Abstract
Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. 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 our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. 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. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.
Highlights
Since the mid-1970s, the United States has seen a consistent rise in obesity in men and women, with rates of approximately 35% and 40%, respectively [1]
We found that human pericardial adipose tissue from obese patients with type 2 diabetes mellitus (T2DM) showed a trend of increased miR-155 transcripts compared with obese patients without T2DM (Figure 1B)
These results demonstrate that WT mice on high-fat diet (HFD) and obese patients without T2DM have reduced miR-155 levels compared with atherogenic mice and obese patients with T2DM
Summary
Since the mid-1970s, the United States has seen a consistent rise in obesity in men and women, with rates of approximately 35% and 40%, respectively [1]. Not all obese individuals develop these associated metabolic dysfunctions. Our model did not meet the criteria for metabolic syndrome (MetS), which is the presence of at least three of five risk factors: enlarged waistline, hypertension, low high-density lipoprotein (HDL) levels, high triglyceride levels, and high fasting blood glucose level. Several studies agree that, compared with metabolically unhealthy obesity (MUO), MHO is associated with a reduced risk for developing cardiovascular diseases (CVDs), type 2 diabetes mellitus (T2DM) [12, 13] and with lower mortality [14, 15]. MHO has an increased risk compared with a metabolically healthy (MH) lean state, which remains the case no matter the stringency of criteria applied [16]. The underlying mechanisms for how MHO transition may occur are unknown
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