ORF51-08 - When Leptin Breaks the Clock: How Central Leptin Signaling Disruption Alters Feeding, Activity and Circadian Rhythms

The Central Nervous System orchestrates complex bioenergetic processes essential for maintaining whole-body homeostasis, acting as a central hub that integrates molecular and hormonal signals between the brain and peripheral tissues. Leptin is a key mediator that links peripheral energy stores to the brain, regulating food intake (FI), adiposity, and fuel mobilization via hypothalamic neural circuits, particularly the arcuate nucleus (ARC). To investigate the mechanisms underlying FI and behavioral alterations associated with hypothalamic leptin signaling deficiency we developed a model of chronic central leptin resistance in lean adult normoleptinemic rats. Three-month-old male Wistar rats were infused intracerebroventricularly with a selective leptin receptor antagonist (SLA, 0.2 µg/day) for 21 days via mini-osmotic pumps. Rats were monitored daily in metabolic cages for indirect calorimetry analysis. SLA-infused rats exhibited a moderate, significant increase in FI, body weight gain, adiposity, and elevated fasting serum glucose and insulin levels compared with PBS-infused controls. Marked reductions in energy expenditure and thermogenic activity were also observed, along with an increased respiratory exchange ratio, indicative of preferential carbohydrate utilization over lipids, suggesting impaired lipid mobilization. Moreover, increased whitening markers was accompanied by decreased browning markers within the interscapular brown adipose tissue in SLA-infused rats. Behaviorally, SLA-infused rats displayed anticipatory feeding during light-to-dark transitions increasing FI during the light phase, and greater feeding responses following 24-hour fasting. These alterations were paralleled by reduced locomotor activity, with movements primarily restricted to feeding and drinking areas, reflecting a sedentary phenotype. The abnormal feeding and behavior patterns in SLA-infused rats lead us to examine targets involved in FI regulation, locomotor activity and circadian system in isolated hypothalamic ARC and suprachiasmatic nuclei (SCN). Hypothalamic neuropeptide Pomc and leptin´s mediator Cpt-1c expression levels in ARC were markedly reduced in SLA-infused rats compared with PBS-infused controls. Interestingly, expression levels of core clock repressor genes (Rev-erb-α, Dpb, Per1, Per2) were notably increased in SCN of SLA-infused rats, together with an increase in protein levels of the circadian clock activator BMAL1 and repressor Per2. Hence, brain leptin signaling deficiency induced by SLA is sufficient to trigger early metabolic disturbances characterized by impaired circadian and satiety signaling. These findings reveal a critical link between central leptin signaling, food reward pathways, and sedentary behavior, underscoring leptin’s central and pivotal role in coordinating energy balance and circadian rhythmicity.