Role of RAGE in obesity-induced adipose tissue inflammation and insulin resistance

Abstract

AbatractObesity is known to be associated with adipose tissue inflammation and insulin resistance. Importantly, in obesity, the accumulation of proinflammatory macrophages in adipose tissue correlates with insulin resistance. We hypothesized that the receptor for advanced glycation end products (RAGE) and associated ligands are involved in adipose tissue insulin resistance, and that the activation of the AGE–RAGE axis plays an important role in obesity-associated inflammation. C57BL/6J mice (WT) and RAGE deficient (RAGE−/−) mice were fed a high fat diet (HFD) and subjected to glucose and insulin tolerance tests. Epdidymal adipose tissue (eAT) was collected and adipose stromal vascular cells isolated using flow cytometry. Visceral adipose tissue macrophage polarization was assessed by quantitative real time PCR. Immunoblotting was performed to evaluate the insulin signaling in adipose tissues. In additional studies, cell trafficking was assessed by injecting labeled blood monocytes into recipient mice. RAGE−/− mice displayed improved insulin sensitivity and glucose tolerance, accompanied by decreased body weight and eAT mass. Exogenous methylglyoxal (MGO) impaired insulin-stimulated AKT signaling in adipose tissues from WT mice fed a normal chow diet, but not in RAGE−/− mice. In contrast, in obese mice, treatment with MGO did not reduce insulin-induced phosphorylation of AKT in WT-HFD mice. Moreover, insulin-induced AKT phosphorylation was found to be impaired in adipose tissue from RAGE−/−-HFD mice. RAGE−/− mice displayed improved inflammatory profiles and evidence for increased adipose tissue browning. This observation is consistent with the finding of reduced plasma levels of FFA, glycerol, IL-6, and leptin in RAGE−/− mice compared to WT mice. Collectively the data demonstrate that RAGE-mediated adipose tissue inflammation and insulin-signaling are potentially important mechanisms that contribute to the development of obesity-associated insulin resistance.

Glycation-Driven Inflammation: COVID-19 Severity in Pregnant Women and Perinatal Outcomes

“…The limitation of the clinical design of the study is that we could not compare the GA and MGO values in a control group matched for obesity and the prevalence of diabetes. However, the interpretation of the data that we are supporting here is greatly supported by the large epidemiological studies on COVID-29 syndrome that found a highly significant association of obesity and diabetes with the severity of SARS-CoV-2 infection [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…It is also of interest that MGO-induced RAGEs play a role in platelet activation [ 14 ], which may lead to additional SARS-CoV-2 infection complications. These metabolic processes are also expressed in control pregnant subjects since pregnancy is characterized by para-physiological dyslipidemia and insulin resistance [ 7 , 15 , 16 ]. This could explain why, even in otherwise clinically normal pregnancies, we observed a wide range of GA and MGO values.…”

“…Methylglyoxal (MGO) is an important advanced glycation end-product (AGE) generated mainly by carbohydrate consumption, as well as by lipid and protein metabolism. This molecule, when above functional levels, is linked to insulin resistance and endothelial dysfunction [ 7 ]. It might also damage the beta-pancreatic cell.…”

Novel Long-Acting Oxytocin Analog with Increased Efficacy in Reducing Food Intake and Body Weight

“…Recent evidence suggests a receptor for advanced glycation end-products (RAGE) mediated mechanism of OXT transport to the brain [ 34 ]. Obesity is known to increase expression of RAGE [ 35 , 36 ], and it is possible that in our DIO Sprague Dawley rats increased transport which needs to be investigated for ASK2131 vs. OXT in a future study.…”

Glycation of Tie-2 Inhibits Angiopoietin-1 Signaling Activation and Angiopoietin-1-Induced Angiogenesis

“…The 8-week-old male C57BL/6J mice were fed with a HFD (fat 60%, carbohydrate 25% and protein 15%) for 16 weeks, as described previously [33,34]. Age-matched male mice fed with a normal chow diet (fat 10%, carbohydrate 75% and protein 15%) were used as controls.…”