In the present study, we demonstrate that obese individuals display more proatherogenic vascular, metabolic, and adipose tissue profiles as compared to lean subjects. The key finding was that for the same degree of severe obesity, individuals with reduced adipose inflammation exhibited an “intermediate” clinical phenotype with arterial function similar to normal weight subjects. We observed parallel trends in adipocytokine expression that mirrored systemic profiles suggesting a biological connection. In this regard, the findings prompt speculation that aspects of cardiovascular disease mechanisms may have origins within the adipose microenvironment.
Animal models consistently show that excess adiposity induces a chronic state of immune system activation characterized by adipose tissue influx of macrophages, neutrophils, and T lymphocytes that stimulate adipocytokine production implicated in the temporal development of insulin resistance (13
). We now recognize that the consequence of adipose inflammation likely extends beyond metabolic disturbance to cause vascular injury and atherosclerosis. For example, adipose tissue inflammation induces endothelial activation and alters blood flow in the microcirculation of obese mice (14
). Inflamed perivascular fat preferentially localizes to atherosclerotic regions and adipocytokines impair vasomotor function (15
). These findings show that functional properties of blood vessels are adversely modulated by the state of the adipose microenvironment. It is thus plausible to speculate that disease at the adipose level may extend and reflect in the systemic vasculature, as this concept is supported by our finding that obese patients with reduced adipose inflammation displayed favorable arterial responses as in lean subjects. This may hold clinical significance as prospective studies consistently show that endothelial dysfunction predicts cardiovascular events (16
The degree of adipose immune activation in humans is more variable than in genetically modified experimental animals, and this heterogeneity in tissue phenotype provides a window of opportunity to investigate how adipose changes relate to clinical disease. In this regard, we demonstrated that a specific pattern of macrophage build-up in fat is associated with metabolic and endothelial dysfunction (2
). The key issue of what sets off the inflammatory cascade in fat is not well understood and likely multifactorial relating to adipocyte hypertrophy and dysfunction, oxidative stress, toxic lipolysis, and deficient neovascular remodeling (17
). Adipose activation and adipocytokine overproduction may have its systemic consequences. For example, we demonstrated over-expression of MMP9 which plays a key role in matrix turnover and remodeling as part of the activated tissue profile. Plasma metalloproteinase concentrations are increased in the obese and clinical studies show that fat is a significant source (5
). As MMP9 destabilizes atherosclerotic plaques, consequences of weight gain may be germane to cardiovascular risk (18
Adipose tissue macrophages largely originate from circulating monocytes (13
). They can exist in at least two differentially activated states characterized as M1 macrophages that produce proinflammatory cytokines linked to insulin resistance and atherosclerosis and alternative M2 phenotypes involved in immunosuppressive functions (19
). In obese animals, these cell lines show predominantly M1 characteristics (20
), while human fat displays mixed phenotypes (5
). Their precise role in human disease is unknown, and whether macrophage polarization influences the pathogenic profile of fat remains an open question (5
). Most probably, immune changes in humans is dynamic with activation of proinflammatory “danger signals” in early phases of weight gain followed by adaptive remodeling, as the expression for many acute phase cytokines was similar in both obese groups. We demonstrated increased expression for M2 markers of CD163 and CD206 suggesting that compensatory immunosuppressive pathways may be triggered in later stages of obesity.
Our seminal finding was that obese individuals without proinflammatory adipose changes displayed more favorable clinical characteristics. This subset represented approximately 30% of our obese cohort, strikingly similar in proportion to metabolically healthier obese phenotypes in large population studies (21
). Both WC and the presence of CLS in adipose tissue were independent predictors of brachial artery FMD, suggesting that both “quantity” and “quality” of fat may be germane to systemic disease (22
Our present study has several limitations. To minimize subject discomfort, we relied on a single subcutaneous biopsy site for adipose tissue characterization; therefore, it remains possible that some individuals were miscategorized owing to sampling error. Our analyses were limited to subcutaneous fat which was readily accessible. Since visceral depots are felt to be more metabolically active and pathogenic in nature, it is possible that stronger correlations could have been observed (23
). Most participants in the present study were female, reflecting general clinical practice and gender differences in populations that seek weight loss treatments (25
). Macronutrient intake plays an important role in adaptive immune responses. While we did not specifically record daily food logs, we acknowledge that chronic differences in dietary patterns could influence metabolic states (26
). These limitations are counterbalanced by the relatively large sample size for this type of invasive clinical study and novel translational information generated in severe human obesity where limited information currently exists.
In conclusion, we identified a group of obese subjects with reduced adipose inflammation that exhibit intermediate risk factor profiles. We hypothesize that individuals prone to inflammatory activation with weight gain may have increased cardiometabolic risk. Therapeutic modulation of the adipose phenotype may represent a novel target for treatment in obesity.