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Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway

Laongdao Thongnak1,2, Nattavadee Pengrattanachot1, Sasivimon Promsan1

  • 1Renal Transporter and Molecular Signaling Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.

Archives of Pharmacal Research
|March 26, 2023
PubMed

Insights

Metformin prevents kidney dysfunction in high-fat diet-induced insulin resistance by activating AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) pathways, offering greater benefits than gemfibrozil.

Area of Science:

  • Metabolic and Renal Physiology
  • Pharmacology and Therapeutics

Background:

  • Long-term high-fat diet (HFD) consumption disrupts insulin signaling and lipid metabolism, leading to insulin resistance, dyslipidemia, and renal dysfunction.
  • This renal dysfunction is linked to the inactivation of key metabolic regulators: AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα).

Purpose of the Study:

  • To investigate the protective effects of metformin against HFD-induced renal dysfunction in insulin-resistant rats.
  • To determine if metformin modulates AMPK-regulated, PPARα-dependent pathways involved in lipid metabolism and kidney protection.

Main Methods:

  • Male Wistar rats were fed an HFD for 16 weeks to induce insulin resistance.
  • Following confirmation of insulin resistance, rats received either metformin (30 mg/kg) or gemfibrozil (50 mg/kg) orally for 8 weeks.
  • Evaluated insulin resistance, dyslipidemia, lipid accumulation, kidney injury markers, lipid oxidation, energy metabolism, and renal transporter expression (Oat3, CD36, SGLT2).

Main Results:

  • HFD-induced insulin resistance, dyslipidemia, lipid accumulation, and kidney injury were observed.
  • Metformin stimulated AMPK/PPARα pathways and suppressed sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling, improving lipid metabolism.
  • Metformin showed superior efficacy over gemfibrozil in reducing renal inflammatory markers, fibrosis, and lipotoxicity via AMPK-regulated SREBP1/FAS signaling. Both drugs improved renal Oat3 function and expression.

Conclusions:

  • Metformin and gemfibrozil mitigate HFD-induced renal injury in obesity via the AMPK/PPARα-dependent pathway.
  • Metformin demonstrates enhanced efficacy in preventing renal lipotoxicity by modulating AMPK-regulated SREBP1/FAS signaling compared to gemfibrozil.
Keywords:
AMPK/PPARαInsulin resistanceMetforminOat3Renal function

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