Serotonin, Leptin, and a Novel Neuronal Circuit: Rewiring Central Appetite Regulation As We Know It

Abstract

Background: The adipocyte-derived hormone leptin is a key mediator in homeostatic appetite regulation and satiety via the arcuate nucleus (ARC) of the hypothalamus. Interestingly, serotonin (5-HT) produced in the dorsal raphe nucleus (DRN) modulates anorectic effects of its own in the ARC, yet the underlying mechanism through which 5-HT acts in tandem with leptin remains inconclusive. Our lab has identified leptin-sensitive serotonergic neurons in the DRN that project to the ARC, and has demonstrated that activation of this circuit significantly decreases food intake. Through the unique co-expression of leptin receptors and 5-HT within these neurons, the current study aimed to elucidate the role of 5-HT in leptin’s regulation of food intake between the DRN and ARC. Methods: To examine the role of 5-HT on leptin’s action in the DRN, adult male Sprague Dawley rats underwent stereotaxic surgery for guide cannula implantation in the DRN. After recovery, rats received 100 μg of intra-raphe p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis, each day for four days. On the fourth day, an additional injection of leptin was administered in the DRN (5 μg/rat) and food intake was measured over a 24-hour time course. To examine the role of 5-HT on leptin’s hypothalamic action, a subsequent experiment was conducted by implanting an additional cannula into the ARC for the administration of leptin on the fourth day of treatment. Post-mortem, DRN tissue sections were immunolabeled to confirm 5-HT depletion and visualize leptin-sensitive serotonergic neurons. Results: 24-hour food intake analyses across both experiments revealed only vehicle-treated rats administered leptin exhibited a significant decrease in food intake compared to controls, an effect not observed in PCPA-treated rats. These results suggest depletion of 5-HT within the DRN attenuated leptin’s ability to decrease food intake in both the DRN and ARC. 5-HT immunolabeling confirmed PCPA significantly decreased 5-HT in the DRN of all treated rats and displayed co-localization of 5-HT and phosphorylated-STAT3 (a marker for leptin receptor activation) in DRN neurons. Conclusion: Depleting DRN-derived 5-HT diminishes leptin’s action on hypothalamic and DRN leptin receptors, suggesting 5-HT is a regulator of leptin-mediated food intake control within this novel neuronal circuit.