Discovery of circadian clock activators with anti-obesity efficacy via suppression of adipocyte development and hypertrophy.

Circadian clock-driven orchestration of metabolic pathways in adipocytes is required to maintain nutrient homeostasis, and clock disruption predisposes to the development of obesity and insulin resistance. However, pharmacological means to promote beneficial clock actions for metabolic disease interventions remain to be explored. Here, we report the identification and characterization of clock-activating molecules with developmental stage-dependent inhibition of adipocyte development and hypertrophy, leading to robust anti-obesity efficacy in vivo. Both chlorhexidine and a new derivative CM002 augmented clock oscillation in adipocytes with induction of core clock components and shortening of period length. Clock activation by these molecules blocked adipogenesis mediated by transcriptional induction of the Wnt signaling pathway, preventing the lineage commitment and terminal differentiation of adipogenic progenitors. In mature adipocytes, CM002 attenuated lipid storage in a clock-dependent manner via inhibition of the lipogenic program. Furthermore, in vivo administration of CM002 in normal or obese mice enhanced clock output in distinct adipose depots with markedly suppressed adipogenic and lipogenic pathways, abrogating adipocyte hypertrophy while promoting insulin sensitivity. Collectively, our study provides the mechanistic underpinning to develop clock activators as a novel avenue for anti-obesity therapy with potential therapeutic benefits against type 2 diabetes.