Adipose tissue microvasculature is linked to insulin resistance and lipidome alterations in treated HIV

Dyslipidemia is common in people with HIV (PWH) and linked to cardiometabolic disease risk. Subcutaneous adipose tissue (SAT) regulates lipid storage and release, but how SAT cellular composition might influence circulating lipids in PWH on contemporary antiretroviral therapy (ART) is not well defined.

Cross-sectional, observational cohort of PWH on long-term contemporary ART with virologic suppression.

We performed untargeted fasting plasma lipidomic profiling on 127 individuals with a range of metabolic fitness (nondiabetes, prediabetes, diabetes). Adjusted logistic and linear regression models identified lipid species associated with diabetes status and HOMA2-IR, respectively. Linear regression assessed the relationship between abdominal SAT cell composition from single-cell RNA sequencing with circulating lipid classes ( n  = 59).

The median age was 48  years, body mass index 31.5 kg/m 2 , and 48% self-identified as non-White, with 23% women. Diabetes as a dichotomous outcome had few differences in lipid species. In contrast, HOMA2-IR was associated with higher levels of several species of tri- and diacylglycerols and inversely associated with phosphatidylcholine, phosphatidylethanolamine species, and many of their derivatives among those without diabetes. Adipose tissue microvasculature remodeling, characterized by a reduction in capillary endothelium and decreased expression of key lipid trafficking receptors ( LPL , GPIHBP1 ), was associated with the insulin-resistant lipidomic signature.

Adipose tissue microvasculature remodeling in PWH on contemporary ART was associated with changes in several plasma lipid species, which are also linked to insulin resistance. Interventions targeting adipose tissue endothelial dysfunction may improve metabolic health in PWH on long-term ART.