SH2B1 Defends Against Energy Imbalance, Obesity, and Metabolic Disease via a Paraventricular Hypothalamus→Dorsal Raphe Nucleus Neurocircuit.

ABSTRACT: SH2B1 mutations are associated with obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD) in humans. Global deletion of Sh2b1 results in severe obesity, type 2 diabetes, and MASLD in mice. Neuron-specific restoration of SH2B1 rescues the obesity phenotype of Sh2b1-null mice, indicating that the brain is a main SH2B1 target. However, SH2B1 neurocircuits remain elusive. SH2B1-expressing neurons in the paraventricular hypothalamus (PVH^SH2B1) and a PVH^SH2B1→dorsal raphe nucleus (DRN) neurocircuit are identified here. PVH^SH2B1 axons monosynaptically innervate DRN neurons. Optogenetic stimulation of PVH^SH2B1 axonal fibers in the DRN suppresses food intake. Chronic inhibition of PVH^SH2B1 neurons causes

SUBMITTER: Li Y 

PROVIDER: S-EPMC11336965 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature