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

Author(s):Show less -

Gaspar, Rafael Calais ^[1] ; Munoz, Vitor Rosetto ^[1] ; Branco Ramos Nakandakari, Susana Castelo ^[2] ; Lins Vieira, Renan Fudoli ^[1] ; da Conceicao, Luciana Renata ^[1] ; de Oliveira, Fellipe ^[1] ; Crisol, Barbara Moreira ^[1] ; da Silva, Adelino S. R. ^{[3, 4]} ; Cintra, Dennys Esper ^{[5, 2]} ; de Moura, Leandro Pereira ^{[1, 5]} ; Ropelle, Eduardo Rochete ^{[1, 5]} ; Zaghloul, Iman ^[6] ; Mekary, Rania A. ^{[6, 7]} ; Pauli, Jose Rodrigo ^{[1, 5]}

Affiliation

^[1] Univ Estadual Campinas, Lab Mol Biol Exercise LaBMEx, UNICAMP, Limeira, SP - Brazil

^[2] Univ Estadual Campinas, Lab Nutr Genom LabGeN, UNICAMP, Limeira, SP - Brazil

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Postgrad Program Rehabil & Funct Performance, Ribeirao Preto, SP - Brazil

^[4] Univ Sao Paulo, Sch Phys Educ & Sport Ribeirao Preto, Postgrad Program Phys Educ & Sport, Ribeirao Preto, SP - Brazil

^[5] Univ Estadual Campinas, OCRC Obes & Comorbid Res Ctr, UNICAMP, Campinas, SP - Brazil

^[6] Massachusetts Coll Pharm & Hlth Sci MCPHS Univ, Boston, MA - USA

^[7] Harvard Med Sch, Dept Neurosurg, Brigham & Womens Hosp, Boston, MA 02115 - USA

• Document type: Journal article
• Source: Experimental Gerontology; v. 139, OCT 1 2020.
• Web of Science Citations: 0

Abstract

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-IRE1 alpha), the protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), eukaryotic translation initiation factor-alpha (peIF2 alpha), 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. (AU)

• FAPESP's process: 19/00227-1 - Effects mediated by the exercise and metformin on rock protein and the regulation of lipogenesis and glucose production in the liver of rodents with celiac disease
• Grantee: José Rodrigo Pauli
• Support type: Scholarships abroad - Research
• FAPESP's process: 18/20872-6 - Effects of physical exercise on Rock protein signaling pathway, and lipogenic regulation and gluconeogenesis in the liver of aged rats
• Grantee: José Rodrigo Pauli
• Support type: Regular Research Grants
• FAPESP's process: 17/20542-3 - Role of physical exercise in regulation of Notch1 protein in obese mice: effects on hepatic lipogenesis and gluconeogenesis
• Grantee: Rafael Calais Gaspar
• Support type: Scholarships in Brazil - Doctorate
• FAPESP's process: 18/07568-6 - The role of physical exercise on Rock protein pathway, and lipogenic regulation and gluconeogenesis in the liver of aged rats.
• Grantee: Vitor Rosetto Muñoz
• Support type: Scholarships in Brazil - Doctorate