Effect of mTOR inhibitor on body weight: from an experimental rat model to human transplant patients.
The aim was to study the influence of sirolimus (SRL) on body weight in a rat model and in kidney transplant patients. Wistar rats (15 weeks old) were either treated with vehicle (VEH; n = 8) or SRL (n = 7) 1.0 mg/kg three times per week for 12 weeks. Body mass and food intake were measured weekly. Adipocyte diameter was determined in hematoxylin-eosin stains. The body mass index (BMI) obtained from clinical kidney transplant trials comparing SRL-based with cyclosporine-based therapy was analyzed.


METHODS
SRL produced a decrease of the weight gain curve. At the end of the study, mean body weight in the SRL group was lower than in the VEH group (356 vs. 507 g, P < 0.01) in spite of comparable food intake normalized for body weight was not different. Mean adipocyte diameter was 36 mum in VEH and 25 mum in SRL rats (P = 0.009). Mean SRL blood trough concentration was 38 ng/ml. Kidney transplant patients: Two years after transplantation, BMI was significantly lower in the SRL-based treatment arm compared to cyclosporine (24.17 +/- 2.99 vs. 25.97 +/- 5.01 kg/m(2), P = 0.031). SRL treatment leads to less body mass. Adipocyte cell diameter was reduced in SRL-treated animals. A possible explanation may be the effects of SRL on metabolic regulation and cell growth.
Rovira
Jordi
J
Department of Nephrology and Renal Transplantation, Laboratori Experimental de Nefrologia i Trasplantament (LENIT), Hospital Clínic i Provincial de Barcelona, Barcelona, Spain. jrovira1@clinic.ub.es
Marcelo Arellano
Edgar
E
Burke
James T
JT
Brault
Yves
Y
Moya-Rull
Daniel
D
Bañón-Maneus
Elisenda
E
Ramírez-Bajo
María J
MJ
Gutiérrez-Dalmau
Alex
A
Revuelta
Ignacio
I
Quintana
Luis F
LF
Campistol
Josep M
JM
Diekmann
Fritz
F
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D015992:Body Mass Index; D001835:Body Weight / Q000187:drug effects*; D016572:Cyclosporine / Q000627:therapeutic use; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D011494:Protein Kinases / Q000187:drug effects*; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011494:Protein Kinases; C546842:MTOR protein, human; C546845:mTOR protein, rat; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus