Chronic binge alcohol dysregulates omental adipose tissue extracellular matrix in simian immunodeficiency virus-infected macaques

Background

Increased survival, prolonged antiretroviral treatment (ART), and lifestyle choices, including alcohol misuse, increase the risk for comorbid conditions, including cardiometabolic comorbidities among people with HIV (PWH). Published studies indicate that dysregulated adipose tissue phenotype, particularly of the visceral adipose depot, contributes to metabolic dysregulation. Using a nonhuman primate model of simian immunodeficiency virus (SIV) infection, we previously demonstrated that chronic binge alcohol (CBA) administration to ART-treated rhesus macaques decreases whole-body glucose-insulin dynamics, increases omental adipose tissue (OmAT) collagen content, decreases OmAT adipocyte size, and alters pancreatic endocrine function. The objective of this study was to delineate the depot-specific effects of CBA on visceral (VAT) and subcutaneous adipose tissue (SAT) extracellular matrix (ECM) phenotype, the potential mechanisms involved in AT ECM remodeling, and the implications of increased tissue stiffness on AT metabolic alterations in female SIV-infected macaques.

Methods

Omental and subcutaneous adipose samples were obtained from female SIV-infected, ART-treated macaques that received intragastric administration of CBA (12–15 g/kg/week, CBA/SIV) or water (VEH/SIV) for 14.5 months.

Results

CBA preferentially altered the ECM phenotype in OmAT, a VAT depot. The CBA-associated changes included increased ECM accumulation, increased collagen I–III ratio, a profibrotic milieu, and decreased matrix metalloproteinase 13 activity. These changes were associated with smaller adipocyte size, decreased triglyceride content, decreased gene expression of perilipins, and a potential dysregulation of peroxisome proliferator-activated receptor gamma signaling.

Conclusions

Collectively, these findings suggest that CBA-mediated ECM remodeling “traps” adipocytes within a stiff environment that we propose disrupts adipocyte metabolic programming and may increase the risk for metabolic comorbidities.