Effect of Weight Loss Surgery on Stem Cells.

The escalating pandemics of obesity and type 2 diabetes mellitus (T2DM) are among the most devastating health crises worldwide. The prevalence of obesity (body mass index (BMI) > 30kg/m^2) is nearly 1 billion individuals worldwide and estimated by the Center for Disease Control at 37.7 percent of the adult population in the United States. The International Diabetes Federation estimates that over 400 million individuals worldwide have T2DM and this number is expected to increase to over 600 million by the year 2040. Diet, exercise, and medications such as metformin have long been the cornerstone of T2DM therapy. Unfortunately, long-term success in the control of T2DM remain disappointing, and even with new medications such as glucagon-like peptide-1 (GLP-1) analogues (Liraglutide) and sodium-glucose co-transporter 2 (SGLT2) inhibitors (Gliflozins), adequate glycemic control remains elusive. Ultimately, T2DM patients will develop severe cardiovascular complications such as peripheral artery disease, heart attack, and stroke. Due to aging population demographics, and the paucity of curative therapies in this area, the prevalence and economic burden of obesity and T2DM is on the rise. Currently, the costs of medical care for obesity-related illnesses in the United States are estimated at $147 - 185 billion per year. Therefore, the search for curative therapies to combat obesity and T2DM are continually sought.

Bariatric surgery is increasingly recognized as one of the most effective interventions to help patients achieve significant and sustained weight loss, and improved metabolic health. Permanent loss of 20-25 percent body weight (35 - 45 kilograms) is common for patients receiving Roux-en-y Gastric Bypass (RYGB) or Vertical Sleeve Gastrectomy (VSG) compared to <5 percent in best non-surgical medical therapy patients. The mechanisms of weight loss following bariatric surgery are multifactorial and include changes in food intake, satiety, alterations in gut hormones and bile acid adaptations. Such drastic weight loss is also associated with improvement in chronic inflammatory diseases, including atherosclerosis and T2DM. Indeed, bariatric surgery leads to improved glycemic control and potential remission of T2DM. Recently, studies have independently reported significant reductions in fasting blood glucose and glycated hemoglobin (HbA1C) in >80 percent of patients receiving bariatric surgery. Amelioration of T2DM commonly occurs within days to weeks of surgery even before substantial weight loss is observed. Finally, adverse cardiovascular events, usually associated with obesity and T2DM, were reduced after bariatric surgery compared to conventional therapies. Despite these phenomenal successes, the mechanisms governing the reversal of diabetes after bariatric surgery remains largely unknown.

Obesity, atherosclerotic plaque formation and the development of T2DM are all associated with heightened inflammation. Obesity involves increases in inflammatory immune cells (M1 macrophages) that are present during the remodeling of adipose tissue. In functional opposition to heightened immunity is the reparative role of tissue-specific stem cells. Central to all regenerative processes, stem cells can be found within every tissue in the body with the capacity to self-renew, and to generate new cell types that promote tissue maintenance or repair. In this capacity, stem cells can be considered "conductors of the orchestra" that co-ordinate the myriad cells and signals involved in the regenerative response. However, during chronic diseases such as T2DM, relentless inflammation and oxidative damage results in stem cell depletion and dysfunction, and the severity of injury overwhelms the capacity to respond. For example, adipose tissue contains a heterogenous mixture of stem and progenitor cells which are likely affected by the inflammation associated with obesity. Similarly, circulating hematopoietic and endothelial progenitor cells, involved in blood vessel maintenance and repair, show aberrant secretory and vessel formative functions that are negatively impacted by chronic hyperlipidemia and hyperglycemia. This concept termed "stem cell exhaustion" is becoming increasingly recognized during chronic diseases, as circulating stem and progenitor cell number and/or regenerative function is altered by the inflammatory environment within obesity/T2DM patients.

What remains unclear is whether reduced circulating stem cell number or aberrant regenerative function can be restored following bariatric surgery. The investigators have recently established novel methodologies to assess inflammatory status (M1 / M2 macrophage status) and circulating progenitor cell content and function by performing detailed flow cytometric analyses using aldehyde dehydrogenase (ALDH, a detoxification enzyme and conserved stem cell function) in combination with cell surface marker analyses. Notably, the investigators have shown that circulating progenitor cell content and inflammatory M1 macrophage content are increased in patients with T2DM compared to age-matched healthy controls. For the first time, the effectiveness of bariatric surgery at the cellular level can be evaluated and regenerative stem cell functions that impact obesity and T2DM can be explored. Elucidating the status of stem cells following bariatric surgery will provide insight into the likelihood of T2DM relapse or reverting to an obese state and provide a potential mechanism for the improvements in cardiovascular health. This study will be able to establish a relationship between the reversal of obesity, T2DM and adverse cardiovascular events with the restoration of regenerative stem cell associated with anti-inflammatory and pro-angiogenic function.

The investigators hypothesize that bariatric surgery will augment circulating, pro-vascular progenitor cell content and will reduce systemic inflammation via restoration of M1 / M2 macrophage balance.