Smith–Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling

Loss of RAI1 causes Smith-Magenis syndrome (SMS) and as of now, no drugs have been developed to improve neurometabolic phenotypes in SMS mouse models. In this work, the Huang lab studied the molecular pathways caused by RAI1 loss and found reduced BDNF protein and its downstream signaling in the hypothalamus of SMS mice. Interestingly, selective deletion of RAI1 from the BDNF-secreting hypothalamic neurons recapitulated neurometabolic features of SMS and enhancing BDNF downstream signaling partially corrected obesity and glucose homeostasis deficits in SMS mice. This is the first work describing a pharmacological therapy in SMS mice, paving the way for future therapies.