A distinct form of fat fibrosis is linked to insulin resistance in people with HIV

Figures

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  Figure 1. PWH have increased SAT fibrosis versus PWoH, particularly in those with normal %BF (NBF). Hydroxyproline (HYP) content (ng/mg) in SAT was compared between people without HIV (PWoH; purple) and people with HIV (PWH; blue). (A) In the overall cohort (PWoH, n = 74; PWH, n = 46), SAT HYP content was significantly higher in PWH than PWoH (P = 0.0004). (B) Subgroup analysis for participants with a high %BF (HBF; PWoH, n = 43; PWH, n = 26) showing no difference in SAT HYP between groups (P = 0.34). (C) Among participants with NBF, SAT HYP content was significantly elevated in PWH compared with PWoH (PWoH, n = 31; PWH, n = 20), (P < 0.0001). Differences between the 2 groups were analyzed by Mann-Whitney U test. *** P < 0.001, **** P < 0.0001.

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  Figure 2. Adjusted associations between adiposity, SAT fibrosis, and IR in PWoH and PWH. Heatmaps depict partial Spearman rank-order correlations among BMI, total %BF, SAT HYP content, and IR as assessed by HOMA-IR. Panel A shows correlations in PWoH; (n = 73), and Panel B shows the same correlations in PWH (n = 46). Correlations were calculated separately within each group and adjusted for age, sex, race, and exposure to legacy d-drugs. Only statistically significant partial Spearman correlation coefficients (ρ; P < 0.05) are displayed. HYP: Hydroxyproline

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  Figure 3. PWH have a distinct transcriptional pattern of fibrosis-associated gene expression in the SAT. Volcano plot of differential gene expression (DGE) in the SAT of PWH (n = 37) versus PWoH (n = 38) using the NanoString Human Fibrosis panel. The x axis shows log2 fold change, and the y axis shows −log10 P value. The dashed horizontal line denotes the nominal significance threshold (P < 0.01). No fold-change threshold was applied. Genes with P < 0.01 are highlighted (red, upregulated in PWH; blue, downregulated in PWH). DGE was assessed using NanoStringDiff with covariate-adjusted negative binomial generalized linear models.

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  Figure 4. HIV and obesity are associated with distinct patterns of SAT gene transcription. (A) Volcano plot of DGE in the SAT of 16 PWH-NBF and 18 PWoH-NBF using the NanoString Human Fibrosis panel. The x axis shows log2 fold change, and the y axis shows −log10 P value. Genes meeting the nominal significance threshold (P < 0.01) are highlighted (red, upregulated compared with PWoH-NBF; blue, downregulated compared with PWoH-NBF). Volcano plots for the remaining pairwise comparisons are in Supplemental Figure 4. (B) Venn diagrams showing the number of genes downregulated (left) and upregulated (right) in pairwise comparisons between PWoH-NBF and PWoH-HBF, PWH-NBF, and PWH-HBF, respectively. Overlapping regions indicate genes shared across comparisons, highlighting distinct and convergent transcriptional patterns associated with HIV and increasing adiposity.

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  Figure 5. Pathway analysis reveals distinct and shared transcriptional programs across HIV and adiposity subgroups. Normalized enrichment scores (NES) from GSEA for select top significantly enriched pathways in (A) PWH-NBF versus PWoH-NBF, (B) PWH-HBF versus PWoH-NBF, and (C) PWoH-HBF versus PWoH-NBF. Positive NES indicates pathway upregulation, and negative NES indicates pathway downregulation relative to PWoH-NBF. FDR < 0.1. Complete GSEA results, including leading-edge genes, are provided in the Supporting Data Values file.

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  Figure 6. PWH have elevated plasma endotrophin levels, particularly among those with normal body fat. Plasma endotrophin (ETP) concentrations (ng/mL) were compared between persons without HIV (PWoH; purple) and persons with HIV (PWH; blue). (A) In the overall cohort (PWoH, n = 73; PWH, n = 46), plasma ETP levels were significantly higher in PWH than PWoH (P = 0.0045). (B) Among participants with normal body fat (NBF; PWoH, n = 31; PWH, n = 20), plasma ETP levels were significantly elevated in PWH compared with PWoH (P = 0.018). (C) Among participants with higher body fat (HBF; PWoH, n = 42; PWH, n = 26), the difference did not reach statistical significance (P = 0.10). Groups were compared using the Mann-Whitney U test. *P < 0.05, **P < 0.01.