QKI regulates adipose tissue metabolism by acting as a brake on thermogenesis and promoting obesity

Abstract

Adipose tissue controls numerous physiological processes, and its dysfunction has a causative role in the development of systemic metabolic disorders. The role of posttranscriptional regulation in adipose metabolism has yet to be fully understood. Here, we show that the RNA-binding protein quaking (QKI) plays an important role in controlling metabolic homeostasis of the adipose tissue. QKI-deficient mice are resistant to high-fat-diet (HFD)-induced obesity. Additionally, QKI depletion increased brown fat energy dissipation and browning of subcutaneous white fat. Adipose tissue-specific depletion of QKI in mice enhances cold-induced thermogenesis, thereby preventing hypothermia in response to cold stimulus. Further mechanistic analysis reveals that QKI is transcriptionally induced by the cAMP-cAMP response elementbinding protein (CREB) axis and restricts adipose tissue energy consumption by decreasing stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1a. These findings extend our knowledge of the significance of posttranscriptional regulation in adipose metabolic homeostasis and provide a potential therapeutic target to defend against obesity and its related metabolic diseases.

PACT establishes a posttranscriptional brake on mitochondrial biogenesis by promoting the maturation of miR-181c

“…S3 , L – O ). While multiple other RNAbps such as HUR, Y-box binding protein 2 (Ybx2), quaking (QKI) have been shown to have an inhibitor effect on adipogenesis of both BAT and WAT ( 40 , 58 , 59 ), our findings show that PACT’s regulatory role in β 3 -AR–stimulated mitobiogenesis is specific to BAT.…”

PWWP2B Fine‐Tunes Adipose Thermogenesis by Stabilizing HDACs in a NuRD Subcomplex

“…The cAMP‐CREB axis induced the RNA‐binding protein QKI transcription, but QKI impedes adipose thermogenesis by decreasing Ucp1 and Pgc1α mRNA stability, cytoplasm localization, and translation efficiency. [ 34 ] The expression level of potassium two pore domain channel subfamily K member 3 ( Kcnk3 ) is much higher in brown and beige than in white adipocytes. It is transcriptionally activated by PRDM16 and cold stimuli in adipose tissues.…”

Non-shivering Thermogenesis Signalling Regulation and Potential Therapeutic Applications of Brown Adipose Tissue

“…The cGMP-AMP (cGAMP) synthase-stimulator of interferon genes (cGAS-STING) pathway activated by mitochondrial stress inhibits PKA signal transduction by activating PDE, thus inhibiting BAT thermogenesis 21 . RNA-binding protein quaking (QKI), induced by CREB, can reduce the stability, nuclear export, and translation of mRNAs encoding UCP1 and PGC1α, thereby restricting BAT energy expenditure 22 .…”