Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation

Abstract

Background-Adipose tissue (AT) dysfunction in obesity contributes to chronic, low-grade inflammation that predisposes to type 2 diabetes mellitus and cardiovascular disease. Recent in vitro studies suggest that AT hypoxia may induce inflammation. We hypothesized that adipose tissue blood flow (ATBF) regulates AT oxygen partial pressure (AT PO 2 ), thereby affecting AT inflammation and insulin sensitivity. Methods and Results-We developed an optochemical measurement system for continuous monitoring of AT PO 2 using microdialysis. The effect of alterations in ATBF on AT PO 2 was investigated in lean and obese subjects with both pharmacological and physiological approaches to manipulate ATBF. Local administration of angiotensin II (vasoconstrictor) in abdominal subcutaneous AT decreased ATBF and AT PO 2 , whereas infusion of isoprenaline (vasodilator) evoked opposite effects. Ingestion of a glucose drink increased ATBF and AT PO 2 in lean subjects, but these responses were blunted in obese individuals. However, AT PO 2 was higher (hyperoxia) in obese subjects despite lower ATBF, which appears to be explained by lower AT oxygen consumption. This was accompanied by insulin resistance, lower AT capillarization, lower AT expression of genes encoding proteins involved in mitochondrial biogenesis and function, and higher AT gene expression of macrophage infiltration and inflammatory markers. Conclusions-Our findings establish ATBF as an important regulator of AT PO 2 . Nevertheless, obese individuals exhibit AT hyperoxia despite lower ATBF, which seems to be explained by lower AT oxygen consumption. This is accompanied by insulin resistance, impaired AT capillarization, and higher AT gene expression of inflammatory cell markers. Clinical Trial Registration-URL: http://www.trialregister.nl. Unique identifier: NTR2451. (Circulation. 2011;124:67-76.)

Effects of hyperoxia exposure on metabolic markers and gene expression in 3T3-L1 adipocytes

“…Furthermore, it has been reported that this tissue is under chronic hypoxic conditions during the development of obesity [22,48], although a situation of decreased adipose tissue oxygen tension in obese compared to lean men may not always occur [18], which would be explained by a lower adipose tissue oxygen consumption. This hypoxic state is linked to an increase in pro-inflammatory cytokine release in adipocytes, while anti-inflammatory adipokines such as adiponectin are often decreased [60].…”

A microarray analysis of the hypoxia-induced modulation of gene expression in human adipocytes

“…There is also evidence for reduced oxygen tension in adipose tissue of obese humans (Pasarica et al, 2009), although a recent report has challenged this view (Goossens et al, 2011). Hypoxia leads to important functional changes in adipocyte metabolism, including an increase in glucose utilisation Yin et al, 2009) and lactate production (Pérez de Heredia et al, 2010), indicative of enhanced glycolysis.…”

Control of Adipose Tissue Expandability in Response to High Fat Diet by the Insulin-like Growth Factor-binding Protein-4

“…This possibility is supported by the finding that adipocytes can secrete numerous potent pro-angiogenic factors, some in response to hypoxia (11), and that VEGF-A expression can mitigate the development of metabolic dysfunction in response to a high fat diet (HFD) 2 (12,13). However, recent studies suggest that hypoxia of adipose tissue may not reach levels sufficient to elicit a pro-angiogenic response (14) and that expression of HIF-1␣ in adipocytes results in fibrosis rather than angiogenesis (15).…”