Sh2b1, also known as SH2-B and PSM, is an intracellular adaptor protein. It is a key regulator in multiple signaling pathways as it contributes to the signal transduction of several receptor tyrosine kinases and Janus kinase 2 (JAK2) [2,5]. SH2B1 enhances leptin and insulin signaling, playing a crucial role in energy balance, body weight regulation, and glucose metabolism [2]. Genetic models, such as gene knockout (KO) mouse models, have been instrumental in understanding its functions.

Global deletion of Sh2b1 in mice leads to severe obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD), indicating its significance in maintaining normal metabolic homeostasis [4]. Neuron-specific Sh2b1 deficiency in an MPTP-induced Parkinson's disease (PD) mouse model exacerbates behavioural defects and increases neuronal apoptosis, while neuron-specific overexpression reverses these effects, suggesting Sh2b1's role in protecting against PD-related neurodegeneration [1]. In addition, selective genetic ablation of Sh2b1 in the mouse hippocampus, especially in inhibitory neurons, impairs working memory and behavioral flexibility, revealing its role in fluid intelligence [3].

In conclusion, Sh2b1 is essential for maintaining energy balance, glucose metabolism, and neuronal function. Studies using Sh2b1 KO mouse models have provided valuable insights into its roles in metabolic diseases like obesity and type 2 diabetes, as well as neurodegenerative diseases such as Parkinson's disease and cognitive function-related aspects. These findings contribute to our understanding of the underlying mechanisms of these diseases and may potentially guide the development of new therapeutic strategies.