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

• Published in: Archives of pharmacal research 2023, 46(5), , pp.408-422
• Main Authors: Thongnak, Laongdao, Pengrattanachot, Nattavadee, Promsan, Sasivimon, Phengpol, Nichakorn, Sutthasupha, Prempree, Jaikumkao, Krit, Lungkaphin, Anusorn
• Format: Article
• Language: English
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; Diet, High-Fat - adverse effects; Gemfibrozil - pharmacology; Gemfibrozil - therapeutic use; Insulin - metabolism; Insulin Resistance; Kidney Diseases - drug therapy; Kidney Diseases - etiology; Kidney Diseases - prevention & control; Male; Medicine; Metformin - pharmacology; Metformin - therapeutic use; Obesity; Pharmacology/Toxicology; Pharmacy; PPAR alpha - metabolism; Rats; Rats, Wistar; Research Article; 약학
• ISSN: 0253-6269; 1976-3786
• DOI: 10.1007/s12272-023-01439-0

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30 mg/kg) or gemfibrozil (50 mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.