Pyridylnidulin exerts anti-diabetic properties and improves non-alcoholic fatty liver disease in diet-induced obesity mice

Sutharinee Likitnukul; Surapun Tepaarmorndech; Theerayuth Kaewamatawong; Arunrat Yangchum; Chanathip Duangtha; Pimrapat Jongjang; Supachoke Mangmool; Darawan Pinthong; Masahiko Isaka

doi:10.3389/fmolb.2023.1208215

Pyridylnidulin exerts anti-diabetic properties and improves non-alcoholic fatty liver disease in diet-induced obesity mice

Front Mol Biosci. 2023 Jun 22:10:1208215. doi: 10.3389/fmolb.2023.1208215. eCollection 2023.

Authors

Sutharinee Likitnukul¹, Surapun Tepaarmorndech², Theerayuth Kaewamatawong³, Arunrat Yangchum⁴, Chanathip Duangtha¹, Pimrapat Jongjang¹, Supachoke Mangmool¹, Darawan Pinthong¹, Masahiko Isaka⁴

Affiliations

¹ Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
² Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
³ Department of Pathology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand.
⁴ National Center for Genetic Engineering and Biotechnology (BIOTEC), National Science and Technology Development Agency (NSTDA), Pathumthani, Thailand.

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the metabolic disorders related to the pathophysiology of type 2 diabetes mellitus (T2DM). Therapeutic strategies are focused on the improvement of energy balance and lifestyle modification. Additionally, the derivative of the bioactive fungal metabolite is of interest to provide health benefits, especially in obese and pre-diabetic conditions. In our screening of anti-diabetic compounds from fungal metabolites and semisynthetic derivatives, a depsidone derivative, namely pyridylnidulin (PN), showed potent glucose uptake-inducing activity. The present study aimed to investigate the liver lipid metabolism and anti-diabetic properties of PN in diet-induced obesity mice. Methods: Male C57BL/6 mice were induced obesity and pre-diabetic conditions by dietary intervention with a high-fat diet (HFD) for 6 weeks. These obese mice were orally administered with PN (40 or 120 mg/kg), metformin (150 mg/kg), or vehicle for 4 weeks. Glucose tolerance, plasma adipocytokines, hepatic gene and protein expressions were assessed after treatment. Results: Improved glucose tolerance and reduced fasting blood glucose levels were found in the PN and metformin-treated mice. Additionally, hepatic triglyceride levels were consistent with the histopathological steatosis score regarding hepatocellular hypertrophy in the PN and metformin groups. The levels of plasma adipocytokines such as tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) were reduced in the PN (120 mg/kg) and metformin-treated mice. In addition, hepatic gene expression involved in lipid metabolism, including lipogenic enzymes was significantly reduced in the PN (120 mg/kg) and metformin-treated mice. The increased protein expression levels of phosphorylated AMP-activated protein kinase (p-AMPK) was also found in PN and metformin-treated mice. Discussion: Considering the increased p-AMPK protein expression levels in PN and metformin-treated mice were revealed as the underlying mechanisms to improve metabolic parameters. These results suggested that PN provided the health benefit to slow the progression of NAFLD and T2DM in obese and pre-diabetic conditions.

Keywords: anti-diabetic; diabetes; metabolic disorders; non-alcoholic fatty liver disease; obesity; pyridylnidulin.