title: Genistein sensitizes hepatic insulin signaling and modulates lipid regulatory genes through p70 ribosomal S6 kinase-1 inhibition in high-fat-high-fructose diet-fed mice.
abstract: BACKGROUND
  Genistein reduces high-calorie diet-induced insulin resistance and fat accumulation in animals, but the mechanism is unresolved.
  
  
  OBJECTIVE
  This study explores whether action of genistein is associated with p70 ribosomal S6 kinase-1 (S6K1) inhibition.
  
  
  METHODS
  Adult male mice were fed either normal diet or high-fat-high-fructose diet (HFFD) for 15 days, after which animals in each dietary group were divided into two groups and administered either genistein (1 mg kg(-1) day(-1), p.o.) in 0.5 ml of 30% dimethylsulfoxide (DMSO) or 30% DMSO (0.5 ml) for the next 45 days. At the end of the study, their liver was analyzed for lipid content. Semi-quantitative RT-PCR and western blotting methods were used to analyze lipid regulatory genes and insulin signaling proteins, respectively.
  
  
  RESULTS
  Genistein significantly (p < 0.05) lowered HFFD-induced body and liver weight gain and plasma and hepatic lipid levels. Histology showed a 2.5-fold increase of lipid in HFFD compared to control. Genistein treatment to HFFD-fed animals significantly decreased lipid accumulation (by 40%) compared to HFFD. Insulin-stimulated tyrosine phosphorylation of insulin receptor-β and insulin receptor substrates-1 (IRS-1), IRS-1 associated phospatidylinositol-3kinase (PI3K) and Akt Ser(473) phosphorylation were improved while IRS-1 serine phosphorylation was significantly (p < 0.05) decreased by genistein in HFFD. Significant (p < 0.05) increase in adenosine monophosphate-activated protein kinase (AMPK) Thr(172) phosphorylation and decrease in S6K1 Thr(389) phosphorylation were observed in HFFD-plus genistein compared to HFFD. Genistein downregulated lipogenic genes and upregulated fatty acid oxidative genes in HFFD-fed mice.
  
  
  CONCLUSIONS
  Genistein improves insulin signaling and attenuates fat accumulation in liver through S6K1 inhibition.
authors.affiliation: Department of Biochemistry and Biotechnology, Annamalai University, Tamil Nadu, India.
authors.forename: Elumalai
authors.initials: E
authors.lastname: Arunkumar
authors.forename: Dhanapalan
authors.initials: D
authors.lastname: Karthik
authors.forename: Carani Venkatraman
authors.initials: CV
authors.lastname: Anuradha
mesh_terms: D000818:Animals; D015153:Blotting, Western; D059305:Diet, High-Fat; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005632:Fructose / Q000008:administration & dosage; D019833:Genistein / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D005227:Fatty Acids; D007328:Insulin; D005632:Fructose; D019833:Genistein; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse