Abstract Visceral adipose tissue (VAT), long dismissed as a passive energy depot, has emerged as a central endocrine and inflammatory organ driving cardiometabolic disease. Recent advances in single-cell omics, spatial transcriptomics, and molecular imaging have fundamentally reshaped our understanding of visceral fat biology. This review highlights breakthroughs in identifying VAT-specific adipocyte progenitors, the role of the gut–visceral adipose axis, novel non-invasive quantification techniques using deep learning and PET tracers, and emerging pharmacological strategies that selectively target visceral adiposity. We conclude by discussing the translational gap between preclinical findings and clinical practice, and propose a roadmap for precision management of visceral obesity.

1. Introduction Visceral fat, anatomically defined as adipose tissue surrounding internal organs within the abdominal cavity, is distinguished from subcutaneous adipose tissue (SAT) by its unique venous drainage into the portal circulation, high metabolic turnover, and robust pro-inflammatory profile. Epidemiological studies have consistently shown that visceral adiposity, independent of body mass index, predicts type 2 diabetes, hypertension, dyslipidemia, and cardiovascular mortality. Despite this clinical significance, the molecular heterogeneity of VAT has only recently been dissected at single-cell resolution. This article synthesizes the latest findings from 2022–2025, focusing on mechanistic insights, imaging innovations, and targeted interventions.

2. Cellular heterogeneity and progenitor plasticity in VAT Single-cell RNA sequencing (scRNA-seq) has revealed that VAT contains distinct adipocyte subpopulations not found in SAT. A landmark study by Emont et al. (2022,Nature Genetics) identified a visceral-specific adipocyte progenitor expressingWt1andGata4, which exhibits higher adipogenic capacity but also greater susceptibility to oxidative stress. This progenitor pool expands under high-fat feeding and gives rise to dysfunctional, hypertrophic adipocytes that secrete CCL2 and IL-6. More recent spatial transcriptomic work by Zhang et al. (2024,Cell Metabolism) mapped the zonal architecture of human omental fat, demonstrating that immune cells, particularly tissue-resident macrophages, are organized into "inflammatory niches" adjacent to dying adipocytes. These niches are enriched forTREM2+ lipid-associated macrophages, which drive a feed-forward cycle of lipotoxicity and fibrosis. Importantly, the same study found thatTREM2+ macrophages can be pharmacologically reprogrammed toward a lipid-scavenging phenotype using a CSF1R inhibitor, reducing VAT inflammation in obese mice.

3. The gut–visceral adipose axis: a new therapeutic frontier The intestinal microbiota has emerged as a critical regulator of visceral fat accumulation. A 2023 multi-omics study by Liu et al. (Nature Medicine) demonstrated that the gut bacteriumAkkermansia muciniphilais inversely correlated with VAT volume measured by MRI in 1,200 participants. Mechanistically,A. muciniphilaproduces a short-chain fatty acid, propionate, which activates intestinal gluconeogenesis and reduces expression of the lipid transporter CD36 on enterocytes, thereby decreasing chylomicron delivery to visceral depots. Building on this, a randomized controlled trial (RCT) published inGut(2024) showed that oral supplementation with pasteurizedA. muciniphilafor 12 weeks reduced visceral fat area by 8.2% (p<0.001) compared to placebo, with no changes in subcutaneous fat. This gut–VAT crosstalk is further modulated by bile acid signaling, as the farnesoid X receptor (FXR) agonist obeticholic acid has been shown to suppress visceral adipogenesis by downregulatingC/EBPβin VAT-resident progenitors (Wang et al., 2024,Hepatology). These findings position the gut–VAT axis as a druggable pathway with high specificity for visceral depots.

4. Imaging and computational breakthroughs for non-invasive VAT quantification Traditional anthropometric measures (waist circumference, waist-to-hip ratio) are poor proxies for actual VAT volume. The recent integration of deep learning with routine CT and MRI scans has revolutionized VAT assessment. A convolutional neural network (CNN) developed by Pickhardt et al. (2023,Radiology) automatically segments VAT from abdominal CT slices with a Dice coefficient of 0.94, requiring no manual contouring. This tool has been validated across 10,000 scans and can predict 10-year cardiovascular risk with an area under the curve of 0.87, outperforming traditional risk scores. For molecular imaging, a novel PET tracer, [18F]F-AraG, targeting the equilibrative nucleoside transporter 1 (ENT1), has been shown to selectively accumulate in activated macrophages within VAT (Tavakoli et al., 2024,Journal of Nuclear Medicine). In a pilot human study, [18F]F-AraG uptake in omental fat correlated strongly with serum IL-6 and with histologically confirmed crown-like structures, offering a real-time readout of visceral inflammation. These imaging tools not only improve risk stratification but also enable monitoring of therapeutic responses at the tissue level.

5. Pharmacological strategies with visceral-selective effects The most promising advance in visceral fat-specific pharmacotherapy is the development of "adipose-targeting" conjugates. Researchers at the University of Copenhagen have engineered a peptide–siRNA conjugate that delivers aHIF1αsilencer specifically to VAT adipocytes via the surface receptor CD36, which is overexpressed on visceral but not subcutaneous adipocytes (Jensen et al., 2025,Nature Biotechnology). In obese mice, a single subcutaneous injection reduced VAT mass by 35% within 4 weeks, while preserving SAT and improving insulin sensitivity. Separately, the glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) dual agonist tirzepatide has shown a selective reduction in VAT (measured by MRI) of 23% at 72 weeks, compared to 10% reduction in SAT (Gastaldelli et al., 2024,The Lancet Diabetes & Endocrinology). This selectivity is hypothesized to arise from higher expression of GIP receptors in visceral adipocytes, which upon activation promote lipid oxidation rather than storage. Furthermore, the combination of tirzepatide with a selective PPARγ modulator (SPPARM) is currently in Phase II trials, aiming to enhance VAT reduction while minimizing fluid retention.

6. Future outlook and translational challenges Despite these advances, several hurdles remain. First, the heterogeneity of VAT across individuals—influenced by genetics, sex, and age—means that a single "visceral fat-specific" target may not be universally applicable. Second, long-term safety of visceral-selective lipolysis is unknown; excessive reduction of omental fat could impair its role in buffering acute energy surplus. Third, the cost and accessibility of MRI-based VAT quantification limit its use in routine clinical settings. Future research should focus on: (i) developing blood-based biomarkers (e.g., circulating microRNAs from VAT-derived exosomes) for surrogate VAT monitoring; (ii) integrating multi-omic data to define VAT endotypes that predict response to specific therapies; and (iii) exploring the interplay between visceral fat and perivascular adipose tissue in arterial remodeling. The next decade will likely witness the transition from "one-size-fits-all" obesity treatment to precision visceral adiposity management, guided by imaging, genomics, and gut microbiome profiling.

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