Abstract Fat mass, once viewed merely as an inert energy depot, is now recognized as a dynamic endocrine organ central to metabolic health. Recent advances in single-cell genomics, lipidomics, and imaging technologies have revolutionized our understanding of adipose tissue heterogeneity, depot-specific functions, and its crosstalk with systemic metabolism. This review highlights key breakthroughs in the molecular regulation of fat mass, including the discovery of thermogenic adipocyte subtypes, the role of adipose tissue immune microenvironment, and the emergence of senolytic and epigenetic therapies targeting obesity-related fat dysfunction. We also discuss the translational potential of these findings for developing precision interventions against obesity and its comorbidities.

1. Introduction The global obesity epidemic has placed fat mass at the forefront of biomedical research. Adipose tissue comprises white, brown, and beige adipocytes, each with distinct metabolic roles. White adipose tissue (WAT) stores excess energy, while brown and beige adipose tissues (BAT/scWAT) dissipate energy as heat via uncoupling protein 1 (UCP1). Dysregulation of fat mass—whether through excessive expansion (hypertrophy/hyperplasia) or loss of thermogenic capacity—underpins insulin resistance, type 2 diabetes, and cardiovascular disease. Recent technological breakthroughs have uncovered novel regulatory layers, from chromatin remodeling to inter-organ lipid signaling.

2. Cellular Heterogeneity and Depot-Specific Programming Single-cell RNA sequencing (scRNA-seq) has unveiled unprecedented cellular diversity within adipose depots. A landmark study by Emont et al. (2022) identified 16 distinct adipocyte subtypes in human WAT, including a ‘lipid-associated macrophage’ cluster that drives inflammation in visceral fat. Concurrently, Li et al. (2023) demonstrated that subcutaneous and visceral adipocytes arise from distinct mesenchymal progenitors, with visceral progenitors exhibiting heightened sensitivity to glucocorticoid-induced hypertrophy via the transcription factor ZFP423. These findings explain why visceral fat accumulation is more metabolically detrimental than subcutaneous fat.

3. Thermogenic Fat: Beyond UCP1 While UCP1-dependent thermogenesis remains central, recent work has revealed UCP1-independent mechanisms. A breakthrough study by Ikeda et al. (2024) identified creatine-driven substrate cycling as a major thermogenic pathway in beige adipocytes, mediated by the mitochondrial creatine kinase 2 (CKMT2). In parallel, Casteilla et al. (2023) reported that the lactate dehydrogenase B (LDHB) axis in BAT can generate heat via futile calcium cycling. These discoveries open new avenues for activating energy expenditure without relying solely on UCP1, which is often compromised in obesity.

4. Adipose Immune Microenvironment and Metabolic Inflammation Chronic low-grade inflammation is a hallmark of obese fat mass. Recent studies have shifted focus from classic M1/M2 macrophage polarization to more nuanced immune states. Using spatial transcriptomics, Weinstock et al. (2024) mapped ‘crown-like structures’ in human WAT and found that dysfunctional adipocytes release oxidized lipids that activate NLRP3 inflammasomes in resident macrophages, triggering IL-1β secretion. Furthermore, a subset of CD4+ T cells expressing PPARγ was shown to promote beige adipogenesis through IL-13 secretion (Qiu et al., 2023). These insights have led to clinical trials testing IL-1β antagonists (e.g., canakinumab) for obesity-related insulin resistance.

5. Technological Breakthroughs: Imaging and Lipidomics Non-invasive quantification of fat mass has advanced with the development of magnetic resonance imaging (MRI)-based fat fraction mapping. A recent multi-center study (Thomas et al., 2024) validated a deep-learning algorithm that accurately distinguishes visceral from subcutaneous fat with 95% accuracy, enabling large-scale phenotyping. On the lipidomic front, mass spectrometry imaging (MSI) has revealed depot-specific lipid signatures: visceral fat is enriched in ceramides and diacylglycerols, which impair insulin signaling, while subcutaneous fat contains higher levels of triacylglycerols with anti-inflammatory ω-3 fatty acids (Yore et al., 2023). These lipid species may serve as biomarkers for metabolic risk stratification.

6. Therapeutic Targeting of Fat Mass Pharmacological interventions now target fat mass through multiple mechanisms. The GLP-1 receptor agonist semaglutide reduces fat mass primarily via caloric restriction, but recent data suggest it also promotes browning of WAT through central melanocortin signaling (Blüher et al., 2024). More targeted approaches include senolytics: a phase II trial (Justice et al., 2025) demonstrated that the combination of dasatinib and quercetin selectively eliminates senescent adipocytes in human visceral fat, reducing inflammatory cytokines and improving glucose tolerance. Epigenetic reprogramming also shows promise; inhibition of the histone methyltransferase EZH2 in obese mice restored UCP1 expression in WAT and increased energy expenditure by 30% (Cao et al., 2024).

7. Future Perspectives The next decade will likely see the integration of multi-omics data to predict individual fat mass trajectories. Organ-on-a-chip models of human adipose tissue, combined with patient-specific induced pluripotent stem cells, are already enabling drug screening for depot-selective effects. However, challenges remain: the heterogeneity of human obesity, the difficulty of sustaining weight loss, and the need to avoid adverse effects such as lipodystrophy. Future research must also address the psychosocial determinants of fat mass accumulation, as stress and sleep disruption are now known to alter adipocyte function via the hypothalamic-pituitary-adrenal axis.

8. Conclusion Fat mass is no longer a passive bystander but a central hub of metabolic regulation. From single-cell maps to senolytic therapies, our understanding has evolved dramatically. Translating these discoveries into clinical practice will require interdisciplinary collaboration among endocrinologists, immunologists, and bioengineers. The ultimate goal—to modulate fat mass in a depot-specific, metabolically beneficial manner—is now within reach.

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