Oleanolic acid inhibits appetite through the TGR5/cAMP signaling pathway

Area of Science:

• Endocrinology
• Neuroscience
• Pharmacology

Background:

• Obesity is a growing health concern, and appetite inhibition is a key strategy for management.
• Bile acids are known to suppress appetite via Takeda G protein-coupled receptor 5 (TGR5), but the role of its downstream signaling molecule, cyclic adenosine monophosphate (cAMP), is not fully understood.
• Oleanolic acid (OA), a plant-derived compound, mimics bile acids and presents a potential therapeutic avenue.

Purpose of the Study:

• To investigate the effect of dietary Oleanolic acid (OA) supplementation on appetite regulation.
• To elucidate the role of the TGR5/cAMP signaling pathway in OA-mediated appetite suppression.
• To explore OA's impact on hypothalamic appetite-regulating factors.

Main Methods:

• Mice were fed diets supplemented with OA (50mg/kg, 100mg/kg) or tauroursodeoxycholic acid (TUDCA, 30mg/kg) alongside a basal diet.
• Hypothalamic gene expression of appetite-stimulating and -suppressing factors was analyzed.
• TGR5 activation and cAMP signaling were assessed in N38 cells treated with OA.
• Agouti-related peptide (AgRP) expression and secretion were measured following OA treatment and TGR5/cAMP inhibition.

Main Results:

• Both OA and TUDCA supplementation significantly suppressed appetite in mice.
• OA and TUDCA altered hypothalamic gene expression, downregulating appetite stimulants and upregulating appetite suppressors.
• OA activated TGR5 signaling in the hypothalamus.
• OA reduced Agouti-related peptide (AgRP) expression and secretion, an effect diminished by TGR5 and cAMP inhibition.

Conclusions:

• Dietary Oleanolic acid (OA) effectively suppresses appetite.
• OA exerts its appetite-suppressing effects through the activation of the TGR5/cAMP signaling pathway in the hypothalamus.
• OA may represent a novel therapeutic agent for obesity by modulating hypothalamic appetite control mechanisms.