A Distinct Form of Subcutaneous Fat Fibrosis Predicts Insulin Resistance in People with HIV.

Background: People with HIV (PWH) are at heightened risk for type 2 diabetes (T2D) and insulin resistance (IR), even with effective antiretroviral therapy (ART). Adipose tissue dysfunction, including subcutaneous adipose tissue (SAT) fibrosis, is a key contributor to metabolic disease. However, the role of SAT fibrosis in IR among PWH remains poorly understood. We therefore investigated the relationship between SAT fibrosis and IR in PWH along with molecular signatures that might distinguish HIV-associated SAT fibrosis from that associated with obesity.

Methods: We studied 112 participants, including 43 PWH and 69 people without HIV (PWoH) and excluding those with established T2D. Body composition was assessed by dual-energy X-ray absorptiometry (DXA), and SAT fibrosis was analyzed by quantifying hydroxyproline levels from biopsies. SAT transcriptional profiles were examined using a targeted fibrosis-related gene panel. Plasma levels of endotrophin, a marker of extracellular matrix remodeling, were also measured.

Results: PWH had significantly greater SAT fibrosis compared to PWoH, with the largest differences observed among participants without obesity. In this subgroup, SAT fibrosis was strongly associated with IR, despite the absence of elevated adiposity. Transcriptomic analysis identified a distinct fibrosis-associated gene expression pattern in PWH, marked by upregulation of and key immune-related genes (e.g. , ). Pathway analysis further supported upregulated extracellular matrix remodeling and immune activation, along with downregulated thermogenesis, lipid metabolism, and insulin signaling in the SAT of non-obese PWH. Plasma endotrophin levels were significantly elevated in PWH and were independently associated with SAT fibrosis.

Conclusion: Our findings identify SAT fibrosis as an obesity-independent driver of IR in PWH. Notably, SAT fibrosis predicts IR at normal body fat levels and can be noninvasively monitored through circulating endotrophin, offering a potential biomarker for early intervention. The distinct transcriptional signature of HIV-associated fibrosis reveals unique mechanisms that may underlie heightened metabolic risk in this population and highlight new therapeutic avenues targeting adipose tissue remodeling and metabolic dysfunction.