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Background  Cathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice. The functional inactivation of the proteases reduces fat accumulation during mammalian adipocyte differentiation. However, beyond degrading extracellular matrix protein fibronectin, the molecular mechanisms by which cathepsins control fat accumulation remain unclear. We now provide evidence from  Caenorhabditis elegans  and mouse models to suggest a conserved regulatory circuit in which peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis.    Results  We established a  C. elegans  model of fat accumulation using dietary supplementation with glucose and palmitic acid. We found that nutrient supplementation elevated fat storage in  C. elegans , and along with worm fat accumulation, an increase in the expression of  cpl-1  was detected using real-time PCR and western blot. The functional inactivation of  cpl-1  reduced fat storage in  C. elegans  through activating serotonin signaling. Further, knockdown of  cpl-1  in the intestine and hypodermis promoted serotonin synthesis in worm ADF neurons and induced body fat loss in  C. elegans  via central serotonin signaling. We found a similar regulatory circuit in high-fat diet-fed mice. Cathepsin L knockout promoted fat loss and central serotonin synthesis. Intraperitoneal injection of the cathepsin L inhibitor CLIK195 similarly reduced body weight gain and white adipose tissue (WAT) adipogenesis, while elevating brain serotonin level and WAT lipolysis and fatty acid β-oxidation. These effects of inhibiting cathepsin L were abolished by intracranial injection of p-chlorophenylalanine, inhibitor of a rate-limiting enzyme for serotonin synthesis.    Conclusion  This study reveals a previously undescribed molecular mechanism by which peripheral CPL-1/cathepsin L inhibition induces fat loss in  C. elegans  and mice through promoting central serotonin signaling.

Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin synthesis