Studies on the links between white adipose tissue phenotype and the circulatory system

Obesity is a strong risk factor for cardiovascular disease. It is defined by an unhealthy excess of white adipose tissue (WAT). Adipose derived weight gains and losses are linked to changes in two other independent cardiovascular risk factors: hypertension, and arterial stiffness. The aim of this thesis was to explore which specific WAT factors associate with hypertension and arterial stiffness.

Subjects undergoing bariatric surgery were utilized as a model system for linking different WAT conditions with vascular outcomes. Phenotyping methods included anthropometric measurements, hyperinsulinemic euglycemic clamp, dual energy Xray absorptiometry assessment of WAT distribution and adipose tissue biopsies for RNA sequencing and in vitro assessments of adipocyte function and characteristics.

Study I assessed the cross-sectional relationships between WAT factors in obese individuals (n = 120) and pulse wave velocity (PWV), a measure of arterial stiffness. After adjusting for relevant confounders, only visceral adipocyte volume was significantly (and positively) associated with PWV. Study II determined if weight loss resulted in long term reductions in PWV and if any WAT factors could predict improvement. The same individuals, except those on antihypertensive pharmacotherapy, were included (n = 82). Subjects were reassessed two years after bariatric surgery and attained a pronounced weight reduction and a significant reduction in PWV. After adjusting for confounders, subcutaneous adipocyte volume and WAT COL4A1 gene expression was found to predict improvements in PWV. Study III investigated which WAT factors associated with blood pressure improvements after weight loss. Here, only hypertensive subjects who underwent RNA sequencing (both at fasting and in hyperinsulinemic state, after a two-hour hyperinsulinemic euglycemic clamp) were included, ten who improved and eight who did not. WAT insulin sensitivity (defined as WAT insulin induced transcriptomics) was the only WAT factor that differed between the two groups, with both a larger response seen at baseline and a larger increase after weight loss observed in the improved group compared to the non-improved group. Finally, perturbed adipose tissue lipolysis is a hallmark of WAT in obesity, contributing to pathophysiological whole-body effects. However, the effects of obesity on atrial natriuretic peptide (ANP) stimulated lipolysis, have never been studied. In Study IV ANP stimulated lipolysis was impaired in vitro in obesity (n=87) but normalized after weight loss (n = 52). Furthermore, ANP stimulated lipolysis was attenuated in situ in overweight men (n = 9). Protein analysis found obese WAT to have a lower expression of NP receptor A which may explain the blunted response.

In summary, studies in this thesis have contributed to the characterization of specific WAT factors that associate with circulatory system pathology and, for the first time, characterized the ANP stimulated lipolytic response in obesity.

List of scientific papers

I. Arner P, Bäckdahl J, Hemmingsson P, Stenvinkel P, Eriksson-Hogling D, Näslund E, Andersson DP, Caidahl K, Rydén M. Regional variations in the relationship between arterial stiffness and adipocyte volume or number in obese subjects. Int J Obes (Lond). 2015 Feb;39(2):222-7.
https://doi.org/10.1038/ijo.2014.118

II. Bäckdahl J, Andersson DP, Eriksson-Hogling D, Caidahl K, Thorell A, Mileti E, Daub CO, Arner P, Rydén M. Long-Term Improvement in Aortic Pulse Wave Velocity After Weight Loss Can Be Predicted by White Adipose Tissue Factors. Am J Hypertens. 2018 Mar 10;31(4): 450-457.
https://doi.org/10.1093/ajh/hpx201

III. Bäckdahl J, Kwok K, Gao H, Mejhert N, Rydén M. Blood Pressure Improvement Following Weight Loss is Predicted by the Transcriptional Response to Insulin in White Adipose Tissue. [Manuscript]

IV. Rydén M, Bäckdahl J, Petrus P, Thorell A, Gao H, Coue M, Langin D, Moro C and Arner P. Impaired atrial natriuretic peptide-mediated lipolysis in obesity. Int J Obes (Lond). 2016 Apr;40(4): 714–720.
https://doi.org/10.1038/ijo.2015.222