title: The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipose tissue.
abstract: Cyclosporin A (CsA), tacrolimus and rapamycin are immunosuppressive agents (IAs) associated with insulin resistance and dyslipidemia, although their molecular effects on lipid metabolism in adipose tissue are unknown. We explored IAs effects on lipolysis, lipid storage and expression of genes involved on lipid metabolism in isolated human adipocytes and/or adipose tissue obtained via subcutaneous and omental fat biopsies. CsA, tacrolimus and rapamycin increased isoproterenol-stimulated lipolysis and inhibited lipid storage by 20-35% and enhanced isoproterenol-stimulated hormone-sensitive lipase Ser552 phosphorylation. Rapamycin also increased basal lipolysis (~20%) and impaired insulin's antilipolytic effect. Rapamycin, down-regulated the gene expression of perilipin, sterol regulatory element-binding protein 1 (SREBP1) and lipin 1, while tacrolimus down-regulated CD36 and aP2 gene expression. All three IAs increased IL-6 gene expression and secretion, but not expression and secretion of TNF-α or adiponectin. These findings suggest that CsA, tacrolimus and rapamycin enhance lipolysis, inhibit lipid storage and expression of lipogenic genes in adipose tissue, which may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.
authors.affiliation: The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at University of Gothenburg, 413 45 Gothenburg, Sweden. maria.pereira@gu.se
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pereira
authors.forename: Jenny
authors.initials: J
authors.lastname: Palming
authors.forename: Magnus
authors.initials: M
authors.lastname: Rizell
authors.forename: Manuel
authors.initials: M
authors.lastname: Aureliano
authors.forename: Eugénia
authors.initials: E
authors.lastname: Carvalho
authors.forename: Maria K
authors.initials: MK
authors.lastname: Svensson
authors.forename: Jan W
authors.initials: JW
authors.lastname: Eriksson
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005990:Glycerol / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000166:cytology; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008066:Lipolysis / Q000187:drug effects* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D002787:Sterol Esterase / Q000378:metabolism; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D002352:Carrier Proteins; C508600:IL6 protein, human; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D000070778:Perilipin-1; D010750:Phosphoproteins; D014409:Tumor Necrosis Factor-alpha; D016572:Cyclosporine; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D002787:Sterol Esterase; D005990:Glycerol; D020123:Sirolimus; D016559:Tacrolimus