Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center, Houston, TX, USA.
Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Nat Metab. 2020 Dec;2(12):1482-1497. doi: 10.1038/s42255-020-00320-4. Epub 2020 Dec 14.
White and beige adipocytes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are maintained by proliferation and differentiation of adipose progenitor cells (APCs). Here we use mice with tissue-specific telomerase reverse transcriptase (TERT) gene knockout (KO), which undergo premature telomere shortening and proliferative senescence in APCs, to investigate the effect of over-nutrition on APC exhaustion and metabolic dysfunction. We find that TERT KO in the Pdgfra cell lineage results in adipocyte hypertrophy, inflammation and fibrosis in SAT, while TERT KO in the Pdgfrb lineage leads to adipocyte hypertrophy in both SAT and VAT. Systemic insulin resistance is observed in both KO models and is aggravated by a high-fat diet. Analysis of human biopsies demonstrates that telomere shortening in SAT is associated with metabolic disease progression after bariatric surgery. Our data indicate that over-nutrition can promote APC senescence and provide a mechanistic link between ageing, obesity and diabetes.
白色和米色脂肪细胞存在于皮下脂肪组织 (SAT) 和内脏脂肪组织 (VAT) 中，它们通过脂肪祖细胞 (APCs) 的增殖和分化来维持。在这里，我们使用组织特异性端粒酶逆转录酶 (TERT) 基因敲除 (KO) 小鼠，这些小鼠的 APCs 中端粒会过早缩短并发生增殖衰老，以此来研究营养过剩对 APC 耗竭和代谢功能障碍的影响。我们发现，Pdgfra 细胞谱系中的 TERT KO 会导致 SAT 中的脂肪细胞肥大、炎症和纤维化，而 Pdgfrb 谱系中的 TERT KO 则会导致 SAT 和 VAT 中的脂肪细胞肥大。两种 KO 模型均出现全身胰岛素抵抗，且这种抵抗在高脂肪饮食的作用下会加剧。对人类活检样本的分析表明，SAT 中的端粒缩短与减重手术后代谢疾病的进展有关。我们的数据表明，营养过剩会促进 APC 衰老，并为衰老、肥胖和糖尿病之间提供了一种机制联系。
