Wu Shanshan, Liang Yixiao, Xu Yang, Ge Yueping, Wang Jing, Wang Lu, Jin Xinchen, Zhan Huidong, Peng Li, Gao Ling, Zhao Jiajun, He Zhao
Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, China.
Key Laboratory of Endocrine Glucose and Lipids Metabolism and Brain Aging, Ministry of Education, Shandong Key Laboratory of Endocrinology and Lipid Metabolism; Shandong Institute of Endocrine and Metabolic Diseases, Shandong Clinical Research Center of Diabetes and Metabolic Diseases, Shandong Prevention and Control Engineering Laboratory of Endocrine and Metabolic Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, China.
Neurosci Bull. 2025 Sep 19. doi: 10.1007/s12264-025-01493-2.
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-p38α to overexpress p38α. Activated p38α was generated by mutating both D176A and F327S in p38α. Inactivated p38α was 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 p38α signaling 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 p38α in AgRP neurons elicits resistance to diet-induced obesity. Inactivated p38α in AgRP neurons abolished the resistance to diet-induced obesity due to SHANK3 deficiency. Our findings suggest that the SHANK3-p38α siganling pathway in AgRP neurons regulates body weight balance in autism, revealing a promising therapeutic target for obesity in children with autism.
自闭症儿童常表现出体重异常，但其潜在机制尚不清楚。突触后致密区支架蛋白SH3和多个锚蛋白重复结构域蛋白3（SHANK3）已被报道与自闭症有关。本研究旨在探讨SHANK3是否以及如何在下丘脑神经元能量稳态调节中影响体重。分别立体定向注射携带CMV-Cre和Agrp-Cre的腺相关病毒9（AAV9），以恢复弓状核（ARC）和刺鼠相关肽（AgRP）神经元中SHANK3的表达。给Agrp-Cre小鼠注射AAV9-p38α以过表达p38α。通过将p38α中的D176A和F327S同时突变产生激活的p38α。通过将p38α中的T180A和Y182F同时突变构建失活的p38α。应用代谢分析、免疫印迹、组织学分析、葡萄糖耐量试验、胰岛素耐量试验和体脂质量分析来研究SHANK3调节体重的潜在机制。我们发现，SHANK3通过下丘脑AgRP神经元中的p38α信号通路调节体重。Shank3基因敲除（Shank3）小鼠对饮食诱导的肥胖具有抗性。在ARC或AgRP神经元中重新表达Shank3可增加具有反向等位基因的Shank3基因敲入小鼠（SKO）体重。在AgRP神经元中过表达或激活p38α可引发对饮食诱导肥胖的抗性。AgRP神经元中失活的p38α消除了由于SHANK3缺乏导致的对饮食诱导肥胖的抗性。我们的研究结果表明，AgRP神经元中的SHANK3-p38α信号通路调节自闭症患者的体重平衡，为自闭症儿童肥胖症揭示了一个有前景的治疗靶点。
