Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. Deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1 knockout mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1β not only corrected the metabolic disorders in mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus [46]. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity. Variations close to or in the SH2B1 gene have been found to be associated with obesity in two large genome-wide association studies [47, 48]. SH2B1 deletions are associated with severe early-onset obesity [31]. Genetic differences among people can derive from lost or duplicated segments of chromosomes, called copy number variants (CNV). Variation in gene copy number can influence the activity of genes and accounts for a significant amount of genetic difference between people [49]. A recent
