Biology subjects

Pangemanan, J.

Publications and source records attributed to Pangemanan, J..

4 recordsLinked to original sources

bioRxiv2026

Circadian Clock Control of Muscle Stem Cells Through Temporal Coordination of Notch and Wnt Signaling

The circadian clock regulates stem cell responses during tissue remodeling and repair. In skeletal muscle regeneration, successful regenerative myogenesis requires a temporally coordinated transition from Notch- to Wnt-driven signaling. However, the mechanisms governing this timing event remain poorly understood. Here, we show that circadian clock activity marks the cycling population of regeneration-activated myogenic progenitors that is induced in concert with Notch signaling. We identify key components of the Notch pathway as direct circadian clock targets and demonstrate that the clock coordinates Notch and Wnt signaling to drive myogenic progression. Genetic activation of the clock in satellite cells, as well as pharmacological clock stimulation, enhanced both proliferative expansion and subsequent differentiation of myogenic progenitors during regeneration. These effects were mediated by early activation of Notch signaling followed by increased Wnt pathway activity at later regenerative stages. Notably, both clock-dependent mechanisms remained functional in dystrophin-deficient mouse muscle and human myoblasts. Furthermore, clock-activating compounds enhanced regenerative myogenesis following acute injury and improved regeneration in dystrophic muscle. Collectively, these findings establish the circadian clock as a temporal regulator of regenerative signaling programs that orchestrate muscle repair with potential for targeted interventions.

cell biology↗

bioRxiv2026

Quercetin and Fisetin activate circadian clock via RORα and inhibit adipocyte growth

The circadian clock maintains temporal control of metabolic processes and exerts a key role in adipocyte development. Discovery of clock-modulatory compounds may provide new avenues for metabolic disease therapy. Here we report the identification of flavonoid compounds, Quercetin and Fisetin, as clock-activating molecules with direct inhibitory action on adipogenesis and adipocyte lipid metabolism. Quercetin and Fisetin displayed robust ROR agonism that promoted clock oscillation with induction of clock genes. Treating preadipocytes with these compounds blocked their adipogenic differentiation. In mature adipocytes, Quercetin and Fisetin suppressed lipid accumulation by inhibiting lipogenic enzymes. Furthermore, activation of ROR by a synthetic agonist or ectopic expression were sufficient to inhibit adipogenesis. In mice treated with Quercetin or Fisetin, ROR was markedly induced in adipose depots with strong suppression of the adipogenic and lipogenic programs. While quercetin significantly attenuated lipid storage in adipose tissue in vivo accompanied with lowering of free fatty acids and improved insulin sensitivity, fisetin displayed a less robust effect with differential regulation of lipolytic pathway. Collectively, these findings uncovered the clock-activating properties of quercetin and fisetin that prevent adipocyte maturation and hypertrophy to limit adipose tissue expansion. These actions contribute, at least in part, to their beneficial effects on metabolic disorders.

cell biology↗

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↗

bioRxiv2025

Clock Modulation by Naringenin via RORα Suppresses Lipogenesis and Promotes Adipose Tissue Browning

The circadian clock orchestrates adipocyte development and lipid remodeling, with its disruption leading to the development of obesity and insulin resistance. Here we demonstrate that the flavonoid compound naringenin displays clock modulatory activity via ROR that suppresses adipocyte lipid storage while promoting browning. In adipogenic progenitors, naringenin activates ROR with induction of clock gene expression to promote circadian clock oscillation with protective effect against cytokine-induced dampening. The clock-enhancing properties of naringenin suppressed lipogenesis in mature adipocytes together with induction of browning characteristics. The inhibitory effect of naringenin on lipogenesis was dependent on clock modulation as it was abolished in ROR-deficient adipocytes. We further show that naringenin administration in vivo up-regulated ROR expression with clock gene induction together with browning of subcutaneous beige fat depot, resulting reduced fat mass and body weight. Naringenin treatment in vivo also lowered plasma glucose and free fatty acid levels, with markedly enhanced insulin signaling in adipose depots and skeletal muscle. Collectively, our findings uncover a new clock-activating mechanism of action in mediating the metabolic benefits of naringenin, suggesting its potential as a natural supplement for anti-obesity and metabolic disease interventions.

cell biology↗