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

Yan Lin,Xianqi Nie,Guo-Ping Shi,Xin Wang,Bin Bao,Hao Yin,Nan Yang,Jian Liu,Airong Feng,Lin Zhao

doi:10.1186/s12915-019-0719-4

Abstract

BackgroundCathepsin 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.ResultsWe 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.ConclusionThis 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.

Highlights

Cathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice
The supplementation of glucose or palmitic acid elevated fat storage and the expression of cathepsin L-like protease CPL-1 in C. elegans In the laboratory, C. elegans is usually grown on Nematode Growth Medium (NGM) plates seeded with Escherichia coli OP50
The supplementation of the nutrients gradually increased the levels of glucose (Additional file 1: Figure S1A and S1B) and palmitic acid (Additional file 1: Figure S1C and S1D) in both E. coli and C. elegans, but they did not affect the developmental rates of worms (Additional file 2: Table S1)

Summary

Introduction

Cathepsin L and some other cathepsins have been implicated in the development of obesity in humans and mice. Beyond degrading extracellular matrix protein fibronectin, the molecular mechanisms by which cathepsins control fat accumulation remain unclear. We 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. Utilizing genetic deficiency and pharmacological inhibition of cathepsin K and cathepsin L, our previous studies demonstrate their essential roles in mouse adipogenesis and body weight gain and attribute the actions to the degradation of extracellular matrix protein fibronectin [2, 9]. Beyond degrading fibronectin, the detailed molecular mechanisms that cathepsins control fat accumulation remain unclear. Caenorhabditis elegans has emerged as a powerful animal model for exploring the molecular mechanism of fat metabolism and obesity [11,12,13]. The possible involvement of worm cathepsinlike protein in fat storage in C. elegans remains untested

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Conclusion