Children with autism often exhibit abnormalities in body weight,but the underlying mechanism remains unclear.SH3 and multiple ankyrin repeat domains protein 3(SHANK3),a scaffold protein of the postsynaptic density,has...Children with autism often exhibit abnormalities in body weight,but the underlying mechanism remains unclear.SH3 and multiple ankyrin repeat domains protein 3(SHANK3),a scaffold protein of the postsynaptic density,has been reported to be associated with autism.This study aimed to investigate whether and how SHANK3 influences body weight in the hypothalamic neuronal regulation of energy homeostasis.Adeno-associated viruses 9(AAV9)carrying CMV-Cre and Agrp-Cre were stereotactically injected to restore SHANK3 expression in the arcuate nucleus(ARC)and agouti-related peptide(AgRP)neurons,respectively.Agrp-Cre mice were injected with AAV9-p38αflox/flox to overexpress p38α.Activated p38αwas generated by mutating both D176A and F327S in p38α.Inactivated p38αwas constructed by mutating both T180A and Y182F in p38α.Metabolic analysis,immunoblotting,histological analysis,the glucose tolerance test,the insulin tolerance test,and body fat mass analysis were applied to investigate the underlying mechanisms by which SHANK3 regulates body weight.We reveal that SHANK3 regulates body weight via the p38αsignaling pathway in the AgRP neurons of the hypothalamus.Shank3 knockout(Shank3−/−)mice exhibit resistance to diet-induced obesity.Shank3 re-expression in the ARC or AgRP neurons increases body weight in Shank3 knock-in mice with an inverted allele(SKO).Overexpression or activation of p38αin AgRP neurons elicits resistance to diet-induced obesity.Inactivated p38αin AgRP neurons abolished the resistance to diet-induced obesity due to SHANK3 deficiency.Our findings suggest that the SHANK3-p38αsiganling pathway in AgRP neurons regulates body weight balance in autism,revealing a promising therapeutic target for obesity in children with autism.展开更多
基金supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project(2023ZD0506800).
文摘Children with autism often exhibit abnormalities in body weight,but the underlying mechanism remains unclear.SH3 and multiple ankyrin repeat domains protein 3(SHANK3),a scaffold protein of the postsynaptic density,has been reported to be associated with autism.This study aimed to investigate whether and how SHANK3 influences body weight in the hypothalamic neuronal regulation of energy homeostasis.Adeno-associated viruses 9(AAV9)carrying CMV-Cre and Agrp-Cre were stereotactically injected to restore SHANK3 expression in the arcuate nucleus(ARC)and agouti-related peptide(AgRP)neurons,respectively.Agrp-Cre mice were injected with AAV9-p38αflox/flox to overexpress p38α.Activated p38αwas generated by mutating both D176A and F327S in p38α.Inactivated p38αwas constructed by mutating both T180A and Y182F in p38α.Metabolic analysis,immunoblotting,histological analysis,the glucose tolerance test,the insulin tolerance test,and body fat mass analysis were applied to investigate the underlying mechanisms by which SHANK3 regulates body weight.We reveal that SHANK3 regulates body weight via the p38αsignaling pathway in the AgRP neurons of the hypothalamus.Shank3 knockout(Shank3−/−)mice exhibit resistance to diet-induced obesity.Shank3 re-expression in the ARC or AgRP neurons increases body weight in Shank3 knock-in mice with an inverted allele(SKO).Overexpression or activation of p38αin AgRP neurons elicits resistance to diet-induced obesity.Inactivated p38αin AgRP neurons abolished the resistance to diet-induced obesity due to SHANK3 deficiency.Our findings suggest that the SHANK3-p38αsiganling pathway in AgRP neurons regulates body weight balance in autism,revealing a promising therapeutic target for obesity in children with autism.
