Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model.
Cyclosporin A (CsA) and sirolimus (SRL) are immunosuppressive agents (IAs) associated with dyslipidemia, insulin resistance and new onset diabetes after transplantation (NODAT). However, the molecular mechanisms involved are not fully understood. We investigated the effects of six-week treatment of either CsA or SRL on glucose and lipid metabolism in Wistar rats. The results show that, compared with vehicle-treated rats, SRL-treated rats were significantly lighter starting at week 5. CsA or SRL caused glucose intolerance, increased storage of lipids in the liver and skeletal muscle, and decreased the insulin-stimulated glucose uptake in isolated adipocytes. Furthermore, these agents significantly decreased genes involved in insulin action and glucose uptake, such as, IRS-1, Glut4 and Glut1, and increased genes and/or proteins involved in hepatic lipogenesis and gluconeogenesis, while decreasing them in adipose tissue. After either treatment PGC1α gene expression was down regulated in skeletal muscle, an important player in fatty acid oxidation. Moreover, there was an increase in IL-6 gene expression in adipose tissue in the SRL-treated rats, suggesting stimulation of lipolysis. The results of the present study suggest that CsA and SRL lead to metabolic alterations in liver, muscle and adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
A
A
Fuhrmann
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
Pc
P
Lopes
Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
J
J
Sereno
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
J
J
Pedro
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal.
D O
DO
Espinoza
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden.
M J
MJ
Pereira
Laboratory of Pharmacology & Experimental Therapeutics, IBILI, Faculty of Medicine, University of Coimbra, 3000-548 Coimbra, Portugal.
F
F
Reis
Department of Medical Sciences, Uppsala University, 75185 Uppsala, Sweden.
J W
JW
Eriksson
Center for Neuroscience and Cell Biology, University of Coimbra, 3000 Coimbra, Portugal; The Portuguese Diabetes Association (APDP-ERC), 1250-203 Lisbon, Portugal. Electronic address: ecarvalh@cnc.uc.pt.
E
E
Carvalho
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016572:Cyclosporine / Q000378:metabolism* / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000378:metabolism* / Q000494:pharmacology
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D005947:Glucose; D020123:Sirolimus
Cyclosporin A; Diabetes; Dyslipidemia; Insulin resistance; Lipogenesis; Sirolimus