The GLP-1 Analog Liraglutide Reduces Fever Through Sex-Dependent Neuroinflammatory Modulation

Background/Objectives: Thermoregulation is essential for survival, with the hypothalamic preoptic area integrating peripheral signals to maintain core body temperature. While fever enhances immune responses, excessive hyperthermia causes cellular damage. Previous work has shown that central glucagon-like peptide-1 (GLP-1) receptor antagonism intensifies lipopolysaccharide (LPS)-induced fever, suggesting a role for GLP-1 signaling in temperature regulation. However, the direct effects of GLP-1 receptor agonists on fever remained unexplored. This study investigated the effects of liraglutide (LIRA), a GLP-1 analog used to treat diabetes and obesity, on temperature regulation and fever in rats, with a focus on sex-dependent mechanisms. Methods: Male and female Wistar rats received lipopolysaccharide (LPS, i.p.) to induce fever, followed by LIRA treatment (0.3 mg/kg, i.p.) one hour later. Body temperature was monitored for up to six hours post-LPS injection. Results: LIRA reduced body temperature in both euthermic and febrile rats of both sexes. LPS increased PGE₂ concentration in both sexes, with males showing a twofold increase compared to females. LIRA treatment reduced PGE₂ levels in LPS-challenged males (62%, p < 0.01) but not in female rats. LPS elevated interleukin (IL)-6 levels in both sexes, while LIRA treatment decreased IL-6 only in females (45%, p < 0.05). In males, LPS reduced hypothalamic serotonin (5-HT) levels, and LIRA further decreased 5-HT in saline-treated animals. In females, LIRA increased 5-HT levels (84%, p < 0.01) in LPS-challenged animals. Additionally, LIRA exhibited sex-specific effects on hypothalamic JNK phosphorylation, increasing activation in LPS-treated males and reducing it in LPS-treated females. Conclusions: LIRA demonstrates antipyretic properties through distinct, sex-specific mechanisms. In males, temperature reduction correlates with decreased hypothalamic PGE₂, whereas in females, antipyretic effects are associated with reduced IL-6, decreased JNK phosphorylation, and increased 5-HT. These findings reveal sexually dimorphic GLP-1R-mediated thermoregulatory pathways during inflammation. However, the causal relationships between these molecular changes and temperature regulation require further investigation, particularly regarding whether observed biochemical alterations represent primary mechanisms or secondary consequences of temperature modulation. Future studies should investigate the functional significance of the apparent contradiction in serotonergic responses between sexes.