Fig. 7

Peripheral cathepsin L inhibition induced fat loss in HFD-fed mice through promoting central serotonin synthesis. a–e Male 6-week-old wild-type mice were fed with HFD for 5 weeks. At 9 weeks old, 30 mg kg⁻¹ of PCPA was injected intracranially into the ventricles; 100 mg kg⁻¹ of CLIK195 was intraperitoneally injected at 9 and 10 weeks old. a Body weight of the mice was measured every 3 days. b White adipose tissue weights were measured at 11 weeks old. c Hematoxylin-eosin staining in the epididymal fat and subcutaneous fat, scale bars 100 μm in length (× 200). d The levels of serotonin in the brain. e Real-time PCR analysis of genes involved in lipolysis and β-oxidation in WAT. β-Actin was used as the reference gene in real-time PCR analysis. f In both C. elegans and mice, peripheral cathepsin L inhibition lowers fat accumulation through promoting central serotonin synthesis. In C. elegans (left), CPL-1 inhibition in the intestine and hypodermis promotes serotonin synthesis in ADF neurons. Thus, a central serotonin signaling, involving octopaminergic SER-6 and serotonin from ADF neurons and serotonergic MOD-1, is activated and hence stimulates lipolysis and β-oxidation in the intestine and hypodermis, which results in fat loss. In HFD-fed mice (right), peripheral cathepsin L inhibition activates lipolysis and β-oxidation and induces fat loss in WAT through promoting central serotonin production. The data in a, b, d, and e are presented as mean ± SEM, n = 10 per group. *p < 0.05; **p < 0.01; ***p < 0.001. n.s. not significant in a nonparametric Mann-Whitney test