Visceral adipose tissue (VAT), the fat depot surrounding internal organs within the abdominal cavity, has transitioned from a passive energy reservoir to a central orchestrator of cardiometabolic disease. Unlike subcutaneous adipose tissue (SAT), VAT exhibits higher lipolytic activity, greater immune cell infiltration, and a pro-inflammatory secretome, directly draining into the portal circulation. Over the past three years, technological breakthroughs in single-cell genomics, spatial transcriptomics, and engineered therapeutic modalities have fundamentally reshaped our understanding of VAT biology. This review highlights recent advances in VAT heterogeneity, its crosstalk with systemic organs, and emerging precision interventions targeting this pathogenic depot.

1. Cellular and spatial atlas of VAT: Beyond adipocytes

The advent of single-cell RNA sequencing (scRNA-seq) and single-nucleus ATAC-seq has unveiled unprecedented heterogeneity within VAT. A landmark study by Emont et al. (2022,Nature Metabolism) profiled human VAT and SAT across body mass index (BMI) strata, identifying distinct adipocyte progenitor subpopulations with differential adipogenic potential. Notably, aDPP4+progenitor subset was enriched in VAT and exhibited a pro-fibrotic transcriptional program, linking it to the characteristic collagen deposition and impaired expandability of visceral fat. Concurrently, spatial transcriptomics (e.g., Visium) applied to human omental adipose tissue by Bäckdahl et al. (2021,Nature Communications) revealed zonated immune microenvironments: M1-like macrophages and CD8+ T cells cluster around crown-like structures, while regulatory T cells (Tregs) are sequestered in perivascular niches. This spatial segregation explains why VAT inflammation is so refractory to systemic anti-inflammatory therapies—drugs fail to penetrate these distinct immune niches.

A pivotal mechanistic breakthrough came from the identification ofmesothelial-to-mesenchymal transition(MMT) in VAT. The mesothelial lining of visceral organs was previously considered inert; however, using lineage tracing in mice, Gupta et al. (2023,Cell Metabolism) demonstrated that mesothelial cells undergo MMT to generate a significant fraction of VAT adipocytes and myofibroblasts under high-fat diet stress. This finding challenges the dogma that all VAT adipocytes derive fromPdgfra+progenitors and opens a new avenue for targeting mesothelial signaling (e.g., TGF-β) to prevent pathological VAT expansion.

2. VAT as a systemic endocrine and immune hub: New communication axes

Recent work has expanded the concept of VAT-derived exosomal cargo as a long-range signaling system. In 2023, a study inScience Advances(Wang et al.) showed that VAT-derived small extracellular vesicles (sEVs) carrying miR-27b-3p are taken up by hepatocytes, where they suppressPPARαexpression, aggravating hepatic steatosis. More strikingly, a 2024Cellpaper by Li and colleagues demonstrated that VAT in obese mice releases mitochondrial DNA (mtDNA) fragments via gasdermin D pores, which activate the cGAS-STING pathway in the brain's circumventricular organs, leading to central leptin resistance. This VAT-brain axis represents a completely novel mechanism for obesity-associated neuroendocrine dysregulation.

On the immune front, the concept of "trained immunity" in VAT-resident macrophages has gained traction. Using epigenetic profiling, Cottam et al. (2023,Journal of Clinical Investigation) showed that a prior high-fat diet induces durable H3K4me1 marks on pro-inflammatory gene enhancers in VAT macrophages, persisting even after weight loss. This finding provides a molecular explanation for the "metabolic memory" phenomenon and suggests that early-life obesity irreversibly primes VAT inflammation.

3. Technical breakthroughs in VAT imaging and quantification

A major translational bottleneck is the inability to non-invasively distinguish VAT from SAT with high precision. Recent advances in deep learning-based automated segmentation of CT and MRI have addressed this. The 2023 UK Biobank release included VAT volume and density measurements derived from a validated convolutional neural network (CNN) trained on abdominal MRI (Linge et al.,Radiology). This tool now enables VAT quantification at scale, linking VAT density (a proxy for lipid content) to incident cardiovascular events independently of total fat mass. Furthermore, a novel PET tracer, [18F]F-AraG, targeting the deoxyguanosine kinase (dGK) pathway—upregulated in activated T cells—has been used in humans to visualize VAT T-cell infiltration in real time (Kang et al., 2024,Nature Medicine). This imaging breakthrough allows longitudinal monitoring of VAT inflammation without biopsy, a critical step for clinical trial endpooints.

4. Targeted therapeutic strategies: From systemic to depot-specific

The ultimate goal of VAT research is to selectively reduce pathogenic fat while preserving beneficial SAT. Several promising approaches have emerged:

5. Future directions and unresolved questions

Despite these advances, several questions remain. First, the causal relationship between VAT inflammation and systemic insulin resistance is still debated; recent Mendelian randomization studies suggest that VAT volume per se may be less causal than its inflammatory status. Second, the heterogeneity of VAT across different depots (omental, mesenteric, retroperitoneal) is poorly understood—do they share the same pathogenic mechanisms? Third, the long-term safety of VAT-targeted interventions (e.g., β3-agonists) requires rigorous cardiovascular outcome trials.

Looking forward, the integration of multi-omics (single-cell, spatial, proteomic) with longitudinal imaging will enable a "dynamic VAT atlas" that tracks cellular state transitions in response to interventions. Moreover, the emergence of organ-on-chip models incorporating VAT, liver, and brain microenvironments may recapitulate the systemic crosstalkin vitro, accelerating drug screening. Finally, the concept of "VAT rejuvenation"—restoring the youthful adipogenic and anti-inflammatory phenotype of visceral progenitors via senolytic or epigenetic reprogramming—represents an exciting frontier.

In conclusion, visceral adipose tissue is no longer merely a risk marker but a tractable therapeutic target. The convergence of high-resolution molecular profiling, advanced imaging, and precision gene-editing tools is poised to transform VAT from a "bad fat" into a clinically actionable axis for cardiometabolic disease management. The next decade will witness the translation of these mechanistic insights into first-in-class therapies that selectively neutralize the visceral pathogenic depot while preserving metabolic resilience.