The circadian clock machinery exerts transcriptional control to modulate adipogenesis and its disruption leads to the development of
obesity. Here we report that
Nobiletin, a clock amplitude-enhancing molecule, displays anti-adipogenic properties via activating a clock-controlled Wnt signaling pathway that suppresses adipocyte differentiation.
Nobiletin augmented clock oscillation with period length shortening in the adipogenic mesenchymal precursor cells and preadipocytes, accompanied by an induction of Bmal1 and core clock components. Consistent with its circadian clock-modulatory activity,
Nobiletin inhibited the lineage commitment and terminal differentiation of adipogenic progenitors. Mechanistically, we show that
Nobiletin induced the re-activation of Wnt signaling during adipogenic differentiation via transcriptional up-regulation of key components of this pathway. Furthermore,
Nobiletin administration in mice markedly reduced adipocyte
hypertrophy, leading to a significant loss of fat mass and
body weight reduction. Lastly,
Nobiletin inhibited the maturation of primary preadipocytes and this effect was dependent on a functional clock regulation. Collectively, our findings uncover a novel activity of
Nobiletin in suppressing adipocyte development, implicating its potential therapeutic application in countering
obesity and its associated metabolic consequences.