Year: 2013
Type: dissertation
Abstract: Post transplant diabetes mellitus (PTDM) is a metabolic syndrome that affects a large number of patients with chronic treatment with immunosuppressive agents (IAs). It is known that IAs modulates negatively insulin sensitive-tissues such as skeletal muscle, liver and white fat. However, the effects of IAs on insulin action and thermogenesis in brown adipose tissue have not been studied. In this study we have analyzed the impact of rapamycin, cyclosporine A (CsA) and tacrolimus (FK506) in the insulin signaling cascade in differentiated brown adipocytes from rat. We found that the three compounds inhibits insulin-mediated protein kinase B (PKB/Akt) phosphorylation as well as glucose transporter 4 (GLUT4) translocation to the plasma membrane and glucose uptake, with the effect of the immunosuppressor rapamycin being more evident (p<0.001). Moreover, degradation of IRS-1 was only observed in rapamycin and CsA-treated cells. Rapamycin induced an early activation of N-terminal Janus activated kinase (JNK) and, as a consequence, increased serine phosphorylation of insulin receptor substrate (IRS-1) at serine 307 residue. However, no effects of rapamycin were found in other stress kinases such as p38 mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK). Rapamycin also inhibited basal (p<0.05) and norepinephrine-induded (p<0.05) mRNA levels of uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Conversely, CsA and FK506 induced the opposite effect by increasing both UCP1 and PGC1α mRNAs. Our results have demonstrated for the first time the unique role of brown adipose tissue as a target of IAs suggesting that insulin resistance in BAT might contribute to PTDM.
Author: Carlos Manuel de Moura Ferreira
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2299145919