Fatty acids differentially regulate insulin resistance through endoplasm reticulum stress-mediated induction of tribbles homologue 3: a potential link between dietary fat composition and the pathophysiological outcomes of obesity

• Published in: Diabetologia Vol. 56; no. 9; pp. 2078 - 2087
• Main Authors: Geng, T., Hu, W., Broadwater, M. H., Snider, J. M., Bielawski, J., Russo, S. B., Schwacke, J. H., Ross, J., Cowart, L. A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2013; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Cell Cycle Proteins - metabolism; Diabetes; Diabetes. Impaired glucose tolerance; Diet; Dietary Fats - adverse effects; Disease; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Endoplasmic Reticulum Stress - physiology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - metabolism; Hep G2 Cells; Human Physiology; Humans; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Internal Medicine; Liver; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Mice; Obesity; Obesity - metabolism; Oils & fats; Phosphorylation; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Repressor Proteins - metabolism; United States > US; ER stress; Animal model; Insulin resistance; Diet-induced obesity; NEFA; Endocrinopathy; Obesity; Reticulum; Diabetes mellitus; Nutrition disorder; Lipids; Metabolic diseases; Trib3; Fatty acids; Stress; Feeding; Target tissue resistance; Diet; Nutritional status
• DOI: 10.1007/s00125-013-2973-2
• ISSN: 0012-186X

Aims/hypothesis Previous studies have shown that saturated fatty acids cause insulin resistance (IR) that is prevented by unsaturated fatty acids. Tribbles homologue 3 (TRIB3) is a putative endogenous inhibitor of insulin signalling, but its role in insulin signalling is controversial. This study aimed to determine whether fatty acids regulate IR via TRIB3. Methods We treated HepG2 cells with saturated and unsaturated fatty acids and evaluated TRIB3 expression. We then tested whether regulation of TRIB3 occurred through endoplasmic reticulum (ER) stress, and whether modulating TRIB3 and ER stress marker genes was necessary and/or sufficient for regulation of insulin signalling. To test the in vivo significance of this mechanism, we fed mice obesogenic diets with different fatty acid profiles and assessed physiological variables of diabetes, ER stress markers and Trib3 expression in the liver. Results Our data show that fatty acids differentially regulate IR through ER stress-mediated induction of TRIB3. Intriguingly, a standard and widely used obesogenic diet high in unsaturated fats failed to induce ER stress, TRIB3 or IR. However, an alternative obesogenic diet with lower unsaturated fat recapitulated the cell studies by causing ER stress, TRIB3 induction and IR. Conclusions/interpretation This study revealed a novel mechanism linking dietary fat composition to IR. Given the emerging roles for ER stress in non-alcoholic liver disease, we conclude that dietary fat composition rather than total amount may mediate hepatic pathology associated with obesity.