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.

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.

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 COL14A1 and key immune-related genes (e.g. CCL4, NLRP3). 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.

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. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by National Institutes of Health grants R01DK141041 (PWH and SKK), R01DK112304 (PWH and SKK), R56DK133997 (PWH and SKK), K08DK124679 (DLA) Robert Wood Johnson Foundation, Harold Amos Medical Faculty Development Program (DLA), NIH T32 Training Grant 5T32DK007418 (MKC), UCSF NORC grant (P30DK098722), National Institutes of Health: UCSF-Bay Area Center for AIDS Research (P30 AI027763). The funding authorities had no role in study design, data collection, analysis, interpretation, the decision to publish, or manuscript preparation Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All participants provided informed consent, and the study received approval from the University of California San Francisco (UCSF) Institutional Review Board (14-14128) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Declaration of Interests: The authors have declared that no conflict of interest exists Update to figure 4. Supplemental data uploaded