Study On The Combined Administration Of Gold Nanoclusters To Inhibit Olanzapine-induced Obesity

Olanzapine(OLZ)is the most widely used antipsychotics(APs),and it is also one of the most obese APs in clinic.However,the mechanism by which OLZ induces obesity is complex,and there is lack of clinically relevant effective therapeutic drugs.Studies have shown that the hypothalamic(HYP)histamine H1 receptor(H1R)-adenine monophosphate activated protein kinase(AMPK)signaling disorder and decreased brown adipose tissue(BAT)thermogenesis play an important role in obesity development during chronic OLZ treatment.Recently,gold nanoparticles(AuNPs)have attracted great attention in nanomedicine due to their good bioactivity and biocompatibility.Studies have shown that AuNPs could significantly inhibit obesity development.The present study explored the inhibitory effect and underlying mechanisms of the ultra-small AuNPs developed by our group,namely gold nanoclusters(AuNCs),on OLZ-induced weight gain.The research contents were as follows:(1)The effects of co-treatment of OLZ(50 μM)and AuNCs(10 and 20 mg/L)on the H1R-AMPK signaling in SH-SY5 Y cells were investigated by immunofluorescence stanning.The results showed that OLZ significantly increased H1 R and phosphorylated AMPK(p AMPK)fluorescence intensity after both 2 h and 24 h treatment.Co-treatment with AuNCs significantly suppressed the OLZ-induced increase in H1 R and p AMPK fluorescence intensity,indicating that AuNCs could significantly inhibit the disorder of H1R-AMPK signaling induced by OLZ treatment in SH-SY5 Y cells.(2)An OLZ-induced obese rat model was established to explore the effects of OLZ(3 mg/kg)and AuNCs(10 and 20 mg/kg)co-treatment on food intake and weight gain.The results showed that OLZ treatment significantly induced hyperphagia and weight gain and increased mesenteric fat accumulation.These effects were largely inhibited by co-treatment of AuNCs in a dose-dependent manner.The effect of cotreatment of OLZ and AuNCs on blood glucose was detected by a glucose tolerance test.Results showed that AuNCs co-treatment reduced the increase in blood glucose caused by OLZ,indicating that AuNCs could inhibit the hyperglycemia caused by OLZ.(3)The potential mechanism of AuNCs in reducing OLZ-induced weight gain was investigated by western blot,immunofluorescence,and immunohistochemistry.The study showed that OLZ significantly increased the expression of H1 R while reducing the expression of p AMPK and proopiomelanocortin(POMC)in the rat HYP,indicating that OLZ administration caused disorder of H1R-AMPK signaling pathway and POMC signaling in the HYP.Co-treatment of AuNCs significantly inhibited the increase in H1 R expression,and reversed the decrease in p AMPK and POMC expression induced by OLZ treatment.Further studies found that OLZ administration significantly inhibited the expression of uncoupling protein-1(UCP1)-peroxisome proliferatoractivated receptor-γ coactivator-1α(PGC-1α)signaling in BAT,indicating that OLZ might evidentially reduce the BAT thermogenesis.AuNCs co-treatment significantly reversed the inhibitory effect of OLZ on UCP-1 and PGC1-α expression.The above results indicated that AuNCs could inhibit OLZ-induced weight gain by inhibiting the disorder of H1R-AMPK signaling and increasing POMC expression in the HYP,while increasing BAT thermogenesis.(4)The short-term,mid-term and long-term toxic effects of AuNCs were studied by hematoxylin-eosin staining and serum biochemical analysis in mice.The results showed that 20,40 and 100 mg/kg AuNCs administration for 7 days did not affect the liver and kidney function of mice.Moreover,the histopathological studies showed the main organs of mice did not show any abnormality.After 28 days’ administration of160 mg/kg AuNCs and 180 days’ treatment of AuNCs at a therapeutic dose(20 mg/kg),no abnormality was also found in the major organs of mice.The above results indicated that AuNCs had good biosafety.In conclusion,AuNCs could inhibit OLZ-induced weight gain partly by regulating H1R-AMPK signaling and POMC expression in the HYP,and mediating BAT thermogenesis.Combined with the good biosafety of AuNCs,this study provides a potential drug candidate for OLZ-induced obesity.