The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice
Article first published online: 15 JAN 2010
© 2010 John Wiley & Sons A/S
Volume 30, Issue 4, pages 603–610, April 2010
How to Cite
De Fraia Pinto, L., Compri, C. M., Fornari, J. V., Bartchewsky, W., Cintra, D. E., Trevisan, M., De Oliveira Carvalho, P., Ribeiro, M. L., Velloso, L. A., Saad, M. J., Pedrazzoli, J. and Gambero, A. (2010), The immunosuppressant drug, thalidomide, improves hepatic alterations induced by a high-fat diet in mice. Liver International, 30: 603–610. doi: 10.1111/j.1478-3231.2009.02200.x
- Issue published online: 22 FEB 2010
- Article first published online: 15 JAN 2010
- Received 22 September 2009Accepted 10 December 2009
- insulin receptor substrate;
- non-alcoholic fatty liver disease;
Background: Pro-inflammatory cytokines, such as tumour necrosis factor (TNF)-α, 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-α blockade may have an effect on experimentally obese animals.
Aims: We studied the effects of thalidomide, an immunosuppressant and anti-TNF-α 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-α 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-α 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.