Critical Role of the Src Homology 2 (SH2) Domain of Neuronal SH2B1 in the Regulation of Body Weight and Glucose Homeostasis in Mice

• Published in: Endocrinology (Philadelphia) 2010-08, Vol.151 (8), p.3643-3651
• Main Authors: Morris, David L, Cho, Kae Won, Rui, Liangyou
• Format: Article
• Language: English
• Subjects: Adaptor proteins; Adaptor Proteins, Signal Transducing - chemistry; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adaptor Proteins, Signal Transducing - physiology; Amino acids; Animals; Body weight; Body Weight - genetics; Central nervous system; Central Nervous System - metabolism; Chromosome deletion; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - genetics; Energy metabolism; Energy Metabolism - genetics; Gene deletion; Genetic Predisposition to Disease; Glucose; Glucose - metabolism; Glucose tolerance; Homeostasis; Homeostasis - genetics; Homeostasis - physiology; Homology; Hyperphagia; Insulin; Insulin resistance; Janus kinase; Janus kinase 2; Kinases; Leptin; Loci; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation - physiology; Neurogenesis; Neurons - metabolism; Nucleotides; Obesity; Obesity - genetics; Organ Specificity - genetics; Protein Isoforms - genetics; Protein turnover; Single-nucleotide polymorphism; src Homology Domains - genetics; src Homology Domains - physiology; Transgenic mice
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-0254

SH2B1 is an SH2 domain-containing adaptor protein that plays a key role in the regulation of energy and glucose metabolism in both rodents and humans. Genetic deletion of SH2B1 in mice results in obesity and type 2 diabetes. Single-nucleotide polymorphisms in the SH2B1 loci and chromosomal deletions of the SH2B1 loci associate with obesity and insulin resistance in humans. In cultured cells, SH2B1 promotes leptin and insulin signaling by binding via its SH2 domain to phosphorylated tyrosines in Janus kinase 2 and the insulin receptor, respectively. Here we generated three lines of mice to analyze the role of the SH2 domain of SH2B1 in the central nervous system. Transgenic mice expressing wild-type, SH2 domain-defective (R555E), or SH2 domain-alone (ΔN503) forms of SH2B1 specifically in neurons were crossed with SH2B1 knockout mice to generate KO/SH2B1, KO/R555E, or KO/ΔN503 compound mutant mice. R555E had a replacement of Arg555 with Glu within the SH2 domain. ΔN503 contained an intact SH2 domain but lacked amino acids 1-503. Neuron-specific expression of recombinant SH2B1, but not R555E or ΔN503, corrected hyperphagia, obesity, glucose intolerance, and insulin resistance in SH2B1 null mice. Neuron-specific expression of R555E in wild-type mice promoted obesity and insulin resistance. These results indicate that in addition to the SH2 domain, N-terminal regions of neuronal SH2B1 are also required for the maintenance of normal body weight and glucose metabolism. Additionally, mutations in the SH2 domain of SH2B1 may increase the susceptibility to obesity and type 2 diabetes in a dominant-negative manner. The SH2 domain of SH2B1 is required but not sufficient for the regulation of body weight, insulin sensitivity, and glucose metabolism.