Obesity: Exploring the Role of Locus Coeruleus GLP-1 Receptors in Food Intake, Nausea-like Behavior, and Autonomic Physiological Responses

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[...] Obesity: Exploring the Role of Locus Coeruleus GLP-1 Receptors in Food Intake, Nausea-like Behavior, and Autonomic Physiological Responses Introduction Obesity has become a global health epidemic, affected people of all ages and contributed to numerous chronic diseases and health complications. Despite the widespread awareness and efforts to combat this issue, effective and well-tolerated anti-obesity drugs remain scarce (Trapp & Brierley, 2022). One promising avenue for developing new pharmacological interventions involves targeting the glucagon-like peptide-1 (GLP-1) system, which regulates food intake, energy balance, and glucose homeostasis. [...]

[...] This research has not only advanced our understanding of the intricate interplay between the GLP-1 system, food intake regulation, and autonomic functions but also paved the way for future explorations into the potential therapeutic applications of GLP-1R modulation in diverse neurological and psychiatric disorders, including Alzheimer's disease, Parkinson's disease, substance abuse disorders, and mood disorders. The insights gained from this study represent a significant stride toward developing more effective and well-tolerated anti-obesity treatments while simultaneously opening doors to novel therapeutic avenues in various clinical settings. [...]

[...] The findings revealed that activation of GLP-1Rs in the LC modulates autonomic physiological responses, such as heart rate, body temperature, and gastric emptying. This indicates the LC's role as a critical central nervous system nucleus mediating the autonomic effects of GLP-1R signaling. Furthermore, the research provided electrophysiological and molecular evidence suggesting that GLP-1Rs in the LC are localized presynaptically on glutamatergic terminals, enhancing glutamate release onto norepinephrine neurons and modulating their activity. These insights pave the way for developing more selective and better-tolerated GLP-1R agonists for treating obesity and related metabolic disorders. [...]

[...] Various compounds, such as the GLP-1 receptor agonist exendin-4 the GLP-1 receptor antagonist exendin-9 the nausea-inducing agent lithium chloride (LiCl), and the GLP-1 analogue semaglutide, were administered directly into the LC or systemically. This enabled the researchers to assess their effects on food intake, body weight, kaolin intake (as a measure of nausea/malaise), and autonomic responses like heart rate, body temperature, and gastric emptying. To gain insights into feeding patterns, the researchers employed the BioDAQ system to continuously monitor food intake, allowing them to analyze meal size, frequency, and overall feeding behavior. [...]

[...] Molecular techniques, such as fluorescence in situ hybridization (FISH), were employed to investigate the expression of GLP-1 receptor (Glp1r), NMDA receptor (Grin1A), and AMPA receptor (GluA1) mRNA transcripts within dopamine beta-hydroxylase (DBH)-expressing LC NE neurons. Immunohistochemistry methods, specifically c-Fos immunohistochemistry, were used to examine the activation of LC NE neurons following peripheral administration of semaglutide. Lastly, biochemical assays, including enzyme-linked immunosorbent assays (ELISAs), were employed to measure plasma corticosterone levels (as a measure of stress response) and plasma acetaminophen levels (as an indicator of gastric emptying rate). [...]