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Blocking iNOS and endoplasmic reticulum stress sinergistically improves insulin sensitivity

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Author(s):
Tamires Marques Zanotto
Total Authors: 1
Document type: Doctoral Thesis
Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas
Defense date:
Examining board members:
Fabio Bessa Lima; Carla Roberta de Oliveira Carvalho; Heloisa Balan Assalin; Rafael Ludemann Camargo
Advisor: Mario José Abdalla Saad
Abstract

Recent studies show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity¿induced ER stress and Unfolded Protein Reponse (UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress¿associated insulin resistance. For this purpose, we have performed physiological assays: the intraperitoneal glucose tolerance test (GTT) and euglycemic-hyperinsulinemic clamp, besides molecular assays: western Blotting and qPCR in liver, gastrocnemius muscle and adipose tissue of iNOS KO and control mice on HFD. The results of the present study demonstrated that, in HFD fed mice, iNOS¿induced alteration in insulin signaling is an essential mechanism of insulin resistance in muscle, suggesting that iNOS may represent an important target that could be blocked in order to improve insulin sensitivity in this tissue. However, in liver and adipose tissue, the insulin resistance induced by HFD was only partially dependent on iNOS, and even in the presence of genetic or pharmacological blockade of iNOS, a clear ER stress, associated with altered insulin signaling, remained evident in these tissues. When this ER stress was blocked pharmacologically, insulin signaling was improved and a complete recovery of glucose tolerance was achieved. Taken together, these results reinforce the tissue-specific regulation of insulin signaling in obesity, with iNOS activation being sufficient to account for insulin resistance in muscle, but in liver and adipose tissue ER stress and insulin resistance can be induced by both iNOS¿dependent and iNOS¿independent mechanisms (AU)