A NOVEL SUBSET OF PRO-INFLAMMATORY MACROPHAGES SERVES AS A SWITCH FROM METABOLICALLY HEALTHY OBESITY TO METABOLICALLY UNHEALTHY OBESITY

Abstract

Over the last 30 years, the United States has seen a steady increase in the obesity rate. More than a body image issue for many patients, obesity is a risk factor for several health conditions. As a result of the various concurrent morbidities, the cost to treat obesity-related complications is steep at nearly 150 billion dollars. The causes and risk factors of obesity are also varied, including certain medical conditions/medications, being at an older age, insufficient sleep, pregnancy, chronic stress, etc. However, overconsumption of low-nutrition foods and inadequate daily activity account for the sustained rise in obesity in the United States. Metabolically healthy obesity (MHO) accounts for roughly 35 percent of all obese patients. No clear consensus has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Furthermore, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissue (lean and obese) as well as in atherosclerosis. There are several subsets of macrophages, of which M1 (pro-inflammatory) and M2 (anti-inflammatory) are best documented. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (apoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO and that inflammation driven by macrophages is a novel mechanism for this transition. We found that with extended high-fat diet (HFD), MHO mice became MUO, as judged by increased atherosclerosis. At the MHO stage, DKO mice exhibited increased pro-inflammatory markers, including CD95, in adipose tissue and serum. We found that total adipose tissue macrophages were increased and that CD95+CD86- subset of adipose tissue macrophages were increased. Moreover, we showed that human aortic endothelial cells (HAECs) were activated (as judged by ICAM1 expression) when incubated with both DKO and human macrophage-conditioned media in comparison to respective controls. To summarize, we have found a molecular mechanism explaining how MHO transition to MUO may occur. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. As a result, we hope that these findings will propel the field of MHO forward towards greater understanding and advise clinical treatment.