Forebrain neuronal SMC3 regulates body weight and metabolic health partially through regulation of hypothalamic Melanocortin 4 receptor

SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Excitatory conditional neuron-specific SMC3 knockout (cKO) mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus displayed dysregulated neuronal morphology and associated transcriptional abnormalities in RNA-seq analysis across various cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level, a pivotal regulator of appetite and metabolism. Correspondingly, ChIP-seq analysis revealed genome-wide alterations in the binding dynamics of SMC3 of the cKO animals, including Mc4r associated regions. Notably, a significant correlation emerged between multiple sites exhibiting a marked decrease in binding and downregulated genes. The administration of Setmelanotide, an MC4r agonist, to cKO group resulted in a notable reduction in both weight and food consumption in these mice. Therefore, we have identified specific and reversable metabolic parameters that are regulated by neuronal Smc3 in adulthood.