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...

Inflammation and infiltration of immune cells in white adipose tissue have been implicated in the development of obesity-associated insulin resistance. Likewise, dysregulation of the fuel-sensing enzyme AMP-activated protein kinase (AMPK) has been proposed as a pathogenetic factor for these abnormalities based on both its links to insulin action and its anti-inflammatory effects. In this study, we examined the relationships between AMPK activity, the expression of multiple inflammatory markers in visceral (mesenteric and omental) and abdominal subcutaneous adipose tissue, and whole-body insulin sensitivity in morbidly obese patients (BMI 48 ± 1.9 kg/m2) undergoing gastric bypass surgery. AMPK activity was assessed by western-blots (P-AMPK/T-AMPK) and mRNA levels of various markers of inflammation by qRT-PCR. Patients were stratified as insulin sensitive obese or insulin resistant obese according to their HOMA-IR values. The results indicate that AMPK activity is lower in visceral than in subcutaneous abdominal adipose tissue of these patients and that this is associated with an increased expression of multiple inflammatory genes. They also revealed that AMPK activity is lower in adipose tissue of obese patients who are insulin resistant (HOMA-IR > 2.3) than in BMI-matched insulin sensitive subjects. Furthermore, this difference was evident in all three fat depots. In conclusion, the data suggest that there are close links between reduced AMPK activity and inflammation in white adipose tissue, and whole-body insulin resistance in obese humans. Whether adipose tissue AMPK dysregulation is a causal factor for the development of the inflammation and insulin resistance remains to be determined.

Objective The purpose of this study was to characterize the relationship between adipose tissue phenotype and depot-specific microvascular function in fat. Methods and Results In 30 obese subjects (age 42±11 yr, BMI 46±11 kg/m2) undergoing bariatric surgery, we intra-operatively collected visceral and subcutaneous adipose tissue and characterized depot-specific adipose phenotypes. We assessed vasomotor function of the adipose microvasculature using videomicroscopy of small arterioles (75–250 μm) isolated from different fat compartments. Endothelium-dependent, acetylcholine-mediated vasodilation was severely impaired in visceral arterioles, compared to the subcutaneous depot (P<0.001 by ANOVA). Non-endothelium dependent responses to papaverine and nitroprusside were similar. Endothelial nitric oxide synthase (eNOS) inhibition with Nω-nitro-L-arginine methyl ester (L-NAME) reduced subcutaneous vasodilation but had no effect on severely blunted visceral arteriolar responses. Visceral fat exhibited greater expression of proinflammatory, oxidative stress-related, hypoxia-induced, and proangiogenic genes; increased activated macrophage populations; and higher capacity for cytokine production ex vivo. Conclusions Our findings provide clinical evidence that the visceral microenvironment may be intrinsically toxic to arterial health providing a potential mechanism by which visceral adiposity burden is linked to atherosclerotic vascular disease. Our findings also support the evolving concept that both adipose tissue quality and quantity may play significant roles in shaping cardiovascular phenotypes in human obesity.