AGE/RAGE/DIAPH1 axis is associated with immunometabolic markers and risk of insulin resistance in subcutaneous but not omental adipose tissue in human obesity

• Published in: International Journal of Obesity Vol. 45; no. 9; pp. 2083 - 2094
• Main Authors: Ruiz, Henry H., Nguyen, Anh, Wang, Chan, He, Linchen, Li, Huilin, Hallowell, Peter, McNamara, Coleen, Schmidt, Ann Marie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Nature Publishing Group
• Subjects: 38; 38/71; 38/90; 631/443/319/1642/393; 692/163/2743/393; 692/308/575; 692/499; 82/1; 82/56; 82/80; Adipose tissue; Adipose Tissue - physiopathology; Adipose tissues; Adult; Advanced glycation end products; Advanced glycosylation end products; Age; Antigens, Neoplasm - analysis; Antigens, Neoplasm - blood; Biomarkers; Body fat; Cell receptors; Cellular signal transduction; Detoxification; Diabetes mellitus; Diet; Epidemiology; Female; Formins - analysis; Formins - blood; Gene expression; Genes; Genetic aspects; Glycosylation; Health aspects; Health Promotion and Disease Prevention; Humans; Immune response; Inflammation; Insulin; Insulin resistance; Insulin Resistance - physiology; Internal Medicine; Male; Medicine; Medicine & Public Health; Metabolic Diseases; Middle Aged; Mitogen-Activated Protein Kinases - analysis; Mitogen-Activated Protein Kinases - blood; Obesity; Obesity - blood; Obesity - physiopathology; Omentum - abnormalities; Omentum - physiopathology; Pathogenesis; Pathophysiology; Physical activity; Public Health; Receptor for Advanced Glycation End Products - analysis; Receptor for Advanced Glycation End Products - blood; Regulation; Risk factors; Signaling; Subcutaneous Fat - abnormalities; Subcutaneous Fat - physiopathology; United States
• ISSN: 0307-0565; 1476-5497; 1476-5497
• DOI: 10.1038/s41366-021-00878-3

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; β ̂ = 0.719 , [0.260, 1.177]; q  = 0.008) and GLO1 ( n  = 16; β ̂ = 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; β ̂ = 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.