Novel circadian clock activators display anti-obesity efficacy via suppression of adipocyte development and hypertrophy

Abstract

The circadian clock exerts temporal coordination of metabolic processes to maintain homeostasis, and its disruption predisposes to the development of obesity and insulin resistance. Despite the established genetic basis of clock modulation in adipocyte development, whether it can be targeted for anti-obesity interventions remains to be explored. Here we report the novel actions of clock-activating molecules, chlorhexidine and a new derivative CM002, on inhibiting adipocyte development and hypertrophy that results in anti-obesity efficacy in vivo. Both chlorhexidine and CM002 were sufficient to activate clock in adipocytes with induction of core clock components and shortening of clock period length. Consistent with their clock-activating properties, these compounds suppressed the distinct lineage commitment and terminal differentiation stages of adipogenic precursor cells mediated via activation of the Wnt signaling pathway. Furthermore, CM002 attenuated lipid storage and adipocyte hypertrophy by suppressing the lipogenic and adipogenic program in a clock-dependent manner. Most importantly, CM002 administration in mice with diet-induced obesity was sufficient to induce clock activation in adipose depots, leading to robust suppression of adipogenic factors and lipogenic enzymes with marked effect on reducing fat mass and promoting insulin sensitivity. Collectively, our findings uncovered the anti-adipogenic properties of novel small molecule clock activators with demonstrated anti-obesity efficacy. These compounds provide novel chemical probes to dissect clock function in metabolic regulations with translational potential toward development of first-in-class clock-targeting drugs for anti-obesity therapy. HighlightsO_LIDiscovery of the anti-adipogenic properties of the clock activator chlorhexidine C_LIO_LIIdentification of a new clock-activating molecule CM002 C_LIO_LICM002 inhibits the lineage commitment and terminal differentiation of adipocytes C_LIO_LIClock activation by CM002 suppresses lipid storage in mature adipocytes C_LIO_LICM002 displays anti-obesity efficacy in diet-induced obesity model C_LI