title: The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice.
abstract: BACKGROUND
  Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-alpha, are known to be involved in the establishment of insulin resistance. Insulin resistance plays a key role in the development of obesity-related pathologies, such as type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). The state of chronic inflammation associated with obesity led us to hypothesize that TNF-alpha blockade may have an effect on experimentally obese animals.
  
  
  OBJECTIVE
  We studied the effects of thalidomide, an immunosuppressant and anti-TNF-alpha drug, on hepatic alterations that were induced by a high-fat diet (HFD) in mice.
  
  
  METHODS
  Obesity was induced in Swiss mice using a HFD for 12 weeks. Thalidomide-treated animals received thalidomide i.p. (100 mg/kg/day, 10 days). Glucose, aspartate aminotransferases and alanine aminotransferases levels were assessed in the blood. Insulin and glucose tolerance tests were performed. The liver was excised for histological, triglyceride, gene and protein expression analyses.
  
  
  RESULTS
  We found improvements in both the basal glucose blood levels and the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of the hepatic insulin receptor substrate (IRS)-1 and AKT phosphorylation. The hepatic expression of TNF-alpha was inhibited and the levels correlated with a significant reduction in the steatosis area. Other hepatic inflammatory markers, such as iNOS and suppressor of cytokine signalling (SOCS-3), were also reduced.
  
  
  CONCLUSIONS
  We suggest that immunosuppressant drugs that target TNF-alpha and that may also contribute to reductions in the inflammatory markers that are associated with obesity could be a therapeutic option in NAFLD and type 2 diabetes.
authors.affiliation: Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Bragança Paulista, SP, Brazil.
authors.forename: Livia de Fraia
authors.initials: Lde F
authors.lastname: Pinto
authors.forename: Cecília Melleti
authors.initials: CM
authors.lastname: Compri
authors.forename: João Victor
authors.initials: JV
authors.lastname: Fornari
authors.forename: Waldemar
authors.initials: W
authors.lastname: Bartchewsky
authors.forename: Dennys Eduardo
authors.initials: DE
authors.lastname: Cintra
authors.forename: Miriam
authors.initials: M
authors.lastname: Trevisan
authors.forename: Patrícia de Oliveira
authors.initials: Pde O
authors.lastname: Carvalho
authors.forename: Marcelo Lima
authors.initials: ML
authors.lastname: Ribeiro
authors.forename: Licio A
authors.initials: LA
authors.lastname: Velloso
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Saad
authors.forename: José
authors.initials: J
authors.lastname: Pedrazzoli
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gambero
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D001786:Blood Glucose / Q000032:analysis; D004032:Diet; D004041:Dietary Fats / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D015850:Interleukin-6 / Q000032:analysis / Q000378:metabolism; D020738:Leptin / Q000032:analysis / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000473:pathology; D011336:Probability; D012313:RNA / Q000032:analysis; D011897:Random Allocation; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D012313:RNA; D019001:Nitric Oxide Synthase