KLF7 induced ADRB3-dependent IL-6 production in brown adipocytes during stress

  • J Lipid Res. 2026 Feb;67(2):100981. doi: 10.1016/j.jlr.2026.100981.
Maodi Liang  1 ,  Meixiu Zhang  2 ,  Yanting Hou  1 ,  Fangyuan Yuan  1 ,  Huizi Zhang  1 ,  Mengyuan Zhao  1 ,  Lili Xu  1 ,  Qin Liu  1 ,  Yurui Su  1 ,  Xiaolong Chu  3 ,  Wei Li  1 ,  Jingzhou Wang  4 ,  Jianxin Xie  5 ,  Cuizhe Wang  6 ,  Qinghua Cui  7 ,  Jun Zhang  8
Affiliations
  • 1. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China.
  • 2. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China; Department of Obstetrics, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi Province, China.
  • 3. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China; Department of Medical Genetics, Medical College of Tarim University, Xinjiang Province, China.
  • 4. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China. Electronic address: [email protected].
  • 5. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China; Department of Medical Genetics, Medical College of Tarim University, Xinjiang Province, China. Electronic address: [email protected].
  • 6. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China. Electronic address: [email protected].
  • 7. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China; School of Sports Medicine, Wuhan Institute of Physical Education, Wuhan, Hubei Province, China. Electronic address: [email protected].
  • 8. Department of Medical Genetics, Shihezi University School of Medicine, Shihezi, Xinjiang Province, China. Electronic address: [email protected].
PMID: 41565113 DOI: 10.1016/j.jlr.2026.100981
Abstract

In recent studies, acute physiological stress has been shown to enhance liver gluconeogenesis by activating β3-adrenergic receptor (ADRB3)-dependent interleukin-6 (IL-6) production in brown adipocytes, effectively fueling "fight or flight" responses. However, the specific molecular mechanism of this IL-6 production in an ADRB3-dependent manner is not fully understood. ADRB3 regulates multiple metabolic programs in adipose tissue, including thermogenesis, lipolysis, and glucose uptake, by activating cAMP-PKA-CREB signaling. Our previous studies revealed that the transcription factor Krüppel-like factor 7 (KLF7) transcriptionally induces IL-6 expression in white adipocytes. Using Klf7-adipocyte knockout mice, we showed that Klf7 is also required for ADRB3-induced IL-6 production during stress. cAMP-PKA-CREB signaling mediates this transduction via stress and ADRB3 agonist administration in a mouse model in vivo, as well as in brown adipocytes cultured in vitro. cAMP response element-binding protein (CREB) positively regulates KLF7 transcription by binding to the promoter of KLF7. These findings indicate that stress-induced IL-6 production is dependent on Klf7 in adipocytes. KLF7, as a target gene of CREB, responds to ADRB3 activation to increase endocrine IL-6 in a cAMP-PKA-CREB signaling-dependent manner. Our study provides a new theoretical basis for elucidating and enriching the novel mechanism of stress-induced IL-6 production in brown adipocytes.

Keywords
ADRB3; IL-6; KLF7; liver gluconeogenesis; stress.
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