Atorvastatin effects on inflammation and insulin resistance in obese mice.

A obesidade é um estado inflamatório crônico. As estatinas têm efeito antiinflamatório e podem afetar a homeostase glicêmica. Estudos, nesse sentido são contraditórios e pouco se sabe sobre os mecanismos moleculares envolvidos. Este estudo verificou em animais obesos por glutamato monossódico (MSG) que além de apresentaram resistência à insulina in vivo, o tecido adiposo branco (TAB) desses animais mostrou aumento de infiltração de macrófagos, fosforilação de IKK-a/b, expressão de mRNA de TNF-a and IL-6, e redução de mRNA e proteína de GLUT4. O tratamento com atorvastatina por 4 semanas restabeleceu a sensibilidade à insulina in vivo, reduziu a inflamação e restabeleceu a expressão de GLUT4 no TAB dos animais obesos. Adicionalmente, esse trabalho encontrou sítios de ligação de NF-kB no promotor do gene GLUT4, sugerindo ligação entre resistência à insulina e inflamação. Em conclusão, a obesidade induzida por MSG em camundongos acompanha-se de resistência à insulina in vivo e atividade inflamatória crônica no tecido adiposo, com prejuízo da expressão de GLUT4. A atorvastatina melhorou esses aspectos, sugerindo que essa estatina tenha efeitos antiinflamatórios que podem melhorar a resistência à insulina na obesidade.Obesity is a chronic inflammatory state. Statins have anti-inflammatory effects and may affect glucose homeostasis; therefore, few are known about the molecular mechanisms. Considering that inflammation contributes to insulin resistance, the aim of the present study was to investigate if atorvastatin treatment has anti-inflammatory, and consequently insulin sensitization action in white adipose tissue (WAT) of obese mice. WAT of insulin-resistant obese mice showed increased macrophage infiltration, IKK-a and IKK-b phosphorylation, TNF-a and IL-6 mRNA expression and decreased GLUT4 mRNA and protein expression. Atorvastatin restored whole-body insulin sensitivity, decreased macrophage infiltration and normalized IKK-a/b phosphorylation, TNF-a, IL-6 and GLUT4 mRNA and GLUT4 protein to control levels. Moreover, NF-kB binding sites were found in GLUT4 gene promoter, pointing out an association between insulin resistance and inflammation. Together, atorvastatin anti-inflammatory effects on WAT may be important to its local and whole-body insulin sensitization effects

Proinsulin C-peptide induces c-Jun N-terminal kinase 1 expression in LEII mouse lung capillary endothelial cells

To characterize the roles of C-peptide in vascular homeostatic processes, we examined the genes regulated by C-peptide in LEII mouse lung microvascular endothelial cells. Treatment of the cells with C-peptide increased the expression of c-Jun N-terminal kinase 1 (JNK1) mRNA dose-dependently, accompanied by an increase in JNK1 protein content. Prior treatment of the cells with PD98059, an ERK kinase inhibitor or SB203580, a p38MAPK inhibitor, abrogated the C-peptide-elicited JNK1 mRNA expression. These results indicate that C-peptide increases JNK1 protein levels, possibly through ERK- and p38MAPK-dependent activation of JNK. gene transcription.Japan Society for the Promotion of Science (JSPS)Japan Society for the Promotion of Science (JSPS)Mombusho Scholarship for International StudentsMombusho Scholarship for International Student

Soybean and sunflower oil-induced insulin resistance correlates with impaired GLUT4 protein expression and translocation specifically in white adipose tissue

Free fatty acids are known for playing a crucial role in the development of insulin resistance. High fat intake is known for impairing insulin sensitivity; however, the effect of vegetable-oil injections have never been investigated. The present study investigated the effects of daily subcutaneous injections (100 mu L) of soybean (SB) and sunflower (SF) oils, during 7 days. Both treated groups developed insulin resistance as assessed by insulin tolerance test. The mechanism underlying the SB- and SF-induced insulin resistance was shown to involve GLUT4. In SB- and SF-treated animals, the GLUT4 protein expression was reduced similar to 20% and 10 min after an acute it? vivo stimulus with insulin, the plasma membrane GLUT4 content was similar to 60% lower in white adipose tissue (WAT). No effects were observed in skeletal muscle. Additionally, both oil treatments increased mainly the content of palmitic acid (similar to 150%) in WAT, which can contribute to explain the GLUT4 regulations. Altogether, the present study collects evidence that those oil treatments might generate insulin resistance by targeting GLUT4 expression and translocation specifically in WAT. These alterations are likely to be caused due to the specific local increase in saturated fatty acids that occurred as a consequence of oil daily injections. Copyright (C) 2010 John Wiley & Sons, Ltd.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP[03/08548-3]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP[07/50554-1

Soybean and sunflower oil‐induced insulin resistance correlates with impaired GLUT4 protein expression and translocation specifically in white adipose tissue

Free fatty acids are known for playing a crucial role in the development of insulin resistance. High fat intake is known for impairing insulin sensitivity; however, the effect of vegetable‐oil injections have never been investigated. The present study investigated the effects of daily subcutaneous injections (100 µL) of soybean (SB) and sunflower (SF) oils, during 7 days. Both treated groups developed insulin resistance as assessed by insulin tolerance test. The mechanism underlying the SB‐ and SF‐induced insulin resistance was shown to involve GLUT4. In SB‐ and SF‐treated animals, the GLUT4 protein expression was reduced ∼20% and 10 min after an acute in vivo stimulus with insulin, the plasma membrane GLUT4 content was ∼60% lower in white adipose tissue (WAT). No effects were observed in skeletal muscle. Additionally, both oil treatments increased mainly the content of palmitic acid (∼150%) in WAT, which can contribute to explain the GLUT4 regulations. Altogether, the present study collects evidence that those oil treatments might generate insulin resistance by targeting GLUT4 expression and translocation specifically in WAT. These alterations are likely to be caused due to the specific local increase in saturated fatty acids that occurred as a consequence of oil daily injections282114121FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP03/08548-3; 07/50554-

Palmitate-induced Slc2a4/GLUT4 downregulation in L6 muscle cells: evidence of inflammatory and endoplasmic reticulum stress involvement

Abstract Background Obesity is strongly associated to insulin resistance, inflammation, and elevated plasma free fatty acids, but the mechanisms behind this association are not fully comprehended. Evidences suggest that endoplasmic reticulum (ER) stress may play a role in this complex pathophysiology. The aim of the present study was to investigate the involvement of inflammation and ER stress in the modulation of glucose transporter GLUT4, encoded by Slc2a4 gene, in L6 skeletal muscle cells. Methods L6 cells were acutely (2 h) and chronically (6 and 12 h) exposed to palmitate, and the expression of several proteins involved in insulin resistance, ER stress and inflammation were analyzed. Results Chronic and acute palmitate exposure significantly reduced GLUT4 protein (~ 39%, P < 0.01) and its mRNA (18%, P < 0.01) expression. Only acute palmitate treatment increased GRP78 (28%, P < 0.05), PERK (98%, P < 0.01), eIF-2A (35%, P < 0.01), IRE1a (60%, P < 0.05) and TRAF2 (23%, P < 0.05) protein content, and PERK phosphorylation (106%, P < 0.001), but did not elicit eIF-2A, IKK phosphorylation or increased XBP1 nuclear content. Additionally, acute and chronic palmitate increased NFKB p65 nuclear content (~ 30%, P < 0.05) and NFKB binding activity to Slc2a4 gene promoter (~ 45%, P < 0.05). Conclusion Different pathways are activated in acute and chronic palmitate induced-repression of Slc2a4/GLUT4 expression. This regulation involves activation of initial component of ER stress, such as the formation of a IRE1a-TRAF2-IKK complex, and converges to NFKB-induced repression of Slc2a4/GLUT4. These results link ER stress, inflammation and insulin resistance in L6 cells