AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity
Open Access
- 8 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in International Journal of Obesity
- Vol. 45 (9), 2083-2094
- https://doi.org/10.1038/s41366-021-00878-3
Abstract
Background/objectives The incidence of obesity continues to increase worldwide and while the underlying pathogenesis remains largely unknown, nutrient excess, manifested by “Westernization” of the diet and reduced physical activity have been proposed as key contributing factors. Western-style diets, in addition to higher caloric load, are characterized by excess of advanced glycation end products (AGEs), which have been linked to the pathophysiology of obesity and related cardiometabolic disorders. AGEs can be “trapped” in adipose tissue, even in the absence of diabetes, in part due to higher expression of the receptor for AGEs (RAGE) and/or decreased detoxification by the endogenous glyoxalase (GLO) system, where they may promote insulin resistance. It is unknown whether the expression levels of genes linked to the RAGE axis, including AGER (the gene encoding RAGE), Diaphanous 1 (DIAPH1), the cytoplasmic domain binding partner of RAGE that contributes to RAGE signaling, and GLO1 are differentially regulated by the degree of obesity and/or how these relate to inflammatory and adipocyte markers and their metabolic consequences. Subjects/methods We sought to answer this question by analyzing gene expression patterns of markers of the AGE/RAGE/DIAPH1 signaling axis in abdominal subcutaneous (SAT) and omental (OAT) adipose tissue from obese and morbidly obese subjects. Results In SAT, but not OAT, expression of AGER was significantly correlated with that of DIAPH1 (n = 16; \(\hat \beta = 0.719\), [0.260, 1.177]; q = 0.008) and GLO1 (n = 16; \(\hat \beta = 0.773\), [0.364, 1.182]; q = 0.004). Furthermore, in SAT, but not OAT, regression analyses revealed that the expression pattern of genes in the AGE/RAGE/DIAPH1 axis is strongly and positively associated with that of inflammatory and adipogenic markers. Remarkably, particularly in SAT, not OAT, the expression of AGER positively and significantly correlated with HOMA-IR (n = 14; \(\hat \beta = 0.794\), [0.338, 1.249]; q = 0.018). Conclusions These observations suggest associations of the AGE/RAGE/DIAPH1 axis in the immunometabolic pathophysiology of obesity and insulin resistance, driven, at least in part, through expression and activity of this axis in SAT.
Keywords
This publication has 48 references indexed in Scilit:
- Depot-specific differences in adipocyte insulin sensitivity in mice are diet- and function-dependentAdipocyte, 2012
- Methylglyoxal Mediates Adipocyte Proliferation by Increasing Phosphorylation of Akt1PLOS ONE, 2012
- Relation of depot-specific adipose inflammation to insulin resistance in human obesityNutrition & Diabetes, 2012
- Prognostic Significance and Gene Expression Profiles of p53 Mutations in Microsatellite-Stable Stage III Colorectal AdenocarcinomasPLOS ONE, 2012
- Body mass index-independent inflammation in omental adipose tissue associated with insulin resistance in morbid obesitySurgery for Obesity and Related Diseases, 2011
- TNF-α Antagonism with Etanercept Decreases Glucose and Increases the Proportion of High Molecular Weight Adiponectin in Obese Subjects with Features of the Metabolic SyndromeJournal of Clinical Endocrinology & Metabolism, 2011
- Gene expression of PPARγ and PGC-1α in human omental and subcutaneous adipose tissues is related to insulin resistance markers and mediates beneficial effects of physical trainingActa Endocrinologica, 2010
- Interaction of the RAGE Cytoplasmic Domain with Diaphanous-1 Is Required for Ligand-stimulated Cellular Migration through Activation of Rac1 and Cdc42Online Journal of Public Health Informatics, 2008
- Analyzing real-time PCR data by the comparative CT methodNature Protocols, 2008
- The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase.JCI Insight, 1995