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Published on: July 21, 2017
Peripheral cathepsin L inhibition induces fat loss in C. elegans and mice through promoting central serotonin
1School of Food and Biological Engineering, Hefei University of Technology, 193 Tunxi Road, Hefei, 230009, Anhui, China.
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.
Insights
Inhibiting cathepsin L in worms and mice reduces fat accumulation by boosting central serotonin synthesis. This conserved mechanism offers a new target for obesity treatment.
Area of Science:
- Metabolic research
- Molecular biology
- Neuroscience
Background:
- Cathepsin L is linked to obesity, but its precise role in fat accumulation is unclear.
- Previous studies show protease inactivation reduces fat, but mechanisms remain elusive.
- Cathepsin L degrades fibronectin, but its broader function in adipogenesis needs elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which cathepsins regulate fat accumulation.
- To identify a conserved regulatory circuit linking peripheral cathepsin L to central serotonin synthesis.
- To explore cathepsin L inhibition as a potential therapeutic strategy for obesity.
Main Methods:
- Established a Caenorhabditis elegans model with dietary fat supplementation.
- Utilized real-time PCR and western blot to measure gene expression (cpl-1).
- Employed functional inactivation (knockdown/knockout) and pharmacological inhibition (CLIK195, p-chlorophenylalanine) in C. elegans and mice.
Main Results:
- Nutrient-supplemented C. elegans showed increased fat storage and cpl-1 expression.
- cpl-1 inactivation reduced fat in C. elegans by activating serotonin signaling.
- Cathepsin L knockout and inhibition in mice reduced body weight, WAT adipogenesis, and increased central serotonin and WAT lipolysis.
Conclusions:
- Peripheral cathepsin L inhibition promotes fat loss through central serotonin signaling.
- A conserved regulatory circuit involving cathepsin L and serotonin controls fat accumulation.
- This study uncovers a novel molecular pathway for therapeutic intervention in obesity.
