THBS1 Marks a Fibro-Inflammatory Shift in Human Visceral Fat
Human visceral adipose tissue is not simply enlarged storage depots in obesity. In this study, it behaves more like an active inflammatory organ undergoing structural remodeling, with THBS1 emerging as a central signal in that process.
Investigators built a single-nucleus and bulk transcriptomic atlas of visceral fat from an ethnically homogeneous cohort spanning three metabolic states: lean with normal glucose tolerance, obesity, and obesity with type 2 diabetes. The design matters because adipose dysfunction is not uniform across obesity. Some tissue remains metabolically adaptable, while other tissue becomes fibrotic, inflamed, and less able to expand through healthy adipogenesis. The data point to THBS1 as a molecule sitting squarely in that second trajectory.
Bulk RNA sequencing separated the three clinical groups along expected biologic lines. Lean tissue showed enrichment for oxidative phosphorylation, adipogenesis, and fatty acid metabolism. Obese tissue, especially when diabetes was present, shifted toward inflammatory response, hypoxia, and TGFβ signaling. Those pathways fit the histology of dysfunctional visceral fat: low oxygen tension, immune-cell recruitment, extracellular matrix accumulation, and loss of normal adipocyte plasticity.
A Single-Cell Atlas Reveals Remodeling at the Niche Level
Single-nucleus RNA sequencing captured 86,000 high-quality nuclei from 21 participants and resolved eight major cell types: adipocytes, adipose stem cells, mesothelial cells, endothelial cells, lymphatic endothelial cells, smooth muscle cells, myeloid cells, and T/NK cells. Even at this coarse level, the tissue was already shifting. Adipocytes and adipose stem cells were proportionally reduced in obesity, while myeloid cells became more prominent.
One sentence captures the clinical direction of the tissue: visceral fat in metabolic disease is losing its regenerative cell populations while gaining inflammatory ones.
Using single-cell interpretable tensor decomposition, the analysis identified a metabolic-state-associated transcriptional program shared across cell types, with adipose stem cells and adipocytes contributing genes tied to metabolism and immune regulation. That overlap is biologically important. It suggests the stromal and parenchymal compartments are not separate observers of disease; they are participants in the same remodeling circuit.
SLC11A1+ Macrophages Expand as Inflammation Deepens
The immune compartment sharpened the picture further. Macrophages divided into two major states, and their trajectories moved in opposite directions across disease severity. SLC11A1+ macrophages expanded from lean to obesity to obesity with diabetes, while LYVE1+ macrophages gradually declined.
The functional signatures align with those shifts. SLC11A1+ macrophages carried inflammatory pathways, including TNF production and NF-κB signaling, along with lipid-associated macrophage markers such as APOE, TREM2, GPNMB, and PLIN2. They also expressed M1-associated markers including TNF and IL1B. In contrast, LYVE1+ macrophages were enriched for vascular-related functions, including endothelial cell chemotaxis and blood vessel morphogenesis, with higher expression of tissue-resident and M2-associated markers such as LYVE1, FOLR2, and MRC1.
Flow cytometry confirmed the expansion of SLC11A1+ macrophages in obese and diabetic visceral fat, and tissue imaging showed SLC11A1 colocalized with CD68 and IL6 in human samples. Those are not abstract transcriptomic shifts. They are visible signs of a macrophage compartment that is becoming more inflammatory and less homeostatic as metabolic disease worsens.
THBS1 Sits at the Intersection of Fibrosis and Immune Activation
The core mechanistic finding centers on THBS1, which was upregulated in a fibro-inflammatory subpopulation of adipose stem cells and adipocytes. In the atlas, these cells were enriched in obesity and obesity with type 2 diabetes relative to lean tissue. Plasma and adipocyte THBS1 levels also correlated with metabolic traits, including BMI and HbA1c, giving the molecule a translational profile that extends beyond tissue transcriptomics.
The functional experiments make the biological case stronger. In vitro work using human primary adipose stem cells, THP-1 macrophages, and Matrigel-captured mature adipocytes showed that THBS1 promoted adipose fibrosis and inflammation. The pathway ran through macrophage-mediated TGFβ activation, which is a plausible mechanism for matrix deposition and scarring in visceral fat. TGFβ drives fibroblast activation, extracellular matrix accumulation, and suppression of differentiation programs; in adipose tissue, that combination would blunt adipogenesis and favor a stiffer, less expandable depot.
A short clinical consequence follows directly from that biology: once visceral fat becomes fibrotic, it loses the capacity to store lipid safely.
Ex vivo experiments in mouse and human visceral adipose tissue explants, along with in vivo gain-of-function and antibody-mediated neutralization studies, reinforced the same axis. Increasing THBS1 intensified fibro-inflammatory features, while inhibiting it attenuated those changes in metabolically dysfunctional adipose tissue. The study also showed that THBS1 impaired adipogenesis and adipocyte function through direct and paracrine mechanisms, especially via adipocyte–macrophage crosstalk. In other words, the molecule is not merely a marker of damaged tissue; it actively helps create the damaged state.
Why THBS1 Matters for Metabolic Disease Biology
The findings place THBS1 in a biologically credible position within visceral fat dysfunction. It links stromal cells, adipocytes, and macrophages through a TGFβ-centered inflammatory-fibrotic circuit. That matters because the pathogenesis of type 2 diabetes and obesity-related cardiometabolic disease depends not only on excess adiposity but also on the quality of adipose expansion. When tissue can expand through new adipocyte formation, lipid can be buffered more safely. When expansion is constrained by fibrosis and immune activation, lipids spill into ectopic sites and insulin resistance deepens.
The cohort design strengthens the interpretation. Participants were stratified by clear metabolic states, and the comparison between lean, obese, and obese with diabetes made it possible to distinguish obesity alone from more advanced metabolic failure. Even so, the biomarker claim remains preliminary. Full validation of THBS1 as a diagnostic blood marker will require larger and more diverse cohorts, and the study does not establish whether lowering THBS1 in humans would reverse disease biology in a durable way.
Still, the mechanistic arc is unusually coherent. Single-cell profiling identified the cellular niche, immune mapping defined the inflammatory arm, and functional experiments connected THBS1 to fibrosis, impaired adipogenesis, and macrophage-driven TGFβ activation. For metabolic disease research, the value lies in that chain of evidence: it turns visceral fat from a descriptive complication of obesity into a tissue with a testable pathogenic program and a candidate therapeutic target.
The unanswered clinical issue is whether this pathway can be interrupted early enough to preserve adipose plasticity before fibrosis becomes fixed.