Celine Gleizes's List: Thèse UPR

• herefore reasoned that modulation of XBP-1s levels in cells should alter insulin action via its potential impact on  the magnitude of the ER stress responses.
• Hence, overexpression of XBP-1s rendered wild-type cells refractory to ER stress
• Next, we examined whether these differences in the ER stress responses produced alterations in insulin action as assessed  by IRS-1 serine phosphorylation and insulin-stimulated IRS-1 tyrosine phosphorylation
• Hence,  loss of an XBP-1 allele predisposes mice to diet-induced peripheral insulin resistance and type 2 diabetes.
• Our experiments with cultured cells demonstrated an increase in ER stress and a decrease in insulin signaling capacity in  XBP-1–deficient cells, as well as reversal of these phenotypes on expression of high levels of XBP-1s.
• examined PERK phosphorylation and JNK activity in the livers
• ncrease in PERK level
• increase in liver PERK phosphorylation
• increase in JNK activity
• er³⁰⁷ phosphorylation of IRS-1 was also increased
• IRS-1, and IRS-2 tyrosine- and Akt serine-phosphorylation, were all decreased in XBP-1^+/–
• in the adipose tissues of XBP-1^+/–
• Hence, our data demonstrate the link between  ER stress and insulin action in vivo but are not conclusive in determining the exact locus in insulin receptor signaling pathway  that is targeted through this mechanism.
• down-regulation of XBP-1 leads  to suppression of insulin receptor signaling in intact cells via IRE-1α–dependent activation of JNK
• Deletion of an XBP-1 allele  in mice leads to enhanced ER stress, hyperactivation of JNK, reduced insulin receptor signaling, systemic insulin resistance,  and type 2 diabetes.
• We therefore postulate  that ER stress underlies the emergence of the stress and inflammatory responses in obesity and the integrated deterioration  of systemic glucose homeostasis.
• a role for ER stress in peripheral insulin resistance, earlier studies  have linked ER stress with islet function and survival
• Therefore, we propose that the effect of chronic ER stress on glucose homeostasis in obesity could represent a central  and integrating mechanism underlying both peripheral insulin resistance and impaired insulin secretion.
• chronic ER stress

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