Abstract
BACKGROUND. Despite antiretroviral therapy (ART), people with HIV (PWH) are at heightened risk for insulin resistance (IR) and type 2 diabetes (T2D). Subcutaneous adipose tissue (SAT) fibrosis contributes to metabolic disease, but its role in IR among PWH is unknown. We investigated the relationship between SAT fibrosis and IR in PWH, along with transcriptional signatures to distinguish it from SAT fibrosis due to obesity. METHODS. We analyzed body composition and SAT fibrosis (hydroxyproline) in 46 PWH and 74 people without HIV (PWoH), excluding individuals with T2D. We examined fibrosis-related gene transcription in the SAT using a targeted panel and measured plasma endotrophin, a marker of extracellular matrix (ECM) remodeling. RESULTS. PWH had substantially more SAT fibrosis than PWoH, notably in non-obese individuals. Moreover, SAT fibrosis in these PWH was strongly associated with IR, independently of prior legacy ART or ongoing integrase strand inhibitor treatment. This SAT fibrosis was highlighted by a distinct transcriptional pattern marked by upregulation of COL14A1, key immune-related genes (e.g., CCL4, NLRP3), and pathways governing ECM remodeling and immune activation, as well as downregulation of thermogenic, lipid metabolic, and insulin signaling pathways. Plasma endotrophin levels were also elevated in PWH and correlated independently with SAT fibrosis. CONCLUSION. SAT fibrosis was associated with IR independent of obesity in PWH and was mirrored by circulating endotrophin levels, offering a plausible noninvasive biomarker for early intervention. The distinct transcriptional signature of HIV-associated SAT fibrosis highlights candidate mechanisms that may underlie metabolic risk and offer therapeutic avenues in this population.
Authors
Diana L. Alba, Alaa Abdellatif, Moon K. Choi, Stephen M. Brown Mayfield, Thuy An T. Pham, David I. Berrios, Antonio E. Rodriguez, Marin Ewing, Tony R. Figueroa, Judy Gonzalez-Vargas, Ningyan Zhang, Zhiqiang An, Dawei Bu, Steven G. Deeks, Philipp E. Scherer, Peter W. Hunt, Suneil K. Koliwad
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
