AGEing Fat – Exploring The Mechanisms Of Glycation-Induced Microvascular Dysfunction In Adipose Tissue

Abstract

Background and aims: Adipose tissue has a crucial role in metabolism and is nowadays recognized as an endocrine organ that produces and potentially secrets more than 600 factors involved in several physiological processes. Adipose tissue dysfunction is associated with increased insulin resistance and systemic dysmetabolism, which contributes to the development of metabolically unhealthy obesity and type 2 diabetes. Methylglyoxal-induced glycation is commonly associated with microvascular dysfunction, namely during chronic hyperglycemia, being a hypothetic factor underlying the impairment of adipose tissue microvasculature and ultimately, tissue dysfunction. Glucagon-like peptide-1 (GLP-1) based therapeutic approaches, specifically metabolic surgery and GLP-1 analogue treatment, have pleiotropic effects, including improved adipose tissue homeostasis, insulin signalling and glucose tolerance. Thus, we hypothesised that methylglyoxal-induced glycation has adverse effects on periepididymal adipose tissue vasculature, expandability and function, which could be targeted by GLP-1-based strategies through glyoxalase-1-dependent mechanisms. Accordingly, our main goal was to evaluate the role of glycation-induced microvascular dysfunction in adipose tissue function, exploring the mechanisms involved and the role of GLP-1-based therapies. Methods: Wistar rats supplemented with methylglyoxal and/or maintained with high-fat diet, were studied regarding periepididymal adipose tissue vasculature and function, namely addressing tissue hypoxia and local and systemic insulin resistance. For the first time, dynamic contrast-enhanced magnetic resonance imaging and adipose tissue angiogenesis assay have been used to quantify rat periepididymal adipose tissue blood flow and angiogenesis, respectively. Additionally, the role of glyoxalase-1 activity in human visceral adipose tissue and systemic metabolism was assessed in a cohort of obese patients (diabetic and non-diabetic). The role of GLP-1-based therapies on adipose tissue glycation was studied in type 2 diabetic Goto-Kakizaki rats (GK) maintained with high-calorie diet and submitted to sleeve gastrectomy (surgical model) and liraglutide-treated GK rats (pharmacological model). The glyoxalase-1-dependent mechanisms in adipose tissue and systemic metabolic profile were studied, as well as the role of liraglutide in preventing methylglyoxal-induced impairment of angiogenesis and modulating glyoxalase-dependent angiogenesis in adipose tissue by matrigel plug and adipose tissue angiogenesis assays, respectively. Kruskal-Wallis test (all pairwise multiple comparisons) was applied, being p<0.05 considered as the criterion for significance. Results: For the first time, our group demonstrated that methylglyoxal supplementation to high-fat diet-induced obese rats impairs periepididymal adipose tissue capillarization and blood flow, causing increased periepididymal adipose tissue hypoxia and insulin resistance as well as systemic and muscle insulin resistance and glucose intolerance. In turn, the adipose tissue angiogenic assay showed decreased capillarization after dose-dependent methylglyoxal exposure and glyoxalase-1 inhibition. Insulin resistant patients have shown a progressive decline in pancreatic -cell and adipose tissue function, which were exacerbated in diabetic obese patients, including decreased serum HDL cholesterol and adiponectin and visceral adipose tissue glyoxalase-1 activity. In visceral adipose tissue from obese patients the activity of this enzyme was negatively correlated with HbA1c. Animal models of vertical sleeve gastrectomy and liraglutide treatment have shown restored periepididymal adipose tissue levels and activity of glyoxalase-1. Liraglutide-treated rats also showed increased levels of periepididymal adipose tissue angiogenic and vasoactive factors, and insulin signalling. Moreover, liraglutide prevented negative methylglyoxal-induced effects on matrigel plug assay, being also effective in increasing periepididymal adipose tissue angiogenesis in a glyoxalase-1-dependent manner. Conclusions: Methylglyoxal-induced glycation impairs periepididymal adipose tissue expandability and function, contributing to insulin resistance and to the onset of metabolically unhealthy obesity. Lower visceral adipose tissue glyoxalase-1 activity follows the progressive decline of adipose tissue function, and is negatively associated with metabolic dysregulation in obese patients. Furthermore, glyoxalase-1 is a target for GLP-1-based therapeutic approaches, improving periepididymal adipose tissue function and insulin sensitivity, preventing early metabolic dysregulation, metabolically unhealthy obesity and type 2 diabetes development.