Abstract
Inflammation and metabolism have been shown to be evolutionary linked and increasing evidence exists that pro-inflammatory factors are involved in the pathogenesis of obesity and type 2 diabetes. Until now, most data suggest that within adipose tissue these factors are secreted by cells of the innate immune system, e. g. macrophages. In the present study we demonstrate that B lymphocyte stimulator (BLyS) is increased in human obesity. In contrast to several pro-inflammatory factors, we found the source of BLyS in human adipose tissue to be the adipocytes rather than immune cells. In grade 3 obese human subjects, expression of BLyS in vivo in adipose tissue is significantly increased (p<0.001). Furthermore, BLyS serum levels are elevated in grade 3 human obesity (862.5+222.0 pg/ml vs. 543.7+60.7 pg/ml in lean controls, p<0.001) and are positively correlated to the BMI (r = 0.43, p<0.0002). In the present study, bariatric surgery significantly altered serum BLyS concentrations. In contrast, weight loss due to a very-low-calorie-formula-diet (800 kcal/d) had no such effect. To examine metabolic activity of BLyS, in a translational research approach, insulin sensitivity was measured in human subjects in vivo before and after treatment with the human recombinant anti-BLyS antibody belimumab. Since BLyS is known to promote B-cell proliferation and immunoglobulin secretion, the present data suggest that adipocytes of grade 3 obese human subjects are able to activate the adaptive immune system, suggesting that in metabolic inflammation in humans both, innate and adaptive immunity, are of pathophysiological relevance.
Highlights
Obesity is associated with a reduced life-span [1] and represents a fast-growing health problem that is reaching epidemic proportions worldwide [2]
The higher magnification shown in figure 1B suggests that the major source of B lymphocyte stimulator (BLyS) within adipose tissue are mature adipocytes, since no obvious staining was observed in the stromal vascular fraction
In order to further examine whether BLyS is only expressed in mature adipocytes or in certain cells of the stromal vascular fraction, we separated mature adipocytes and the stromal vascular fraction of visceral and subcutaneous adipose tissue biopsies from n = 5 obese humans by collagenase digestion and performed western blots for BLyS and the BLyS receptor BCMA
Summary
Obesity is associated with a reduced life-span [1] and represents a fast-growing health problem that is reaching epidemic proportions worldwide [2] It leads to several chronic co-morbidities including type 2 diabetes, dyslipidemia and atherosclerosis [3]. It is already known that the development of insulin resistance and type 2 diabetes is associated with inflammatory mechanisms in adipose tissue [5] This relationship can be explained by hypertrophic and functionally impaired adipocytes in visceral and subcutaneous fat depots due to a positive energy balance. In this pathophysiological condition various bioactive molecules are being produced and secreted by adipocytes which can activate the infiltration of cells of the innate immune system, e. This results in ectopic lipid accumulation in liver and skeletal muscle leading to insulin resistance of these metabolically important tissues and eventually type 2 diabetes [9,10]
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