Madani Aisha Y, Majeed Yasser, Abdesselem Houari B, Agha Maha V, Vakayil Muneera, Sukhun Nour K Al, Halabi Najeeb M, Kumar Pankaj, Hayat Shahina, Elrayess Mohamed A, Rafii Arash, Suhre Karsten, Mazloum Nayef A
College of Health & Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation, Doha 34110, Qatar.
Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar (WCM-Q), Qatar Foundation, Doha 24144, Qatar.
Antioxidants (Basel). 2021 Feb 23;10(2):334. doi: 10.3390/antiox10020334.
Obesity promotes premature aging and dysfunction of white adipose tissue (WAT) through the accumulation of cellular senescence. The senescent cells burden in WAT has been linked to inflammation, insulin-resistance (IR), and type 2 diabetes (T2D). There is limited knowledge about molecular mechanisms that sustain inflammation in obese states. Here, we describe a robust and physiologically relevant in vitro system to trigger senescence in mouse 3T3-L1 preadipocytes. By employing transcriptomics analyses, we discovered up-regulation of key pro-inflammatory molecules and activation of interferon/signal transducer and activator of transcription (STAT)1/3 signaling in senescent preadipocytes, and expression of downstream targets was induced in epididymal WAT of obese mice, and obese human adipose tissue. To test the relevance of STAT1/3 signaling to preadipocyte senescence, we used Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR associated protein 9 (CRISPR/Cas9) technology to delete STAT1/3 and discovered that STAT1 promoted growth arrest and cooperated with cyclic Guanosine Monophosphate-Adenosine Monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) to drive the expression of interferon β (IFNβ), C-X-C motif chemokine ligand 10 (CXCL10), and interferon signaling-related genes. In contrast, we discovered that STAT3 was a negative regulator of STAT1/cGAS-STING signaling-it suppressed senescence and inflammation. These data provide insights into how STAT1/STAT3 signaling coordinates senescence and inflammation through functional interactions with the cGAS/STING pathway.
肥胖通过细胞衰老的积累促进白色脂肪组织（WAT）过早衰老和功能障碍。WAT中衰老细胞的负担与炎症、胰岛素抵抗（IR）和2型糖尿病（T2D）有关。关于肥胖状态下维持炎症的分子机制的了解有限。在这里，我们描述了一种强大且与生理相关的体外系统，用于在小鼠3T3-L1前脂肪细胞中触发衰老。通过转录组学分析，我们发现衰老前脂肪细胞中关键促炎分子上调，干扰素/信号转导和转录激活因子（STAT）1/3信号通路激活，肥胖小鼠附睾WAT和肥胖人类脂肪组织中诱导了下游靶点的表达。为了测试STAT1/3信号通路与前脂肪细胞衰老的相关性，我们使用成簇规律间隔短回文重复序列/CRISPR相关蛋白9（CRISPR/Cas9）技术删除STAT1/3，发现STAT1促进生长停滞，并与环磷酸鸟苷-磷酸腺苷（GMP-AMP）合酶-干扰素基因刺激因子（cGAS-STING）协同驱动干扰素β（IFNβ）、C-X-C基序趋化因子配体10（CXCL10）和干扰素信号相关基因的表达。相反，我们发现STAT3是STAT1/cGAS-STING信号通路的负调节因子——它抑制衰老和炎症。这些数据为STAT1/STAT3信号通路如何通过与cGAS/STING途径的功能相互作用协调衰老和炎症提供了见解。
