Perinatal leptin effects on hypothalamic brain-derived neurotrophic factor and energy balance-related gene regulation

Brain-derived neurotrophic factor (BDNF) and leptin are essential in neurodevelopment and central regulation of feeding and energy balance. We studied the metabolic imprinting effects of physiological leptin supplementation during suckling in the brain of 5-week-old mouse pups. Leptin-treated animals showed lower cumulative food intake and increased energy efficiency, which was related to higher lean mass. Among different brain areas, hypothalamic expression of Bdnf and upstream transcription control-related genes, such as Ppargc1a and Fndc5, was increased by leptin supplementation, especially in females. This was accompanied by higher expression of energy balance key genes (such as Prkaa2 and Cpt1c) and insulin/leptin signalling pathways, primarily in females, also with lower levels of total/phosphorylated AMPK, ACC or STAT3, mainly in males. In leptin-treated females, the exon IV Bdnf promoter showed increased methylation at a specific CpG site. Leptin supplementation during suckling can sex-dependently imprint hypothalamic gene expression, regulating the Ppargc1a/Fndc5/Bdnf pathway and related genes involved in energy balance, associated with a leaner phenotype, with a higher positive impact in females.