title: Spironolactone improves glucose and lipid metabolism by ameliorating hepatic steatosis and inflammation and suppressing enhanced gluconeogenesis induced by high-fat and high-fructose diet.
abstract: Recent evidence suggests that treatment with mineralocorticoid receptor antagonist suppressed local inflammation in vascular tissues or cardiomyocytes; therefore, we examined the effect of spironolactone on glucose and lipid metabolism in a mouse model with diet-induced diabetes and nonalcoholic fatty liver disease. C57BL/6 mice were fed either the control diet, 60% fat diet with 30% fructose water (HFFD), or HFFD with spironolactone for 8 wk. HFFD mice demonstrated apparent phenotypes of metabolic syndrome, including insulin resistance, hypertension, dyslipidemia, and fatty liver. Although treatment with spironolactone did not affect the increased calorie intake and body weight by HFFD, the increments of epididymal fat weight, blood pressure, serum triglyceride, free fatty acids, leptin, and total cholesterol levels were significantly suppressed. Elevation of blood glucose during glucose and insulin tolerance tests in HFFD mice was significantly lowered by spironolactone. Notably, increased glucose levels during pyruvate tolerance test in HFFD mice were almost completely ameliorated to control levels by the treatment. Staining with hematoxylin-eosin (HE) and Oil-red-O demonstrated marked accumulation of triglycerides in the centrilobular part of the hepatic lobule in HFFD mice, and these accumulations were effectively improved by spironolactone. Concomitantly HFFD feeding markedly up-regulated hepatic mRNA expression of proinflammatory cytokines (TNFalpha, IL-6, and monocyte chemoattractant protein-1), gluconeogenic gene phosphoenolpyruvate carboxykinase, transcription factor carbohydrate response element binding protein, and its downstream lipogenic enzymes, all of which were significantly suppressed by spironolactone. These results indicate that inhibition of mineralocorticoid receptor might be a beneficial therapeutic approach for diet-induced phenotypes of metabolic syndrome and fatty liver.
authors.affiliation: Department of Clinical Pharmacology, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Wada
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kenmochi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Miyashita
authors.forename: Motohiro
authors.initials: M
authors.lastname: Sasaki
authors.forename: Minoru
authors.initials: M
authors.lastname: Ojima
authors.forename: Masakiyo
authors.initials: M
authors.lastname: Sasahara
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koya
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tsuneki
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sasaoka
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002478:Cells, Cultured; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D004041:Dietary Fats / Q000008:administration & dosage; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013148:Spironolactone / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors
chemical_list: D004040:Dietary Carbohydrates; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D000451:Mineralocorticoid Receptor Antagonists; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D013148:Spironolactone; D005947:Glucose