Adipose Macrophage Infiltration Is Associated With Insulin Resistance and Vascular Endothelial Dysfunction in Obese Subjects

Abstract

Objective-Experimental studies suggest that adipose inflammation is etiologically linked to obesity-induced systemic disease. Our goal was to characterize the state of inflammation in human fat in relation to vascular function and metabolic parameters in obese individuals. Methods and Results-We collected subcutaneous abdominal fat in 77 obese subjects (BMI Ն30 kg/m 2 ) and quantified adipose macrophage population using targeted immunohistochemistry. Brachial artery vasodilator function was examined using high-resolution vascular ultrasound. In 50 subjects, an inflamed adipose phenotype characterized by tissue macrophage accumulation in crown-like structures was associated with systemic hyperinsulinemia and insulin resistance (HOMA-IR 5.5Ϯ4.5 versus 2.6Ϯ1.9, Pϭ0.002) and impaired endothelium-dependent flow-mediated vasodilation (8.5Ϯ4.4% versus 10.8Ϯ3.8%, PϽ0.05), as compared to subjects with quiescent noninflamed adipose architecture (nϭ27). Macrophage retention in fat was linked to upregulated tissue CD68 and tumor necrosis factor (TNF)-␣ mRNA expression in addition to increased plasma hs-CRP. Conclusions-In a cohort of obese subjects, we demonstrate that proinflammatory changes in adipose tissue are associated with systemic arterial dysfunction and insulin resistance. These findings suggest that adipose inflammation may be linked to vascular injury and increased cardiovascular risk in obese subjects. (Arterioscler Thromb Vasc Biol. 2008;28:1654-1659)Key Words: obesity Ⅲ endothelium Ⅲ inflammation Ⅲ insulin Ⅲ vasculature O besity represents a disease state characterized by chronic subclinical inflammation linked to increased risk of type-2 diabetes and atherosclerosis. 1,2 Although the stimulus or source for persistent immune activation remains unclear, fat tissue is increasingly being recognized as an important hotbed of metabolic activity and a significant source of proatherogenic and proinflammatory adipocytokines that orchestrate metabolic and vascular dysfunction. 3,4 Animal studies suggest that adipose tissue macrophage (ATM) activity is functionally intertwined with systemic disease mechanisms. [5][6][7] The pathogenic link is supported by pharmacogenetic studies demonstrating that attenuation of ATM influx alters cytokine production and improves insulin sensitivity. 8,9 From a clinical perspective, inflammatory changes in fat have not been commonly investigated in human disease nor examined in the context of functional cardiovascular abnormalities.Inflammatory mechanisms are critical to all stages of cardiovascular disease progression and play a causal role in vascular endothelial dysfunction that represents a crucial early event in atherosclerosis and subsequent coronary heart disease (CHD) events. 10,11 These mechanisms are, in part, supported by local and systemic release of inflammatory cytokines that mediate activation of neutrophils, monocytes, and T-cells, promote lipid-laden foam cell accumulation, weaken atherosclerotic plaque stability, and impair nitric oxide (NO)-mediated endothelium-depend...

Dietary intervention-induced weight loss decreases macrophage content in adipose tissue of obese women

“…19,20 Moreover, ATM-induced inflammation has been associated with other co-morbidities such as cardiovascular diseases, liver steatosis or type 2 diabetes. 14,[21][22][23] Macrophages represent various cell populations with marked plasticity that mirror different functions depending on the stimuli that come from tissue microenvironment. [24][25][26] In mouse models, it has been reported that ATMs have reparative (remodeling) function with anti-inflammatory phenotype (known as M2-alternatively activated macrophages), whereas newly recruited macrophages activated during obesity are mainly pro-inflammatory (known as M1-classically activated macrophages).…”

Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis

“…On the other hand, M2 macrophages are scattered in the interstitial spaces between adipocytes 10 . Notably, the number of CLS is positively correlated with systemic insulin resistance in obese subjects 11,12 , suggesting the pathophysiologic role of CLS in adipose tissue inflammation and systemic energy metabolism. However, how CLS is formed in adipose tissue during the course of obesity and how it is involved in adipose tissue remodelling are poorly understood.…”

Le tissu adipeux

“…Certaines études rapportent une relation inverse entre la sensibilité à l'insuline et l'expression de marqueurs de macrophages dans le tissu adipeux, particulièrement dans le tissu adipeux viscéral [38]. La présence accrue de macrophages en couronne a également été associée à l'altération de la sensibilité à l'insuline [39]. À l'inverse, nos travaux ne permettent pas d'établir de relation entre l'abondance des macrophages et les paramètres sanguins de l'homéostasie glucidique chez des sujets très obèses [40].…”