The study addressed a persistent gap in adipose biology. Previous single-cell studies of human fat tissue had catalogued cell types and marker genes, but often relied on cohorts that mixed people of different ancestries and metabolic stages, making it hard to pin down stage-specific signatures or to assign functional roles to the subpopulations identified. The new work took a different approach: 21 participants were stratified by body mass index and hemoglobin A1c into lean (BMI below 23 kg/m², HbA1c below 6.5%), obesity (BMI of 30 kg/m² or above without diabetes), and obesity with type 2 diabetes (BMI of 30 kg/m² or above with HbA1c of 6.5% or higher).

Bulk RNA sequencing of 20 samples showed that lean tissue was enriched for oxidative phosphorylation, adipogenesis, and fatty acid metabolism genes, while tissue from the obesity and diabetes groups was enriched for inflammatory response, hypoxia, and TGFβ signaling programs. Single-nucleus RNA sequencing of 86,000 high-quality nuclei from the same donors resolved eight major cell types, including adipocytes, adipose-derived stem cells, endothelial cells, mesothelial cells, smooth muscle cells, myeloid cells, and T/NK lymphocytes. As metabolic disease advanced, the proportions of adipocytes and stem cells fell while myeloid cells expanded.

An unbiased tensor decomposition analysis identified a transcriptional program tied to metabolic state and concentrated in adipose stem cells and adipocytes, with genes enriched for metabolic processes and immune response regulation—echoing the bulk tissue results and pointing to a coordinated remodeling of the fat-cell and immune compartments. Within the immune compartment, the researchers found two macrophage populations moving in opposite directions across disease states. Macrophages expressing SLC11A1, a gene associated with inflammatory TNF production and NF-κB signaling, expanded progressively from lean tissue to obesity to obesity with diabetes, while macrophages expressing LYVE1, linked to vascular maintenance functions, declined over the same spectrum.

Flow cytometry in an independent validation cohort confirmed the increase in SLC11A1-positive macrophages, which carried markers of pro-inflammatory M1 polarization such as CD11c and CD80 and were mutually exclusive with the M2 marker CD163. Microscopy showed these cells clustered around dying adipocytes in crown-like structures and co-expressed the inflammatory cytokine IL6. Their abundance correlated with adipose fibrosis scores, HbA1c, fasting glucose, and circulating IL6, tying this macrophage subset to both local tissue scarring and systemic metabolic dysfunction.

The central discovery concerned the adipose stem cell compartment. Unsupervised clustering resolved three stem cell subpopulations: one expressing canonical progenitor markers such as PI16, one primed for adipogenic commitment through PPARG expression, and a third defined by high THBS1 expression together with a fibro-inflammatory, extracellular-matrix-remodeling signature including collagens, HAS1, and FGFR1. Trajectory analysis suggested a branching path in which progenitors could either mature toward healthy adipocytes or veer toward a fibro-inflammatory terminal state, and the THBS1-positive fraction grew steadily from lean to obese to diabetic tissue—a trend confirmed by flow cytometry in an independent cohort of 12 people.

Isolated THBS1-positive stem cells showed elevated protein levels of the fibrosis markers ACTA2 and COL6A1 compared with their THBS1-negative counterparts. Functional experiments showed that THBS1 alone could push progenitors down the pathological path. Treating primary human stem cells or an immortalized stem cell line with recombinant THBS1 impaired adipogenic differentiation, reducing lipid accumulation and PPARγ expression and shifting cells away from the committed preadipocyte fate toward a non-adipogenic, fibrotic state.

The treatment dose-dependently increased the proportion of CD9-positive and COL6A1-positive cells and raised collagen and ACTA2 protein levels, demonstrating that THBS1 is sufficient to drive both suppressed adipogenesis and extracellular matrix production in fat progenitors. A parallel adipocyte subpopulation expressing THBS1 also expanded across disease states, and THBS1 protein in primary human adipocytes rose from lean to obese to diabetic donors, correlating with BMI and HbA1c. In mature adipocytes, recombinant THBS1 suppressed adipogenic and functional genes, reduced adiponectin secretion, and induced collagen and TNF production, while silencing THBS1 in adipocytes from obese mice improved insulin-stimulated glucose uptake and AKT signaling.

The mechanism connecting THBS1 to tissue scarring ran through macrophages. Treating human macrophage-like THP-1 cells with recombinant THBS1 triggered TGFβ secretion in a dose-dependent manner, an effect blocked by LSKL, a peptide that disrupts THBS1-mediated activation of latent TGFβ. Transwell co-culture experiments reproduced the same THBS1-dependent, TGFβ-mediated fibrotic conversion in both stem cell and mature adipocyte settings, although TNF induction persisted despite TGFβ blockade, hinting at additional THBS1 pathways that may involve its receptors CD36 or CD47.

THBS1 also reprogrammed macrophages toward a profibrotic transcriptional state in a polarization-dependent manner. In vivo experiments in mice strengthened the causal case. Injecting a THBS1 expression vector into one epididymal fat pad and a control vector into the opposite pad of the same animal produced progressive collagen deposition, peri-adipocyte COL6A1 accumulation, and infiltration of SLC11A1-positive macrophages around THBS1-expressing adipocytes, while the control pad remained largely spared.

Conversely, injecting a neutralizing anti-THBS1 antibody into inguinal fat pads of obese mice significantly reduced fibrosis scores at both four and six weeks. In a translational step, visceral fat samples from people with obesity and diabetes cultured for five days with the anti-THBS1 antibody showed reduced expression of fibrosis and extracellular matrix genes, including FN1, COL5A3, and ADAMTS5, along with lower TGFBI, TGFB2, TNF, and CCL8, and suppression of cell adhesion, matrix-receptor, and TGFβ signaling pathways. The study also traced the upstream regulation of THBS1 to the Hippo signaling pathway.

Transcription factor inference showed elevated YAP/TAZ activity in THBS1-positive stem cells, and chromatin analysis confirmed that the YAP/TAZ partner WWTR1 and the transcription factor TEAD1 bind directly to the THBS1 promoter in human visceral fat. Activating YAP/TAZ with a LATS1/2 inhibitor raised THBS1 and ACTA2 expression in adipocytes, an effect reversed by the TEAD1 inhibitor verteportin. Plasma THBS1 levels rose across disease states and correlated with BMI and HbA1c, and integration with UK Biobank genetic data linked the THBS1-positive stem cell population to BMI, cholesterol, and hypertension traits.

The authors caution that the cohort was small, exclusively Korean, and insufficient for sex-stratified analysis, that single-nucleus sequencing may underrepresent some inflammatory transcripts, and that validating THBS1 as a diagnostic biomarker will require larger, more diverse cohorts with formal diagnostic performance testing.

Subject of Research: Single-nucleus transcriptomics of human visceral adipose tissue identifying THBS1 as a driver of adipose fibro-inflammation in obesity and type 2 diabetes

Article Title: Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease

Article References: Jung, J., Park, E. S., Lee, N. K., Lee, J.-J., Juang, U., Huang, Q., Park, Y. S., Kim, H. J., Kim, J.-K., Oh, T. J., Suh, J. M., Kim, J. B., Moon, J. H., Kim, J. K., & Choi, S. H. (2026). Single-cell landscape of human adipose tissue reveals THBS1 as a potential driver of fibro-inflammation in metabolic disease. Nature Communications, 17(1), Article 11136. https://doi.org/10.1038/s41467-026-77107-w

Image Credits: AI Generated

DOI: 10.1038/s41467-026-77107-w

Keywords: THBS1, adipose tissue, single-nucleus RNA sequencing, obesity, type 2 diabetes, fibrosis, TGF-beta, macrophages, adipogenesis, Hippo signaling, YAP/TAZ, metabolic disease