Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice

• Published in: World journal of gastroenterology : WJG 2022-05, Vol.28 (17), p.1814-1829
• Main Authors: Silva-Veiga, Flavia Maria, Miranda, Carolline Santos, Vasques-Monteiro, Isabela Macedo Lopes, Souza-Tavares, Henrique, Martins, Fabiane Ferreira, Daleprane, Julio Beltrame, Souza-Mello, Vanessa
• Format: Article
• Language: English
• Subjects: Animals; Basic Study; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dysbiosis - drug therapy; Dysbiosis - metabolism; Endotoxemia - complications; Endotoxemia - drug therapy; Linagliptin - pharmacology; Linagliptin - therapeutic use; Lipid Metabolism - drug effects; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease - metabolism; Obesity - complications; Obesity - drug therapy; Obesity - metabolism; Phylogeny; PPAR alpha - agonists; PPAR alpha - metabolism
• ISSN: 1007-9327; 2219-2840; 2219-2840
• DOI: 10.3748/wjg.v28.i17.1814

Obesity and comorbidities onset encompass gut dysbiosis, altered intestinal permeability, and endotoxemia. Treatments that target gut dysbiosis can cope with obesity and nonalcoholic fatty liver disease (NAFLD) management. Peroxisome proliferator-activated receptor (PPAR)-alpha activation and dipeptidyl-peptidase-4 (DPP-4) inhibition alleviate NAFLD, but the mechanism may involve gut microbiota modulation and merits further investigation. To address the effects of PPAR-alpha activation and DPP-4 inhibition (isolated or combined) upon the gut-liver axis, emphasizing inflammatory pathways in NAFLD management in high-fat-fed C57BL/6J mice. Male C57BL/6J mice were fed a control diet (C, 10% of energy as lipids) or a high-fat diet (HFD, 50% of energy as lipids) for 12 wk, when treatments started, forming the groups: C, HF, HFA (HFD + PPAR-alpha agonist WY14643, 2.5 mg/kg body mass), HFL (HFD + DPP-4 inhibitor linagliptin, 15 mg/kg body mass), and HFC (HFD + the combination of WY14643 and linagliptin). The HFD was obesogenic compared to the C diet. All treatments elicited significant body mass loss, and the HFC group showed similar body mass to the C group. All treatments tackled oral glucose intolerance and raised plasma glucagon-like peptide-1 concentrations. These metabolic benefits restored / ratio, resulting in increased goblet cells area of the large intestine and reduced lipopolysaccharides concentrations in treated groups. At the gene level, treated groups showed higher intestinal , , and expression than the HFD group. The reduced endotoxemia suppressed inflammasome and macrophage gene expression in the liver of treated animals. These observations complied with the mitigation of liver steatosis and reduced hepatic triacylglycerol, reassuring the role of the proposed treatments on NAFLD mitigation. PPAR alpha activation and DPP-4 inhibition (isolated or combined) tackled NAFLD in diet-induced obese mice by restoration of gut-liver axis. The reestablishment of the intestinal barrier and the rescued phylogenetic gut bacteria distribution mitigated liver steatosis through anti-inflammatory signals. These results can cope with NAFLD management by providing pre-clinical evidence that drugs used to treat obesity comorbidities can help to alleviate this silent and harmful liver disease.