SHANK3 Deficiency in AgRP Neurons Inhibits Diet-Induced Obesity by Activating p38α

Area of Science:

• Neuroscience
• Metabolic Research
• Autism Spectrum Disorder Research

Background:

• Children with autism often experience body weight abnormalities, with unclear underlying mechanisms.
• SHANK3, a postsynaptic scaffold protein linked to autism, is investigated for its role in energy homeostasis.

Purpose of the Study:

• To investigate how SHANK3 influences body weight through hypothalamic neuronal regulation.
• To explore the involvement of the p38α signaling pathway in SHANK3-mediated body weight control.

Main Methods:

• Utilized adeno-associated viruses (AAV9) to manipulate SHANK3 and p38α expression in specific hypothalamic neurons (ARC, AgRP).
• Employed metabolic analysis, immunoblotting, histological analysis, glucose and insulin tolerance tests, and body fat mass analysis.
• Generated activated and inactivated p38α variants for mechanistic studies.

Main Results:

• SHANK3 deficiency (Shank3 knockout) conferred resistance to diet-induced obesity.
• Re-expressing SHANK3 in the arcuate nucleus (ARC) or AgRP neurons increased body weight in knockout mice.
• Overexpression or activation of p38α in AgRP neurons mimicked obesity resistance, while inactivation abolished it.

Conclusions:

• SHANK3 regulates body weight via the p38α signaling pathway in hypothalamic AgRP neurons.
• This SHANK3-p38α pathway in AgRP neurons is crucial for body weight balance in the context of autism.
• Findings suggest a potential therapeutic target for obesity in children with autism.