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Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron\u2010specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1\u2010null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1\u2010expressing neurons in the paraventricular hypothalamus (PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    ) and a PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    \u2192dorsal raphe nucleus (DRN) neurocircuit are identified here. PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    neurons causes obesity. In male and female mice, either embryonic\u2010onset or adult\u2010onset deletion of Sh2b1 in PVH neurons causes energy imbalance, obesity, insulin resistance, glucose intolerance, and MASLD. Ablation of Sh2b1 in the DRN\u2010projecting PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    subpopulation also causes energy imbalance, obesity, and metabolic disorders. Conversely, SH2B1 overexpression in either total or DRN\u2010projecting PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    neurons protects against diet\u2010induced obesity. SH2B1 binds to TrkB and enhances brain\u2010derived neurotrophic factor (BDNF) signaling. Ablation of Sh2b1 in PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    neurons induces BDNF resistance in the PVH, contributing to obesity. In conclusion, these results unveil a previously unrecognized PVH\n                    <jats:sup>SH2B1<\/jats:sup>\n                    \u2192DRN neurocircuit through which SH2B1 defends against obesity by enhancing BDNF\/TrkB signaling.\n                  <\/jats:p>","DOI":"10.1002\/advs.202400437","type":"journal-article","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T15:14:41Z","timestamp":1718637281000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus\u2192Dorsal Raphe Nucleus Neurocircuit"],"prefix":"10.1002","volume":"11","author":[{"given":"Yuan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Molecular &amp; Integrative Physiology University of Michigan Medical School  Ann Arbor MI 48109 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