Forebrain neuronal Smc3 regulates weight and metabolic parameters partly through regulation of hypothalamic Melanocortin 4 receptor

SMC3 is a major component of 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 especially in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Neuron-specific SMC3 knockout 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 of these mice displayed dysregulated morphology and RNA-seq in the hypothalamus reveals dysregulation in multiple cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level , a main regulator of appetite. Treatment of these mice with Setmelanotide, a MC4r agonist, induced a decrease of weight and food consumption in these mice. Therefore, we have identified specific metabolic pathways that are regulated by Smc3 in forebrain neurons, and specific mechanisms that are involved. To understand the function of SMC3 in the adulthood brain, we established a neuron-specific knockout of Smc3 specifically in adulthood in mice. Mice with floxed Smc3 and Camk2a-cre/ERT2+ (Cre+) or Camk2a-cre/ERT2- (Cre-). Mice with Cre+ named as cKO due the lack of Smc3 gene after tamoxifen treatment; mice with Cre- served as WT.