Abstract
Background/objectivesThe 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/methodsWe 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.ResultsIn 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).ConclusionsThese 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.
Highlights
We previously reported that mice globally devoid of Ager; the gene encoding receptor for AGEs (RAGE), wild-type (Wt) mice receiving bone marrow transplanted from mice devoid of Ager, or Wt mice treated with soluble RAGE, a splice isoform of AGER yielding a circulating protein which is hypothesized to act as a decoy receptor, all are protected from diet-induced obesity (DIO) and insulin resistance (IR) [16]
When compared to lean subjects, obese individuals exhibit lower levels of circulating advanced glycation end products (AGEs) in parallel with higher adipose tissue expression of RAGE and greater tissue accumulation of AGEs [26], which has led to the tissue “AGE trapping” hypothesis, whereby obesity is characterized by excess tissue AGE buildup and, low circulating AGEs [26]
If the expression of GLO1/RAGE/Diaphanous 1 (DIAPH1) in adipose tissue is altered by increasing degrees of obesity and whether the expression of these genes associates with adipose tissue inflammation and adipocyte metabolism markers was addressed in the present studies
Summary
While the precise cause of this phenomenon is not fully understood, increases in rates of obesity have been accompanied by nutrient excess, decreases in physical activity and a “westernization” of diet composition. In addition to higher fat and sugar content, Western-style diets are highly processed and represent a principal source of proteins nonenzymatically modified by sugars and/or lipids called advanced glycation end products (AGEs) [1], which have been linked to the pathophysiology of obesity and other cardiometabolic disorders [2]. Recent observations suggest that excess MG due to inhibition or genetic deletion of glyoxalase 1 (Glo1) promotes obesity and impairs glucose metabolism and insulin resistance (IR) [4, 5]; likely by altering adipose tissue vascularization and promoting its expansion [6, 7]. Dietary manipulations to increase GLO1 activity improve vascular function and glycemic control in obese individuals [8]
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