Signal transducer and activator of transcription 3 (Stat3) suppresses stat1/interferon signaling pathway and inflammation in senescent preadipocytes

Aisha Y. Madani, Yasser Majeed, Houari B. Abdesselem, Maha V. Agha, Muneera Vakayil, Nour K. Al Sukhun, Najeeb M. Halabi, Pankaj Kumar, Shahina Hayat, Mohamed A. Elrayess, Arash Rafii, Karsten Suhre, Nayef A. Mazloum*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number334
Pages (from-to)1-26
Number of pages26
JournalAntioxidants
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 2021

Keywords

  • Cellular senescence
  • Inflammation
  • Preadipocytes
  • ROS
  • SASP
  • Type 2 diabetes

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