Repeated Binge‐Like Alcohol Intoxication Increases Mesenteric Lymphatic Permeability Disrupting Lymphatic‐Perilymphatic Adipose Tissue Crosstalk

Abstract

Repeated binge‐like alcohol intoxication (RBAI) episodes induce whole‐body insulin resistance, possibly increasing the risk for metabolic syndrome and type 2 diabetes. Our previous studies showed that acute alcohol intoxication increases mesenteric lymphatic permeability and circulating adiponectin levels. We hypothesize that lymphatic hyperpermeability resulting from RBAI promotes perilymphatic adipose tissue (PLAT) inflammation and dysregulates insulin signaling. Chronically instrumented (intragastric catheter) male Sprague‐Dawley rats received an intragastric bolus of 2.5 g/kg/day of alcohol (12.5% alcohol w/v) or isocaloric dextrose in Vanilla Ensure (116 kcal/kg/day) for 3 days. Mesenteric lymphatic permeability, PLAT inflammatory milieu, and insulin (0.25 U/kg)‐stimulated AKT phosphorylation were determined following alcohol/dextrose administration. RBAI resulted in greater leak of Evans Blue into PLAT, higher tissue expression of inflammatory cytokines (IL1α, IL1β, IL6, and GM‐CSF), and attenuation of insulin‐stimulated AKT phosphorylation (Ser473) compared to dextrose‐treated control animals. These results suggest that RBAI‐induced mesenteric lymphatic hyperpermeability promotes PLAT inflammatory milieu, and impairs insulin signaling in PLAT. We speculate that increased gut‐derived toxins directly mediate these early alterations, reflecting lymphatic/PLAT crosstalk, which we predict disrupts metabolic regulation and contributes to increased risk for systemic alcohol‐induced insulin resistance. Supported by NIH F32AA021049 and LSUHSC Department of Physiology.