Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats.,Experimental Gerontology

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Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats.
Experimental Gerontology ( IF 3.3 ) Pub Date : 2020-07-10 , DOI: 10.1016/j.exger.2020.111021
Rafael Calais Gaspar ₁ , Vitor Rosetto Muñoz ₁ , Susana Castelo Branco Ramos Nakandakari ₂ , Renan Fudoli Lins Vieira ₁ , Luciana Renata da Conceição ₁ , Fellipe de Oliveira ₁ , Barbara Moreira Crisol ₁ , Adelino S R da Silva ₃ , Dennys Esper Cintra ₄ , Leandro Pereira de Moura ₅ , Eduardo Rochete Ropelle ₅ , Iman Zaghloul ₆ , Rania A Mekary ₇ , José Rodrigo Pauli ₈

Affiliation

Laboratory of Molecular Biology of Exercise (LaBMEx), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
Laboratory of Nutritional Genomics (LabGeN), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil.
Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, and Postgraduate Program in Physical Education and Sport, School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, São Paulo, Brazil.
Laboratory of Nutritional Genomics (LabGeN), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Laboratory of Molecular Biology of Exercise (LaBMEx), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil.
Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA.
Massachusetts College of Pharmacy and Health Sciences (MCPHS) University, Boston, MA, USA; Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Laboratory of Molecular Biology of Exercise (LaBMEx), University of Campinas (UNICAMP), Limeira, São Paulo, Brazil; OCRC - Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil..

TRB3, a mammalian homolog of Drosophila tribbles, plays an important role in multiple tissues and it has been implicated in stress response regulation and metabolic control. However, the role of hepatic TRB3 and its relationship with endoplasmic reticulum stress (ER stress) during aging has not been elucidated. Thus, the present study aimed to explore the association of aging with TRB3 and ER stress on the hepatic glucose production in Wistar rats. We found the TRB3 protein content to be higher in livers of old rats (27 months) compared to young (3 months) and middle-aged (17 months) rats. The increased content of hepatic TRB3 of the old rats was associated with insulin resistance (decreased protein kinase B (Akt) and Forkhead Box O1 (FoxO1) phosphorylation) and increased enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6Pase)). Moreover, aging was associated with activation of the endoplasmic reticulum stress pathway-related molecules, with an increase in phosphorylation of Inositol-requiring enzyme 1 (p-IRE1α), the protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), eukaryotic translation initiation factor-α (p-eIF2α), binding immunoglobulin protein (BiP), and the C/EBP homologous protein (CHOP) contents in rats. These molecular changes resulted in increased liver glucose production in response to the pyruvate challenge and hyperglycemia of the old rats. In conclusion, our results suggested that, by interfering with insulin signaling in the liver, TRB3 was associated with ER stress and increased hepatic glucose production in aging rats.

中文翻译：

衰老与大鼠肝脏中 TRB3、ER 应激和肝葡萄糖生成增加有关。

TRB3 是果蝇 tribbles 的哺乳动物同源物，在多种组织中发挥重要作用，并与应激反应调节和代谢控制有关。然而，肝脏TRB3的作用及其与衰老过程中的内质网应激（ER应激）的关系尚未阐明。因此，本研究旨在探讨衰老与 TRB3 和 ER 应激对 Wistar 大鼠肝葡萄糖产生的关系。我们发现，与年轻（3 个月）和中年（17 个月）大鼠相比，老年大鼠（27 个月）肝脏中的 TRB3 蛋白含量更高。老年大鼠肝脏 TRB3 含量增加与胰岛素抵抗（蛋白激酶 B (Akt) 和 Forkhead Box O1 (FoxO1) 磷酸化降低）和糖异生酶（磷酸烯醇丙酮酸羧激酶 (PEPCK) 和葡萄糖 6-磷酸酶 (G6Pase ））。此外，衰老与内质网应激通路相关分子的激活有关，肌醇需要酶 1 (p-IRE1α)、蛋白激酶 RNA 样内质网激酶 (p-PERK)、真核生物的磷酸化增加大鼠中的翻译起始因子-α (p-eIF2α)、结合免疫球蛋白 (BiP) 和 C/EBP 同源蛋白 (CHOP) 含量。这些分子变化导致肝脏葡萄糖产生增加，以应对老年大鼠的丙酮酸挑战和高血糖症。综上所述，

更新日期：2020-07-31

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