化和米色脂肪生成之间的平衡。
我们研究了饮食挑战后脂肪组织库中TGF-β信号激活的特异性差异。进行RNA测序和荧光激活细胞分选，以鉴定和表征对TGF-β信号状态变化作出反应的细胞。利用小鼠模型、药理学策略和人体脂肪组织分析，进一步确定TGF-β信号对纤维化和功能性米色脂肪生成的影响。
在内脏脂肪组织库中观察到基础状态下以及高脂饮食诱导的TGF-β/Smad3信号激活升高。TGF-β/Smad3信号的激活与脂肪组织纤维化增加有关。对附睾白色脂肪组织库的基质血管部分进行RNA测序并结合荧光激活细胞分选，鉴定出TGF-β/Smad3调节的整合素α5（ITGA5）+成纤维祖细胞。通过基因或药理学方法抑制TGF-β/Smad3信号，可减少纤维化并增加功能性米色脂肪生成。TGF-β/Smad3拮抗过氧化物酶体增殖物激活受体γ（PPARγ）的有益作用，而抑制TGF-β受体1则与PPARγ激动剂罗格列酮协同作用，减轻纤维化并促进米色脂肪生成。在人体脂肪组织中观察到TGF-β激活与ITGA5之间呈正相关，内脏脂肪组织库比皮下或棕色脂肪组织库表现出更高的纤维化潜能。
基础状态下以及高脂饮食诱导的TGF-β激活是脂肪组织库异质性的基础。TGF-β/Smad3激活促进脂肪组织纤维化并抑制米色祖细胞。这两种机制共同作用阻止了功能性米色脂肪生成。对TβRI信号进行可控抑制并同时刺激PPARγ，可抑制脂肪组织纤维化并促进米色脂肪生成以改善代谢。
