Agua, A. | bioRxiv Science

bioRxiv2026

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

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

physiology↗

bioRxiv2023

Anti-adipogenic properties of clock activator chlorhexidine and a new derivative

BackgroundThe circadian clock exerts temporal control of metabolic pathways to maintain homeostasis, and its disruption leads to the development of obesity and insulin resistance. In adipose tissue, key regulators of clock machinery orchestrate adipogenic processes via the Wnt signaling pathway to impact mature adipocyte development. MethodsBased on the recent finding of chlorhexidine as a new clock activator, we determined its potential anti-adipogenic activities in distinct adipogenic progenitor models. Furthermore, we report the structural optimization of chlorhexidine leading to the discovery of analogs with improved efficacy in inhibiting adipogenesis. ResultsIn adipogenic progenitors with Per2::dLuc luciferase reporter, Chlorhexidine shortened clock period length with induction of core clock components. Consistent with its clock-activating function, Chlorhexidine robustly suppressed the lineage commitment and maturation of adipogenic mesenchymal precursors, with comparable effect on inhibiting preadipocyte terminal differentiation. Mechanistically, we show that Chlorhexidine induces signaling components of the Wnt pathway resulting in activation of Wnt activity. Via modification of its chemical scaffold, we generated analogs of chlorhexidine that led to the identification of CM002 as a new clock- activating molecule with improved anti-adipogenic activity. ConclusionsCollectively, our findings uncovered the anti-adipogenic functions of a new class of small molecule clock activators. These compounds provide novel chemical probes to dissect clock function in maintaining metabolic homeostasis and may have therapeutic implications in obesity and associated metabolic disorders.

cell biology↗