Metabolic and Vascular Consequences of Adipose Tissue Dysfunction

Adipose Tissue Dysfunction (ATD) has been proposed as the pathophysiological route by which obesity confers its associated increased risk for cardiovascular disease and is characterized by an increased secretion of pro-inflammatory cytokines and adipokines and reduced secretion of anti-inflammatory adipokines such as adiponectin from adipose tissue. A review of literature shows that a range of currently available (non-)pharmacological interventions such as weight loss and statins influence ATD. The recently proposed intervention of blood letting, aimed at a reduction in free iron induced inflammation, is partly based on the relation between body iron stores and ATD while the etiologic relation remains poorly understood. This relation was absent in patients with manifest vascular disease probably due to the inflammation associated with vascular disease. In vitro studies did show a potential causal relation between body iron stores and ATD via free iron-induced inflammation in preadipocytes. ATD has mainly been researched in the fasting state while subjects in the western world spend most of the day in the postprandial phase. We showed that in the postprandial phase ATD plays a contraintuitive, but modest anti-inflammatory role probably with the aim of limiting the mostly pro-inflammatory postprandial phase. ATD is linked with thyroid function to influence energy expenditure and intake based on available energy stores in the form of adipose tissue. In patients with manifest vascular disease this relation is shown by the association between thyroid stimulating hormone (TSH) within the normal range (0.5-5.0 mU/L) and visceral adipose tissue thickness. Small changes in TSH in the normal range are associated with an increased risk for myocardial infarction in patients with manifest vascular disease per point increase in TSH (HR 1.33; 95%CI 1.03-1.73). The most important intervention available for improving cardiovascular risk in high-risk patients such as those with ATD is LDL-cholesterol lowering. To compare different LDL-cholesterol-lowering strategies (high-dose statin versus low-dose statin in combination with ezetimibe) we performed a multicenter cross-over trial comparing both lipid-lowering strategies on fasting and postprandial lipids and endothelial function as measured by Flow Mediated Dilatation (FMD) and EndoPAT in patients with metabolic syndrome. Strict attention was given to endothelial function test methodology as we also showed, using a meta-regression-based approach on available FMD-studies, that small alterations in methodology influence endothelial function test results. Both lipid-lowering strategies were associated with similar fasting LDL-cholesterol levels (1.79 mmol/L versus 1.81 mmol/L) and were associated with similar postprandial lipids, fasting and postprandial changes in endothelial function (change in FMD -0.34±0.21 vs. -0.43±0.20, p=0.766). ATD has complicated relations with other regulatory systems and organ systems such as iron-metabolism and thyroid function in patients with manifest vascular disease and metabolic syndrome. ATD has a modest contraintuitive anti-inflammatory role in the postprandial phase in which we place ourselves almost daylong. Interventions aimed at influencing ATD are already available while different lipid-lowering strategies designed for reducing the adipose tissue dysfunction associated cardiovascular risk are probably equally effective as witnessed by their similar effects on fasting and post fat-load endothelial function.