Role of hypothalamic SH2B1 neurocircuits and SH2B1 signal transduction pathways in obesity and metabolic disease - Abstract (Description) SH2B1 is an adaptor protein that mediates signal transduction in response to a range of ligands, including brain-derived neurotrophic factor (BDNF). SH2B1 defends against energy imbalance and obesity in both humans and mice. We reported that systemic deletion of Sh2b1 results in obesity and type 2 diabetes in mice. Neuron-specific restoration of SH2B1 completely rescues the obesity phenotype in Sh2b1-null mice. We attempted to identify SH2B1-expressing neurons that control body weight and metabolism. The paraventricular hypothalamus (PVH) has long been recognized as a key brain center to control energy balance, body weight, and metabolism. In the preliminary study, we found that PVH neuron-specific deletion of Sh2b1 causes obesity and metabolic disorders. We observed that a subset of SH2B1 neurons in the PVH (PVHSH2B1) project to the dorsal raphe nucleus (DRN). The DRN emerges as an important hub of the energy balance neural network. The DRN houses serotonergic (DRN5-HT), glutamatergic (DRNVglut3), and GABAergic (DRNVgat) neurons. DRN5- HT and DRNVglut3 neurons suppresses appetite and food intake, whereas DRNVgat neurons have the opposite effects. However, upstream neurons, which shape the metabolic function of DRN neurons, remain elusive. Remarkably, optogenetic stimulation of PVHSH2B1 fibers in the DRN suppressed food intake. Deletion of Sh2b1 in DRN-projecting PVHSH2B1 neurons also resulted in obesity. These results define a novel PVHSH2B1→DRN energy balance circuit. At the molecular level, SH2B1 binds to BDNF receptor TrkB and enhances BDNF/TrkB signaling. We observed that ablation of SH2B1 in PVHSH2B1 neurons induced BDNF resistance in the PVH. We also observed that high fat diet (HFD) feeding substantially increases Ser phosphorylation of SH2B1 (pSer157) in the hypothalamus. These results raise the possibility that Ser phosphorylation may impair the ability of SH2B1 to safeguard the PVHSH2B1→DRN circuit. Based on these findings, we hypothesize that PVHSH2B1 neurons send monosynaptic outputs to DRN5-HT, DRNVglut3, and/or DRNVgat neurons to shape their activation. DRN5-HT, DRNVglut3, and/or DRNVgat neurons act downstream to mediate SH2B1 protection against energy imbalance and obesity. The BDNF/TrkB/SH2B1 pathway cell-autonomously and critically regulates the ability of PVHSH2B1 neurons to control the behavior of DRN5-HT, DRNVglut3, and/or DRNVgat neurons. Obesogenic factors impair the PVHSH2B1→DRN energy balance circuit by stimulating, at least in part, Ser phosphorylation of SH2B1 in PVHSH2B1 neurons. We will test the hypothesis in three aims. Aim 1 will determine whether PVHSH2B1→DRN5-HT, DRNVglut3, and/or DRNVgat circuits mediate SH2B1 protection against obesity. Aim 2 will determine whether PVHSH2B1 neuron-intrinsic SH2B1 safeguards, via the BNDF/TrkB/SH2B1 pathway, PVHSH2B1→DRN circuit functions. Aim 3 will determine whether SH2B1 Ser phosphorylation and human obesity associated SH2B1 variants in PVHSH2B1 neurons promote obesity.
