Postprandial activation of leukocyte‐endothelium interaction by fatty acids in the visceral adipose tissue microcirculation

Abstract

High‐fat diet (HFD)‐induced obesity is associated with accumulation of inflammatory cells predominantly in visceral adipose depots [visceral adipose tissue (VAT)] rather than in subcutaneous ones [subcutaneous adipose tissue (SAT)]. The cellular and molecular mechanisms responsible for this phenotypic difference remain poorly understood. Controversy also exists on the overall impact that adipose tissue inflammation has on metabolic health in diet‐induced obesity. The endothelium of the microcirculation regulates both the transport of lipids and the trafficking of leukocytes into organ tissue. We hypothesized that the VAT and SAT microcirculations respond differently to postprandial processing of dietary fat. We also tested whether inhibition of endothelial postprandial responses to high‐fat meals (HFMs) preserves metabolic health in chronic obesity. We demonstrate that administration of a single HFM or ad libitum access to a HFD for 24 h quickly induces a transient P‐selectin‐dependent inflammatory phenotype in the VAT but not the SAT microcirculation of lean wild‐type mice. Studies in P‐selectin‐deficient mice confirmed a mechanistic role for P‐selectin in the initiation of leukocyte trafficking, myeloperoxidase accumulation, and acute reduction in adiponectin mRNA expression by HFMs. Despite reduced VAT inflammation in response to HFMs, P‐selectin‐deficient mice still developed glucose intolerance and insulin resistance when chronically fed an HFD. Our data uncover a novel nutrient‐sensing role of the vascular endothelium that instigates postprandial VAT inflammation. They also demonstrate that inhibition of this transient postprandial inflammatory response fails to correct metabolic dysfunction in diet‐induced obesity.—Preston, K. J., Rom, I., Vrakas, C., Landesberg, G., Etwebe, Z., Muraoka, S., Autieri, M., Eguchi, S., Scalia, R. Postprandial activation of leukocyte‐endothelium interaction by fatty acids in the visceral adipose tissue microcirculation. FASEB J. 33, 11993‐12007 (2019). http://www.fasebj.org

Glucose‐dependent insulinotropic polypeptide modifies adipose plasticity and promotes beige adipogenesis of human omental adipose‐derived stem cells

“…Obesity and its metabolic complications such as type 2 diabetes mellitus (T2DM), pose a threat to global health. 1 However, current anti-obesity drugs cannot provide long-term agreeable outcomes to most obese patients because of limited efficacy and/or substantial adverse effects. 2 Indeed, the classic pharmacotherapy for obesity mainly works through activating anorexigenic effect in central nervous system (CNS) and decreasing fat absorption.…”

“…Obesity and its metabolic complications such as type 2 diabetes mellitus (T2DM), pose a threat to global health 1 . However, current anti‐obesity drugs cannot provide long‐term agreeable outcomes to most obese patients because of limited efficacy and/or substantial adverse effects 2 .…”

Adipocyte Phenotype Flexibility and Lipid Dysregulation

“…Clinical and animal studies on inflammatory cascade intervention have demonstrated that inflammation is a contributor to cardiometabolic pathologies [ 105 ]. Inflammatory signaling [ 106 ] and immune cell accumulation [ 116 , 117 , 118 , 119 , 120 ] in adipose tissue cause metabolic dysfunction; however, the initial source of the inflammatory action has remained elusive. Whether the pathogenesis of cardiometabolic disease is initiated by metabolic dysfunction or inflammatory action has long been debated.…”

“…It is hypothesized that repetitive nutrient overload is the impetus for cardiometabolic pathogenesis. Lean mice fed single high-fat meals undergo a transient inflammatory response in the visceral adipose tissue that is extended with continued high-fat feeding [ 120 ]. Perhaps the most convincing evidence that the chronic overfed state is responsible for pathogenesis comes from studies employing intermittent fasting.…”

“…Further, experiments with 3T3L1 adipocytes have shown that adipocyte hypertrophy and metabolic dysfunction occur in the absence of inflammation when treated with monounsaturated fatty acids [ 125 ]. The relationship between hypertrophic adipocytes and metabolic function does not explain observable disturbances in metabolism and inflammation that occur in lean individuals [ 135 , 136 ] and rodents [ 120 ]. In mice, the ultimate culprit appears to be frequent, repetitive high-fat feeding [ 138 ].…”