PPAR gamma activation attenuates glucose intolerance induced by mTOR inhibition with rapamycin in rats

Autor(es):Mostrar menos -

Festuccia, William T. ^[1] ; Blanchard, Pierre-Gilles ^[2] ; Belchior, Thiago ^[1] ; Chimin, Patricia ^[1] ; Paschoal, Vivian A. ^[1] ; Magdalon, Juliana ^[1] ; Hirabara, Sandro M. ^{[1, 3]} ; Simoes, Daniel ^[1] ; St-Pierre, Philippe ^[2] ; Carpinelli, Angelo ^[1] ; Marette, Andre ^[2] ; Deshaies, Yves ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[2] Quebec Heart & Lung Inst Res Ctr, Fac Med, Dept Med, Quebec City, PQ G1V 4G5 - Canada

^[3] Cruzeiro do Sul Univ, Inst Phys Act & Sports, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM; v. 306, n. 9, p. E1046-E1054, MAY 2014.
• Citações Web of Science: 21

Resumo

mTOR inhibition with rapamycin induces a diabetes-like syndrome characterized by severe glucose intolerance, hyperinsulinemia, and hypertriglyceridemia, which is due to increased hepatic glucose production as well as reduced skeletal muscle glucose uptake and adipose tissue PPAR gamma activity. Herein, we tested the hypothesis that pharmacological PPAR gamma activation attenuates the diabetes-like syndrome associated with chronic mTOR inhibition. Rats treated with the mTOR inhibitor rapamycin (2 mg.kg(-1).day(-1)) in combination or not with the PPAR gamma ligand rosiglitazone (15 mg.kg(-1).day(-1)) for 15 days were evaluated for insulin secretion, glucose, insulin, and pyruvate tolerance, skeletal muscle and adipose tissue glucose uptake, and insulin signaling. Rosiglitazone corrected fasting hyperglycemia, attenuated the glucose and insulin intolerances, and abolished the increase in fasting plasma insulin and C-peptide levels induced by rapamycin. Surprisingly, rosiglitazone markedly increased the plasma insulin and C-peptide responses to refeeding in rapamycin-treated rats. Furthermore, rosiglitazone partially attenuated rapamycin-induced gluconeogenesis, as evidenced by the improved pyruvate tolerance and reduced mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Rosiglitazone also restored insulin's ability to stimulate glucose uptake and its incorporation into glycogen in skeletal muscle of rapamycin-treated rats, which was associated with normalization of Akt Ser(473) phosphorylation. However, the rapamycin-mediated impairments of adipose tissue glucose uptake and incorporation into triacylglycerol were unaffected by rosiglitazone. Our findings indicate that PPAR gamma activation ameliorates some of the disturbances in glucose homeostasis and insulin action associated with chronic rapamycin treatment by reducing gluconeogenesis and insulin secretion and restoring muscle insulin signaling and glucose uptake. (AU)

• Processo FAPESP: 10/52191-6 - Envolvimento dos sensores de nutrientes mTOR e PPARgama no início, manutenção e término da inflamação associada à obesidade e resistência à insulina
• Beneficiário: William Tadeu Lara Festuccia
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/15354-7 - Envolvimento do tecido adiposo no desenvolvimento da obesidade e patologias associadas: investigação dos mecanismos moleculares e busca de novas alternativas terapêuticas
• Beneficiário: William Tadeu Lara Festuccia
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores