Glycation impairs adipose tissue capillarization, blood flow and expandability causing insulin resistance

Abstract

Aims/hypothesis: Microvascular dysfunction has been suggested as a trigger for adipose tissue (AT) dysfunction in obesity[1]. We investigated the role of glycation[2] in impairing AT capillarization, blood flow and expandability. Methods: We used an animal model of high-fat diet supplemented with methylglyoxal (HFDMG), compared with high-fat diet (HFD) or methylglyoxal (MG) alone and the type 2 diabetic Goto-Kakizaki rats (GK). Hypoxia, angiogenic pathways, insulin resistance and blood flow (through magnetic resonance imaging) were addressed. MG effects on AT capillarization were assessed through the AT angiogenesis assay. Results: Impaired adipose tissue blood flow was observed in groups with MG-induced glycation and GK rats, but not in the HFD group. Moreover, increased adipocyte size and leptin secretion in HFD rats were not followed by hypoxia development. Instead, this was observed in the HFDMG group, which also showed an impairment of hypoxia-response mechanisms and angiogenic pathways. HFDMG rats also had less insulin receptor activation (Tyr1163), glucose intolerance and systemic insulin resistance, similarly to diabetic rats. Accordingly, MG decreased ex vivo AT capillarization in a concentration-dependent manner. Conclusions: Glycation impairs AT capillarization and blood flow, hampering its expandability during a high-fat diet challenge and leading to hypoxia and insulin resistance.