Misalignment of physiological circadian rhythms promotes
obesity which is characterized by white adipose tissue (WAT) expansion. Differentiation of Adipose stem/progenitor cells (ASCs) contributes to WAT increase but the importance of the cellular clock in this process is incompletely understood. In the present study, we reveal the role of the circadian
transcription factor Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) in human ASCs, isolated from subcutaneous (s)WAT samples of patients undergoing routine elective
plastic abdominal surgery. We show that circadian synchronization by serum-
shock or stimulation with adipogenic stimuli leads to a different expression pattern of ARNTL2 relative to its well-studied paralogue ARNTL1. We demonstrate that ARNTL2
mRNA is downregulated in ASCs upon
weight-loss (WL) whereas
ARNTL2 protein is rapidly induced in the course of adipogenic differentiation and highly abundant in adipocytes.
ARNTL2 protein is maintained in ASCs cooperatively by mechanistic Target of
Rapamycin (mTOR) and
Mitogen-activated Protein Kinase (MAPK) signalling pathways while ARNTL2 functions as an inhibitor on both circuits, leading to a feedback mechanism. Consistently, ectopic overexpression of ARNTL2 repressed adipogenesis by facilitating the degradation of ARNTL1, inhibition of
Kruppel-Like Factor 15 (KLF15) gene expression and down-regulation of the MAPK-
CCAAT/enhancer-binding protein β (C/EBPβ) axis. Western blot analysis of sWAT samples from normal-weight, obese and WL donors revealed that
ARNTL2 protein was solely elevated by WL compared to ARNTL1 which underscores unique functions of both
transcription factors. In conclusion, our study reveals ARNTL2 to be a WL-regulated inhibitor of adipogenesis which might provide opportunities to develop strategies to ameliorate
obesity.