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SH2B1(previously named SH2-B), a cytoplasmic adaptor protein, binds via its Srchomology 2 (SH2) domain to a variety of protein tyrosine kinases, includingJAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic.Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma,and/or delta) were expressed in numerous tissues, including the brain,hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1betawas specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg))mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice togenerate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not inother tissues. Systemic deletion of the SH2B1 gene resulted in metabolicdisorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance,hyperphagia, obesity, hyperglycemia, insulin resistance, and glucoseintolerance. Neuron-specific restoration of SH2B1beta not only corrected themetabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptinsignaling and leptin regulation of orexigenic neuropeptide expression in thehypothalamus. Moreover, neuron-specific overexpression of SH2B1dose-dependently protected against high-fat diet-induced leptin resistance andobesity. These observations suggest that neuronal SH2B1 regulates energybalance, body weight, peripheral insulin sensitivity, and glucose homeostasisat least in part by enhancing hypothalamic leptin sensitivity.Leggil'articolo: full text disponibile!