Reduced adipose tissue inflammation represents an intermediate cardiometabolic phenotype in obesity

Abstract

Objectives: The purpose of this study was to determine whether obese individuals with reduced adipose tissue inflammation exhibit a more favorable cardiovascular risk profile.

Background: Obesity is associated with a low-grade state of chronic inflammation that might be causally related to cardiometabolic disease.

Methods: With immunohistochemistry, we categorized obese individuals dichotomously as having inflamed fat (n = 78) or noninflamed fat (n = 31) on the basis of the presence (+) or absence (-) of macrophage crown-like structures (CLS) in subcutaneous abdominal fat biopsy samples. We compared their metabolic, vascular, and adipose tissue characteristics with lean subjects (n = 17).

Results: Inflamed CLS+ obese individuals displayed higher plasma insulin, homeostasis model assessment, triglycerides, glucose, blood pressure, high-sensitivity C-reactive protein, low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, and brachial artery flow-mediated dilation compared with lean subjects (p < 0.05). Adipose messenger ribonucleic acid expression of inflammatory genes including CD68, leptin, matrix metalloproteinase-9, CD163, and CD8A were significantly greater and vascular endothelial growth factor was lower in the CLS+ group (p < 0.05). In contrast, obese subjects with noninflamed fat exhibited a mixed clinical phenotype with lower insulin resistance, reduced proatherogenic gene expression, and preserved vascular function as in lean subjects. In multiple linear regression adjusting for age and sex, CLS status (beta = -0.28, p = 0.008) and waist circumference (beta = -0.25, p = 0.03) were independent predictors of flow-mediated dilation.

Conclusions: These findings lend support to the novel concept that factors in addition to absolute weight burden, such as qualitative features of adipose tissue, might be important determinants of cardiovascular disease. Therapeutic modulation of the adipose phenotype might represent a target for treatment in obesity.

Figures 1. Representative histology of inflamed human subcutaneous adipose tissue as demonstrated using light microscopy

CD68+ macrophages (brown color) are organized into multiple “crown-like-structures” that encircle necrotic adipocytes as a hallmark of chronic local inflammation in human fat tissue. A. left panel, 20x power; B. right panel, 40x power, solid arrows indicate macrophages, dotted arrow illustrates an adipocyte.

Figures 2. Adipose tissue mRNA gene expression

Lean subjects and obese individuals are stratified by CLS status for A) CD68; B) MMP-9; C) Leptin; D) CD 163; E) CD8A; and F) VEGF-A. * p<0.05 vs. lean; † p<0.05 vs. CLS- obese.