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Abstract
Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity. This study investigates the hypothesis that glycation impairs microvascular architecture and expandability with an impact on insulin signalling. Animal models supplemented with methylglyoxal (MG), maintained with a high-fat diet (HFD) or both (HFDMG) were studied for periepididymal adipose (pEAT) tissue hypoxia and local and systemic insulin resistance. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to quantify blood flow in vivo, showing MG-induced reduction of pEAT blood flow. Increased adipocyte size and leptin secretion were observed only in rats feeding the high-fat diet, without the development of hypoxia. In turn, hypoxia was only observed when MG was combined (HFDMG group), being associated with impaired activation of the insulin receptor (Tyr1163), glucose intolerance and systemic and muscle insulin resistance. Accordingly, the adipose tissue angiogenic assay has shown decreased capillarization after dose-dependent MG exposure and glyoxalase-1 inhibition. Thus, glycation impairs adipose tissue capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance. Such events have systemic repercussions in glucose metabolism and may lead to the onset of unhealthy obesity and progression to type 2 diabetes.
Highlights
Microvascular dysfunction has been suggested to trigger adipose tissue dysfunction in obesity
In this study we investigated a new mechanism for adipose tissue dysfunction in obesity and type 2 diabetes
We demonstrate that glycation in periepididymal adipose tissue (pEAT) has adverse vascular effects, impairing blood flow, hypoxia-response mechanisms and expandability which is tightly associated with local and systemic insulin resistance and glucose dysmetabolism
Summary
Glycation increases glycoconjugates and fibrosis in adipose tissue. Ne(carboxyethyl)lysine (CEL). MG supplementation increased angiotensin II receptor (AT1) expression, given that the HF diet decreased AT1 levels in adipose tissue but such decrease was not observed in HF diet-fat rats supplemented with MG (Fig. 3F) Such effects may increase angiotensin signalling decreasing blood flow. HFD rats developed glucose intolerance, with higher AUC during the IPGTT (p < 0.001 vs Ct and p < 0.01 vs MG), but no significant differences were observed for HbA1c, fasting glycemia, insulinemia and FFA levels (Fig. 5A–D; Table 1). Such effects were very similar to GK rats, which showed decreased phopho-IR, total-IR, phospho-Akt and GLUT4 (Fig. 5E–G) Such results show that glycation impairs skeletal muscle insulin signalling, contributing to systemic insulin resistance and glucose intolerance
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