Methylglyoxal-induced glycation changes adipose tissue vascular architecture, flow and expansion, leading to insulin resistance

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.

Methylglyoxal, Glycated Albumin, PAF, and TNF-α: Possible Inflammatory and Metabolic Biomarkers for Management of Gestational Diabetes

“…The only significant increase was observed in the triglycerides values, confirming the results already shown in literature [32,33]. Despite the stability of the standard glycemic parameters, this increase could reflect an obesogenic pathway [34] due to an inflammatory and metabolic effect on insulin resistance of PAF, TNF-alfa [35], MGO [36], and GA [37], that needs further investigation. (2) Maternal body weight increased after 12 weeks, while fat mass reduced.…”

Adipose Morphology: a Critical Factor in Regulation of Human Metabolic Diseases and Adipose Tissue Dysfunction

“…In recent decades, some studies suggested that the contribution of adipocyte hypertrophy to the hypoxia response becomes less important [84,85]. One study found that in obese patients, only a small proportion of adipocytes diameter exceed 100 μm, suggesting that the hypoxic condition within hypertrophic adipocytes may also have been caused by other factors [86].…”

“…Notably, in obese state, AT blood flow is about 30-40% lower than subjects with normal weight [87]. It was noteworthy that glycation-induced inability of angiogenesis decreased blood flow [85]. Moreover, imbalance of VEGF/ Ang-2 ratio inhibits endothelial cell proliferation and prevents capillarization, the disarrangement of vascular formation, and reduced blood flow exacerbate hypoxia [85], further leading to impairment of AT insulin sensitivity.…”

Another Player in the Field: Involvement of Glycotoxins and Glycosative Stress in Insulin Secretion and Resistance

“…MG production was observed in adipocytes due to increased Aldolase-A activation and decreased antioxidant defenses [59]. Our group has shown the accumulation of adipose tissue MG at levels similar to diabetic rats following oral administration (75 mg/Kg), but with little effects on adipose tissue insulin signaling [60,61]. MG was only observed to change plasma free fatty acids levels and to induce structural changes in the tissue (fibrosis, hypoxia, macrophage accumulation, and hypoadiponectinemia) and decreased blood supply, but normal insulin signaling and GLUT4 levels [61].…”

“…Adipose tissue insulin resistance in the presence of MG was only observed after high-fat diet-induced obesity. In obese rats, MG-induced alterations of the vascular architecture impair adipose tissue blood flow and expandability, conducting to hypoxia and adipose tissue insulin resistance, namely lower insulin receptor phosphorylation and GLUT4 levels [60]. Similar observations were made in the liver of the same animal model, where MG-induced AGE accumulation impairs the lipid metabolism of diet-induced obese rats, changing the hepatic lipidemic profile to less esterification and unsaturation and causing inflammation, oxidative stress, and insulin resistance [63].…”