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Citronellal Alleviates Insulin Resistance in High-Fat Diet/Streptozocin Model: Role of Asprosin/Olfactory Receptor

Aya Abdelaziz1, Yousra M El-Far1, Noha Abdel-Rahman1

  • 1Biochemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Molecular Nutrition & Food Research
|January 17, 2025
PubMed

Insights

Citronellal treatment improved insulin resistance and Type II diabetes in rats by blocking Asprosin/OR4M1 signaling. This suggests potential for citronellal as an antidiabetic agent targeting olfactory receptor 4M1 (OR4M1).

Area of Science:

  • Endocrinology
  • Pharmacology
  • Molecular Biology

Background:

  • Ectopic olfactory receptors (ORs) in non-olfactory tissues regulate physiological processes like glucose homeostasis.
  • Insulin resistance and Type II diabetes necessitate novel therapeutic targets and antidiabetic agents.

Purpose of the Study:

  • To investigate the anti-diabetic effects of citronellal by modulating olfactory receptor 4M1 (OR4M1) signaling in a rat model.
  • To validate citronellal's therapeutic potential through Asprosin/OR4M1 pathway interaction.

Main Methods:

  • Established a Type II diabetes model in Sprague-Dawley rats using a high-fat diet and streptozotocin (STZ).
  • Administered oral citronellal (100 mg/kg) for 4 weeks and assessed metabolic parameters.
  • Utilized molecular docking to analyze citronellal's interaction with Asprosin and OR4M1.
  • Quantified hepatic gene and protein expression, including OR4M1, Asprosin, TLR-4, JNK, NF-κB, and downstream signaling molecules.

Main Results:

  • Citronellal significantly lowered serum glucose, triglycerides, and improved oral glucose tolerance test (OGTT) and HOMA-IR.
  • Molecular docking indicated citronellal blocks Asprosin binding to OR4M1, reducing hepatic OR4M1 and Asprosin expression.
  • Citronellal decreased cAMP levels, attenuated protein kinase A, and inhibited gluconeogenic enzymes (G6Pase, PEPCK).
  • Citronellal inhibited hepatic TLR-4 expression, JNK phosphorylation, and downstream inflammatory markers (NF-κB, MCP-1, TNF-α).

Conclusions:

  • Citronellal effectively alleviates insulin resistance and Type II diabetes in rats.
  • The anti-diabetic mechanism involves the mitigation of Asprosin/OR4M1 and Asprosin/TLR4/JNK signaling pathways.
  • Citronellal demonstrates potential as a novel therapeutic agent for diabetes management.
Keywords:
G6PaseOR4M1PEPCKPKAinsulin resistance

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