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

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.