The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice.
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.
Pinto
Livia de Fraia
Lde F
Clinical Pharmacology and Gastroenterology Unit, São Francisco University Medical School, Bragança Paulista, SP, Brazil.
Compri
Cecília Melleti
CM
Fornari
João Victor
JV
Bartchewsky
Waldemar
W
Cintra
Dennys Eduardo
DE
Trevisan
Miriam
M
Carvalho
Patrícia de Oliveira
Pde O
Ribeiro
Marcelo Lima
ML
Velloso
Licio A
LA
Saad
Mario J
MJ
Pedrazzoli
José
J
Gambero
Alessandra
A
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
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