A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate
A PRDM16-Driven Metabolic Signal from Adipocytes Regulates Precursor Cell Fate
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DOI：
10.1016/j.cmet.2019.05.005
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发表时间：
2019-07-02
期刊：
影响因子：
29
通讯作者：
Seale, Patrick
中科院分区：
文献类型：
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作者：
Wang, Wenshan;Ishibashi, Jeff;Seale, Patrick
对代谢有益的米色脂肪细胞的前体细胞也可以纤维化并导致脂肪纤维化。我们发现，小鼠的冷暴露或β3-肾上腺素能激动剂治疗降低了前体细胞的纤维化特征并刺激了米色脂肪细胞的分化。这种纤维生成到脂肪生成的转变在老年动物中受到损害，这与转录因子 PRDM16 的脂肪细胞表达减少相关。 Prdm16 的遗传缺失模拟了衰老对促进纤维化的影响，而老年小鼠中 PRDM16 的增加则减少了纤维化并恢复了米色脂肪的发育。表达 PRDM16 的脂肪细胞分泌代谢物 β-羟基丁酸 (BHB)，可阻止前体纤维生成并促进米色脂肪生成。 BDH1 介导的前体细胞中的 BHB 分解代谢是体内米色脂肪分化所必需的。最后，在老年动物中膳食补充 BHB 可减少脂肪纤维化并促进米色脂肪的形成。总之，我们的结果表明脂肪细胞分泌控制米色脂肪重塑的代谢信号。
The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or beta 3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite beta-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.