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

Area of Science:

• Neuroendocrinology
• Thermoregulation
• Pharmacology

Background:

• Thermoregulation is vital for survival, with the hypothalamus regulating core body temperature.
• Fever, while beneficial for immunity, can cause cellular damage if excessive.
• Glucagon-like peptide-1 (GLP-1) signaling influences temperature regulation, but GLP-1 receptor agonist effects on fever are unknown.

Purpose of the Study:

• To investigate the antipyretic effects of liraglutide (LIRA), a GLP-1 analog, on fever in rats.
• To explore the sex-dependent mechanisms underlying LIRA's effects on temperature regulation during inflammation.

Main Methods:

• Male and female Wistar rats were injected with lipopolysaccharide (LPS) to induce fever.
• Liraglutide (LIRA) was administered one hour post-LPS.
• Body temperature, prostaglandin E2 (PGE2), interleukin-6 (IL-6), serotonin (5-HT), and JNK phosphorylation were measured.

Main Results:

• LIRA reduced body temperature in both sexes under normal and febrile conditions.
• LPS increased PGE2 and IL-6 levels; LIRA reduced PGE2 in males and IL-6 in females.
• Sex-specific changes in hypothalamic 5-HT and JNK phosphorylation were observed following LIRA treatment.

Conclusions:

• Liraglutide (LIRA) exhibits antipyretic properties through distinct, sex-specific mechanisms.
• Male rats showed reduced PGE2, while females exhibited reduced IL-6, increased 5-HT, and decreased JNK phosphorylation.
• These findings highlight sexually dimorphic GLP-1 receptor-mediated thermoregulatory pathways during inflammation.