Adipose Tissue Dysfunction and Impaired Metabolic Health in Human Obesity: A Matter of Oxygen?

The number of studies in the field of adipose tissue biology has increased exponentially over the last decade. This shift in research focus is primarily driven by the tremendous increase in the prevalence of obesity and related chronic diseases, including cardiovascular disease and type 2 diabetes mellitus. Adipose tissue is a fascinating and complex organ, with marked effects on whole-body physiology. Intriguingly, expansion of adipose tissue does not necessarily translate into increased metabolic and cardiovascular disease risk. A proportion of obese individuals seems to be relatively protected against worsening of metabolic health (1), suggesting that adipose tissue dysfunction, rather than the amount of fat mass, may be a key factor in the pathophysiology of obesity-related metabolic and cardiovascular diseases (2–4). It is widely accepted that impairments in adipose tissue lipid metabolism, a decreased adipose tissue blood flow (ATBF) and an increased production of pro-inflammatory cytokines by hypertrophic adipocytes and infiltrating adaptive and innate immune cells are characteristics of dysfunctional adipose tissue in obesity (2, 5). These impairments not only induce insulin resistance locally in the adipose tissue but also have detrimental effects at the whole-body level, thereby affecting metabolic health. The reason for this is that adipose tissue dysfunction in obesity is accompanied by lipid spillover in the circulation and subsequent lipid accumulation in non-adipose tissues (ectopic fat storage), and may contribute to systemic low-grade inflammation, thereby accelerating the development and progression of obesity-related insulin resistance and chronic metabolic diseases (Figure ​(Figure1)1) (2). Figure 1 Adipose tissue dysfunction in obesity is related to impaired metabolic health. A long-term positive energy balance, leading to body weight gain, will increase adipocyte size. Adipocyte hypertrophy in obesity is accompanied by disturbances in lipid metabolism . Adipose Tissue Oxygen Tension in Human Obesity Since adipose tissue dysfunction has been recognized as a key process in the pathophysiology of obesity-related disorders (2, 5), the number of studies aimed at identifying the trigger of adipose tissue dysfunction in obesity has increased substantially. A prevailing concept is that an insufficient amount of oxygen within adipose tissue, commonly referred to as “adipose tissue hypoxia,” may underlie adipose tissue dysfunction in obesity (6, 7). Adipose tissue hypoxia in obesity: The concept It has been postulated that adipose tissue angiogenesis is insufficient to maintain normoxia in the entire fat depot during the progressive development of obesity (8). In other words, a reduced supply of oxygen to the tissue has been proposed to instigate adipose tissue dysfunction. Indeed, a lower expression of angiogenic genes (e.g., VEGF) and lower capillary density have been found in abdominal subcutaneous adipose tissue of obese as compared to lean individuals (9, 10). The net result of structural and functional properties of the adipose tissue vasculature determines tissue blood flow. A consistent observation made by our lab and others is that fasting and postprandial ATBF is decreased in obese insulin resistant versus lean insulin sensitive subjects (9, 11–13), indicating that oxygen delivery to adipose tissue is indeed impaired in obesity. We have recently demonstrated, for the first time, that both pharmacological (local administration of vasoactive agents into adipose tissue) and physiological (oral glucose drink) manipulation of ATBF induce concomitant alterations in adipose tissue oxygen partial pressure (AT PO2) in humans (9), indicating that adipose tissue oxygen supply indeed affects AT PO2. A second argument that has been put forward to develop the concept of adipose tissue hypoxia in obesity is that the diameter of hypertrophic adipocytes in obesity exceeds the normal diffusion distance of oxygen across tissues (100–200 μm) (14). However, in human adipose tissue, there seems to be only a very small proportion of adipocytes with a diameter >100 μm (9, 15, 16). Therefore, the significance of reduced oxygen diffusion from the capillaries to hypertrophic fat cells in obese humans can be questioned.