SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Human genetic studies reveal de novo mutations in SMC3 gene, found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, and behavioral patterns such as self-injury, and metabolic dysregulation. Nonetheless, little is known about the exact role of SMC3 in neuronal maintenance and gene expression especially in adulthood. This study aimed to determine the role of SMC3 in adulthood brain, using in-vivo models of adulthood excitatory neuron Smc3 knockout in male and female mice. Neuron-specific SMC3 knockout mice displayed dysregulated anxiety-like behavior and self-injury in males and females compared to wild-type littermates. Of interest, female knockouts displayed less anxiety while males displayed more anxiety, although both displayed self-injury, a known phenotype in the human condition.In parallel, significant metabolic changes were displayed in both male and female mice, including overweight phenotype, loss of muscle mass, differences at respiratory exchange, heat production and hormonal changes after knockout of SMC3 gene in excitatory neuron cells of adult brain. RNA-seq and Chip-seq in the hypothalamus reveal changes in several peptide pathways and receptors that moderate proper hormonal balance, including melanocortin receptor 4. These findings associate with reports of adultness obesity in a subset of individuals with CdLs.Therefore, we have uncovered epigenetics mechanisms in the brain involved in weight, metabolic health, and anxiety.