Characterizing the effects of weight loss on human adipose tissue gene transcription and cell composition

Sammanfattning: Obesity is a globally prevalent metabolic disease that affects more than one billion people according to the World Health Organization and the number continues to increase. Obesity has detrimental effects on health and predisposes individuals to various types of diseases, particularly type 2 diabetes. Among all available treatment options, bariatric surgery is considered in severe forms of obesity (BMI > 35 kg/m2) and obesity with additional metabolic disorders. Several studies have shown that bariatric surgery has beneficial effects on health, including improving circulating lipid profiles and lowering fasting blood glucose concentrations, which together reduce mortality and morbidity rates. However, as obesity is a chronic metabolic disorder, it is important to follow up effects of weight-reducing surgery over longer time periods. To investigate this, we followed up 22 women with obesity, ten years after bariatric surgery. In addition to monitoring clinical parameters, we obtained biopsies before and after surgery from subcutaneous adipose tissue in the periumbilical region. Based on these samples, we isolated fat cells and measured functional and genomic features that could be associated with clinical outcomes. We found that bariatric surgery improved long-term insulin sensitivity in the adipocytes. This was paralleled by epigenetic modifications in genes that according to gene ontology, were associated with insulin signaling and lipid storage. Thus, the long-term improvement in adipocyte insulin sensitivity following bariatric surgery is linked to altered gene transcription possibly due to epigenetic regulation. We also explored whether bariatric surgery could impact on the cellular composition of adipose tissue. For this, we collected single-cell, single-nucleus and spatial transcriptomic data from multiple large clinical cohorts. Over 60 subpopulations of cell types were identified and broadly classified into adipocytes, immune cells, vascular cells and fibroblast and adipogenic progenitors. Using these results, we deconvolved bulk transcriptomic data from additional clinical cohorts including longitudinal follow-ups after weight loss which enabled us to uncover interactions between different subpopulations as well as correlations between specific cell types and weight loss. Altogether, these studies provide new insights into the long-term effects of weight loss which may explain the long-term beneficial effects of bariatric surgery on insulin sensitivity.