Endocrine and neural mechanisms in metabolic control

Abstract

The regulation of eating behavior and metabolism is governed by complex inter-actions between central and peripheral signals, with hormones such as oxytocin (OT) and glucagon-like peptide-1 (GLP-1) playing pivotal roles. Both OT and GLP-1 are known for their involvement in appetite control, energy homeostasis, and motivated behavior, yet their mechanisms of action across different tissues and the potential sex differences in these processes remain incompletely under-stood. This thesis investigates these hormonal pathways, focusing on the distinct contributions of peripheral and central OT signaling and the effects of GLP-1 neurons activation at the level of Nucleus of the Solitary Tract (NTS). Through a series of studies using rodent models, we explore the impact of OT and GLP-1 on eating behavior, metabolic regulation, and related physiological processes, providing new insights into their therapeutic potential for addressing obesity and metabolic disorders. In Paper I, we investigated the effects of peripherally restricted OT, demonstrat-ing that activation of peripheral oxytocin receptors (OTR) is sufficient to sup-press food intake and food-motivated behaviors in both male and female rats, without triggering the adverse centrally mediated effects, such as locomotor sup-pression and conditioned taste avoidance, typically associated with OT that crosses the blood-brain barrier. These findings suggest that targeting peripheral OT pathways could offer a viable approach for appetite regulation with fewer side effects. In Paper II, we examined the role of vagal OTR in regulating eating behavior and upper gastrointestinal tract function. Using a virogenetic approach to reduce OTR expression in the vagus nerve, this study reveals that vagal OTR are essential for normal esophageal motility and proper swallowing function. Disruption of these receptors leads to impaired esophageal peristalsis, increasing the risk of aspiration and mortality, particularly in male rats. These findings un-derscore a previously unrecognized role of peripheral OT signaling in maintain-ing vital gastrointestinal functions. In Paper III, we identified the adrenal gland as a previously overlooked source of peripheral OT, released in response to food consumption. This discovery is significant, as it establishes the adrenal gland as a key peripheral contributor to circulating OT levels post-meal. Bilateral adren-alectomy abolishes this meal-induced OT release, further confirming the adrenal gland’s critical role in this regulatory process. This expands the understanding of OT’s peripheral actions beyond its traditional functions in reproduction. In Pa-per IV, we focused on the effects of activating GLP-1-producing neurons in the hindbrain concerning eating behavior and motivation. While activation of these neurons consistently reduces food intake across sexes, a notable sex divergence is observed in food-motivated behavior, with only females exhibiting a signifi-cant reduction in their drive for sucrose rewards. These findings suggest that GLP-1 signaling may differentially influence reward pathways in males and fe-males, offering important insights into sex-specific mechanisms in the regulation of eating behavior. Overall, this thesis advances the understanding of peripheral and central neuro-endocrine mechanisms in the regulation of eating and metabolism, with a special focus on sex differences. The findings highlight the therapeutic potential of tar-geting peripheral pathways, such as OT receptors, to modulate eating behavior while minimizing central side effects. Additionally, the sex-divergent responses to GLP-1 neuron activation provide a foundation for the development of sex-specific interventions for metabolic disorders, ultimately contributing to more tailored and effective treatment strategies.