Lipedema and obesity are chronic, frequently progressive disorders that can present with increased adipose-tissue volume, functional impairment and reduced quality of life. Although often approached as differential diagnoses, they frequently coexist and may aggravate one another. This narrative review addresses how lipedema and obesity interact biologically and clinically and what evidence supports a staged interdisciplinary approach to diagnosis and management. Obesity is increasingly conceptualized as an adiposity-based chronic disease characterized by excess adipose, abnormal adipose-tissue distribution or dysfunction, and associated medical or functional impairment. Obesity can impair lymphatic morphology and function, whereas lymphatic dysfunction may promote subcutaneous adipose-tissue expansion and fibrosis. Literature was identified through iterative PubMed searches and focused supplementary searches in Embase and the Cochrane Library. Publications were selected purposively for their relevance to predefined clinical and mechanistic domains; no systematic screening or formal risk-of-bias assessment was performed. This review synthesizes clinical overlap, biological evidence, diagnostic implications, and staged management for predominantly adult women with suspected or confirmed lipedema, including those with coexisting overweight or obesity. The proposed framework is intended to support clinical reasoning rather than serve as a formal guideline.
Perivascular adipose tissue (PVAT) is recognized as the functional fourth layer of the vasculature. Unlike non-PVAT depots, PVAT is continuously exposed to haemodynamic forces, potentially altering the morphometry of its adipocytes. While transcriptomics studies have identified diverse adipocyte populations, characterizing these cells remains difficult because their inherent fragility limits standard antibody-based phenotyping. Autofluorescence has emerged as a label-free alternative for characterizing cellular heterogeneity. However, autofluorescence-based characterization of PVAT adipocytes remains unexplored, and it is unknown if these cells exhibit distinct profiles reflecting their specific anatomical location. This study aimed to define the autofluorescence profiles of PVAT and non-PVAT adipocytes. Using Sprague-Dawley rats (n = 6), we assessed intrinsic fluorescence in adipocytes from PVATs of thoracic and abdominal aorta, and from mesenteric arteries alongside phenotype-matched non-PVAT counterparts: interscapular brown, subcutaneous, and retroperitoneal tissues. Using optimized methods to maintain adipocyte integrity, we demonstrate that thoracic and intrascapular exhibit similar autofluorescence profiles. In contrast, PVAT sites mesenteric and abdominal diverge across the yellow, red, and violet channels compared with non-PVAT depots, retroperitoneal and subcutaneous. In conclusion, PVAT and non-PVAT adipocytes exhibit depot-specific spectral patterns, with higher autofluorescence observed in PVAT cells, validating autofluorescence as a marker-independent approach for identifying adipocyte differences.
Factors limiting fat cell expandability remain scarcely explored, and comprehensive functional comparisons of adipose depots in humans are limited. In the present study, we collected visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) paired-samples from 22 patients with obesity undergoing elective Roux-en-Y gastric bypass surgery. Whole tissue samples were used to determine adipocyte cell size using a coulter counter and gene expression levels using bulk mRNA sequencing. Isolated adipocytes from the same tissue samples were used to functionally assess glucose uptake using glucose tracer assay, and lipolysis by measuring glycerol release. Western blotting was used to determine Caveolin 1 levels in adipocytes. The relationship between COL3A1 expression and systemic health outcomes was assessed using data from the Adipose Tissue Knowledge Portal. We found that SAT adipocytes were larger in size, displayed higher basal lipolysis and higher lipolysis-related gene expression than VAT adipocytes. Isoprenaline-induced lipolytic responsiveness, as well as basal and insulin-stimulated glucose uptake were higher in VAT than in SAT adipocytes. SAT displayed higher levels of extracellular matrix components associated with cellular flexibility and higher cellular Caveolin 1 levels than VAT. Further, we identified subcutaneous adipose tissue COL3A1 as a potential contributor to insulin resistance in obesity, positively associated with BMI, HOMA-IR and adipocyte size. In summary, our findings underscore distinct metabolic properties of subcutaneous and visceral adipocytes in obesity, with SAT adipose tissue exhibiting characteristics that possibly promote greater cellular expandability.
β-Adrenergic receptors (β-ARs) drive the induction of beige adipocytes in rodents and humans, yet the dominant human subtype, β2-AR or β3-AR, remains debated. This study aimed to confirm whether human adipose-derived mesenchymal stem cell (hADSCs)-derived adipocytes can serve as a beiging-competent model under human-relevant browning stimuli and to compare the involvement of β2-AR and β3-AR in hADSCs-derived beige adipocyte differentiation. hADSCs were differentiated into adipocytes using an adipogenic cocktail in the presence or absence of human-relevant browning stimuli or β2-AR/β3-AR-selective agonists with or without β2-AR/β3-AR-selective antagonists. Non-selective β-AR activation induces beige adipogenesis along with mRNA and/or protein expression of beiging markers, including uncoupling protein 1 (UCP1), appearance of multilocular adipocytes, and enhanced mitochondrial respiratory readouts. Moreover, norepinephrine, forskolin, and trigonelline increased mRNA and/or protein expression of UCP1. Pharmacological dissection with subtype-selective agonists and antagonists revealed that activation of β2-AR, but not β3-AR, is necessary and sufficient for inducing UCP1. The β2-AR blockade abolished UCP1 upregulation, whereas the β3-AR blockade had minimal effects. β2-selective stimulation recapitulated the beiging response. This study establishes hADSCs-derived adipocytes as a practicable, human-relevant platform for screening pharmacological agents and food-derived compounds and identifies β2-AR as a translationally actionable target for inducing beige adipocytes in humans.
Obesity involves white adipose tissue (WAT) expansion via hyperplasia and hypertrophy. Impaired adipocyte proliferation leads to pathological hypertrophy, inflammation and metabolic dysfunction. Aberrant F‑actin turnover disrupts proliferation/differentiation. Twinfilin‑1 (Twf1) regulates actin dynamics and cell proliferation/differentiation, but its role in adipocytes is unknown. Obese mice were induced by high‑fat diet (HFD) and weight loss by calorie restriction. Inguinal, epididymal and scapular adipose tissues were collected. Proteomics used pressure cycling, DDA library building and DIA quantification. Twf1 expression was validated by RT‑qPCR and Western blot. In C3H10T1/2 preadipocytes, Twf1 knockdown and overexpression were established. Differentiation was induced with dexamethasone, rosiglitazone, insulin and IBMX. Adipogenesis and proliferation were assessed by RT‑qPCR, Western blot, Oil Red O and CCK8. Nuclear‑cytoplasmic fractionation evaluated Yap localization and HIPPO activity. HFD mice showed weight gain, dyslipidemia and adipocyte hypertrophy, reversed by weight loss. Proteomics identified 43 proteins intersecting obesity, weight loss, and actin‑related datasets; Twf1 was upregulated in obese epididymal/inguinal fat and downregulated after weight loss. In C3H10T1/2 cells, Twf1 knockdown enhanced white adipocyte differentiation (upregulated Pparg2, Fsp27, Fabp4) and proliferation (2.28‑fold vs. control), promoted Yap nuclear accumulation, and inhibited HIPPO signalling. Twf1 overexpression reduced differentiation, lipid droplets, and proliferation (to 44.7% of control). Twf1 is upregulated in white/beige adipose tissue of obese mice and downregulated after weight loss. Twf1 knockdown promotes Yap nuclear accumulation, inhibits HIPPO and enhances adipocyte proliferation and white adipocyte maturation, indicating a key role in obesity development.
Given the established positive role of Lipoxin A4 (LXA4) in adipose browning at the cellular level, this study investigated its possible effect on white fat browning and the underlying molecular mechanisms. The obese insulin resistance mouse model was established. The body weight, subcutaneous and visceral fat, and food intake of the mice were observed. Haematoxylin-eosin staining was used to determine the effects of LXA4 on the morphology of inguinal white adipose tissue and brown adipose tissue, and to analyse the changes in fat mass and serum insulin levels, lipid metabolism and other indexes. The cellular experiments included the induction of browning in 3T3-L1 precursor adipocytes, the screening of miRNAs related to adipose browning and their downstream target genes using TargetScan, qRT-PCR, RNA immunoprecipitation and dual luciferase reporter assay. LXA4 attenuated weight gain, inhibited fat accumulation, and improved hyperlipidaemia and insulin resistance in high-fat diet-treated mice. LXA4 also promoted browning of 3T3-L1 precursor adipocytes. Activation of miR-133a-3p partially abrogated LXA4-induced promotion of white adipose browning. The effects of LXA4 and miR-133a-3p could be reversed by SIRT1. Collectively, LXA4 alleviates obesity-related metabolic disorders by promoting inguinal white adipose browning and improving insulin resistance possibly through the miR-133a-3p/SIRT1 pathway.
Periprostatic adipose tissue (PPAT) is a potential factor closely associated with prostate cancer (PCa) development. This study aimed to introduce normalized PPAT thickness, a novel imaging biomarker, as a PCa predictor for patients within the diagnostic 'double gray zone', defined as the combination of Prostate Imaging Reporting and Data System (PI-RADS) score 3 lesions and serum prostate-specific antigen (PSA) levels of 4-10 ng/mL. A total of 219 patients were retrospectively enrolled. PPAT thickness was measured on pre-biopsy MRI. Pearson correlation analysis was performed to assess the relationship between BMI and PPAT thickness. Independent predictors of PCa were investigated by logistic regression analysis. Normalized PPAT thickness was defined as the ratio of PPAT thickness to prostate volume, and its predictive performance was compared with PSA density (PSAD). Restricted cubic spline analysis was performed to determine its optimal threshold for PCa prediction. A negative correlation was observed between PPAT thickness and BMI (ρ = -0.154, p = 0.023), suggesting that PPAT is less affected by overall obesity. PPAT thickness was significantly higher in PCa patients (0.52 vs. 0.36 cm, p < 0.001) and was identified as an independent PCa predictor (OR 1.523, 95% CI 1.252-1.853, p < 0.001). Normalized PPAT thickness outperformed PSAD for predicting clinically significant PCa (csPCa) (AUC 0.819 vs. 0.690, p = 0.003), and its threshold of 14 outperformed the traditional PSAD threshold > 0.15 (csPCa detection rate 39.2% vs. 21.7%). In conclusion, we proposed normalized PPAT thickness as a novel PCa predictor in the diagnostically challenging 'double gray zone' cohort.
Adipogenesis from mouse embryonic stem cells (mESCs) offers a tractable model for dissecting early adipocyte commitment, yet the mechanisms coordinating this transition across multiple biological layers remain incompletely understood. Here we present the first simultaneous five-layer multi-omics characterization of mESC-derived adipocyte differentiation, integrating transcriptomics, proteomics, secretomics, lipidomics, and metabolomics from matched adipogenic (Pos) and non-differentiating (Neg) cell populations at day 30. Applying Multi-Omics Factor Analysis (MOFA+), we identified a dominant shared latent axis that perfectly segregated Pos from Neg cells across all five views. Layer-specific functional enrichment converged on two principal biological axes: ECM remodeling — encompassing collagens, laminins, thrombospondins, and lysyl oxidases — and lipid metabolic reprogramming, with phospholipid and glycerolipid metabolic processes dominating the lipidomics/metabolomics layer. Ensemble Machine Learning Feature Ranking (EMFR) identified a secreted factor (Scpep1; importance score 0.90) as the top-ranked discriminatory feature. Network analysis revealed indirect ECM-lipid connectivity mediated by four bridging nodes (Plod1, Thbs2, Plg, Pmp22) through a hub subnetwork of phospholipid-metabolizing enzymes. Targeted qPCR validation of six candidate regulators (Itga5, Igfbp6, Pik3cg, Lpl, Acer3, Sirt1) confirmed RNA-seq concordance. These findings establish convergent ECM remodeling and lipid metabolic reprogramming as central axes of adipocyte identity acquisition from mESCs.
Visceral fat has weaker beige adipogenesis than subcutaneous fat with unclear mechanisms. The Wilms tumour gene (Wt1), a visceral adipocyte marker, is highly expressed in visceral adipose tissue (VAT) and visceral adipose-derived stem cells (vADSCs). In our present study, we found its protein levels in VAT decreased under high-fat diet or dexamethasone treatment, but rised in cold exposure or β3-adrenergic receptor agonist treatment, and positively correlate with uncoupling protein-1 (UCP1). Wt1 knockdown in vADSCs elevated PR domain containing 16 (PRDM16) and UCP1 mRNA but reduced their protein levels, alongside decreased ubiquitin-conjugating enzyme 9 (UBC9). Knockdown of UBC9 did not affect the mRNA levels of Wt1, PRDM16 or UCP1, but significantly reduced PRDM16 and UCP1 protein levels. Glucocorticoids including hydrocortisone, methylprednisolone and dexamethasone (Dex) dose-dependently suppress Wt1, UCP1, Alpha-enolase (ENO1) and Pyruvate kinase muscle isozyme M2 (PKM2) levels, which could be reversed by Wt1 overexpression. These findings explore the effects of Wt1 on beige remodelling of visceral adipose which might be related to the up-regulation of UBC9, and provide clues for treating abdominal obesity caused either by HFD or by glucocorticoids in a non-sympathetic-dependent manner.
Cre recombination is a widely used technique for mechanistic insights in physiology and disease. However, available constitutive and inducible Cre systems present challenges that can be prohibitive for some study designs. For example, Cre expression can result in cell types targeted across numerous tissues and organs, or when a gene is expressed across multiple cell types in a tissue, Cre-Lox restricted knockout will not enable ablation across an entire tissue or organ. Photoactivatable Cre (PA-Cre) systems enable temporally and spatially restricted gene expression control in delimited anatomical regions, typically requiring a micro-LED or fibre optic implantation. Here, we report as proof-of-concept the effective knockout of BDNF in subcutaneous adipose tissue after PA-Cre activation through external blue light illumination in awake, freely moving mice. We demonstrated that for mice with black fur, shaving can be used to anatomically limit PA-Cre activation. BDNF protein expression was decreased by 87% in the inguinal scWAT after blue light exposure, with no effect observed in the perigonadal (deep) or axillary subcutaneous (non-shaved) adipose tissues. We propose blue light induction of PA-Cre as safe and effective to study adipose tissue physiology and pathology across models. Considerations for applying this tool to future studies are also presented.
Tumour-associated macrophages (TAMs) exert a pivotal function in tumour progression, and M2-type TAMs are closely linked to tumour-promoting functions. Mechanistic target of rapamycin complex 2 (mTORC2) may mediate TAM polarization and subsequent tumour development, yet their roles in liposarcoma (LPS) remain unclear. Macrophage polarization was assessed via flow cytometry for CD206. Western blot for Arg-1, Rictor, PPAR-γ, CD36, ACSL1 and CPT2, qPCR for IL-10, Arg-1 and Ym1, and ELISA for IL-10 secretion. Fatty acid metabolism was evaluated using free fatty acid (FFA) uptake assays and Oil Red O staining for intracellular lipid droplets. A Transwell assay was established to assess the effect of treated macrophages on LPS cell biology, and EdU assays were used for proliferation assessment. Transwell migration and invasion assays were utilized for assessing cellular motility. IL-4 induced RAW264.7 macrophages to undergo M2 polarization, characterized by upregulated CD206, Arg-1, and IL-10. During this process, mTORC2 was activated, promoting FFA uptake, lipid droplet accumulation, and fatty acid oxidation via the PPAR-γ/CD36 axis. Co-culture experiments showed that IL-4-polarized M2 macrophages enhanced LPS cell proliferation, migration, and invasion; these effects were inhibited by JR-AB2-011 and restored by LPA, confirming mTORC2-PPAR-γ/CD36-mediated TAMs drive LPS progression. mTORC2 regulates M2 TAM polarization and metabolic reprogramming via the PPAR-γ/CD36 pathway, thereby promoting LPS cell proliferation, migration, and invasion.
Obesity is one of the most significant health challenges today, with its prevalence increasing rapidly worldwide. The associated inflammatory state is a major risk factor for developing type 2 diabetes, cardiovascular diseases, and sleep apnoea, putting immense pressure on global healthcare systems. Abnormal accumulation or dysfunction of adipose tissue can lead to obesity, which is a major risk factor for metabolic and cardiovascular diseases. The mitochondrial unfolded protein response (UPRmt) serves as a critical adaptive mechanism that safeguards cellular homoeostasis during mitochondrial proteostatic stress by orchestrating the expression of chaperones, proteases, and metabolic regulators to restore protein folding capacity and mitigate organelle dysfunction. This review discusses the role of UPRmt in adipocytes, a key player in maintaining metabolic homoeostasis and thermogenesis. Understanding UPRmt's mechanisms could offer novel therapeutic strategies to combat obesity and its complications.
Adipose tissue (AT) dysfunction can lead to increased visceral AT (VAT) and metabolic damage. The adiponectin/leptin ratio (ALR) has been proposed as a biomarker of AT functionality. However, its participation in VAT accumulation and the impact of sex on these associations have not been evaluated. In an analytical cross-sectional study, 54 adults (29 male, 25 postmenopausal females, aged 30-70 years, BMI 19-31 kg/m2) were analysed. Anthropometric data, fasting serum samples, and subcutaneous AT (SAT) biopsies were obtained. Morpho-functional AT characteristics included ALR, adipocyte size, macrophage content and AT insulin resistance (ADIPO-IR). Using multivariate and mediation models, we evaluated the associations of SAT characteristics with systemic IR (TyG index), systemic inflammation (C-reactive protein), and VAT area. In postmenopausal females, ALR was inversely associated with adipocyte size, macrophage number, TyG index, CRP, and VAT area. SAT inflammation and ADIPO-IR were independently associated with VAT, and a mediation model suggested ALR as a possible precursor of VAT. Among males, ADIPO-IR and ALR were independently associated with VAT. These findings emphasize the importance of considering sex differences in the prevention and treatment strategies for metabolic diseases among Mexican-Mestizo populations, although these results should be confirmed by prospective studies.
Volume-activated chloride current (VACC), the most common and abundant anion current in organisms, is involved in various physiological and pathological processes. However, its expression and characteristics in preadipocytes remain unclear. Whole-cell patch clamp technique was used to investigate the presence and properties of VACC in 3T3-L1 preadipocytes, as well as the effects of chloride channel blockers (NPPB, DIDS, and tamoxifen) on this current under different osmotic conditions. Additionally, 3T3-L1 preadipocytes were treated with the chloride channel blocker TMEM16A to observe its effect on cell differentiation. Hypotonic stimulation significantly induced whole-cell currents in 3T3-L1 preadipocytes, which exhibited obviously outward-rectifying and volume-activated characteristics. Under hypotonic stimulation, NPPB, DIDS, and tamoxifen all inhibited the current, with NPPB showing a significantly stronger inhibitory effect than DIDS and tamoxifen. Moreover, growth-arrested 3T3-L1 preadipocytes at 2 days post-confluence were successfully induced, with mRNA levels of C/EBPα, C/EBPβ, PPARγ and FABP4 peaking on day 3 and decreasing by day 14. Protein levels of PPARγ, perilipin 1 and LRRC8A were significantly upregulated during differentiation. Treatment with TMEM16A significantly reduced adipocyte lipid droplet formation and FABP4 mRNA/protein levels, but increased C/EBPα and PPARγ mRNA levels, as well as LRRC8A protein levels after 3 days. Collectively, our results clarify the characteristics of VACC in 3T3-L1 preadipocytes, confirm the inhibitory effect of chloride channel blockers on 3T3-L1 preadipocyte differentiation, fill the gap in the understanding of VACC in preadipocytes, and lay a preliminary experimental foundation for further exploring the role of VACC in adipocyte differentiation.
Regulation of adipogenesis has classically been viewed through the lens of transcription initiation driven by lineage defining transcription factors. In this study, we uncover transcription elongation as a critical and previously underappreciated regulatory layer controlling adipocyte cell fate. We demonstrate that the elongation factors Spt4 and Spt6 are indispensable for adipogenic differentiation, as their depletion severely impairs adipogenic gene induction and perilipin expression. Spt4 and Spt6 directly regulate the genes coding for core adipogenic transcription factors, including Cebpa, Pparg, Krox20, and Stat3, by promoting RNA polymerase II (Pol II) progression through their gene bodies. In the absence of these factors, Pol II becomes stalled at the transcriptional start sites of these adipogenic genes. These data support a post transcription initiation requirement for Spt4 and Spt6 in productive elongation rather than promoter loading. Our findings identify transcription elongation control as a key determinant of adipogenic fate.
Obesity and its metabolic complications represent a major and growing public health burden, for which effective therapeutic strategies remain limited. Although super-enhancers are recognized as key regulators of cell identity and adipogenesis, the roles of super-enhancer- microRNAs in obesity and adipocyte dysfunction remain insufficiently characterized. Here, we identify miR-1260b as a super-enhancer-associated miRNA that influences human adipogenesis. Analysis of adipose-related datasets from SEdb 2.0 revealed that MIR1260B is consistently linked to a clustered SE region across multiple human adipose tissues. Integrated ATAC-seq and Hi-C analyses demonstrated progressive chromatin opening and dynamic enhancer-promoter interactions between this SE and the MIR1260B promoter during adipogenic differentiation. Functionally, miR-1260b overexpression markedly inhibited adipocyte differentiation of human adipose-derived stem cells. Quantitative proteomic profiling revealed that miR-1260b suppresses adipogenic and lipogenic programmes while activating lipid catabolic pathways. Notably, the MIR1260B-associated SE overlaps with a previously reported diabetes-associated SNP, and external clinical datasets indicate reduced miR-1260b levels in umbilical cord serum from children at increased risk of obesity. Together, these findings suggest that miR-1260b may function as a super-enhancer-associated regulator that inhibits adipogenesis and indicate that SE-informed multi-omics approaches can aid in identifying miRNA regulators relevant to metabolic disorders of obesity.
Fever reflects a physiological rise in body temperature accompanied by elevated production of adrenaline. The increased body temperature in fever is caused by shivering thermogenesis in skeletal muscle and non-shivering thermogenesis in brown adipose tissue (BAT), the latter being mediated by uncoupled oxidation of free fatty acids (FFAs). We hypothesized that an acute temperature rise to 40°C increases adrenalin-induced lipolysis in white adipocytes, thereby potentially providing FFAs as an energy substrate to sustain fever-induced thermogenesis in skeletal muscle and BAT. In 3T3-L1 and primary murine white adipocytes, isoproterenol-induced extracellular FFA accumulation was significantly increased at 40°C compared to 37°C. In contrast, isoproterenol-induced increase in extracellular glycerol concentrations and the protein levels of phosphorylated hormone sensitive lipase were comparable at both temperatures, suggesting a similar degree of lipolysis. Moreover, incubation at 40°C did neither increase isoproterenol-induced oxygen consumption nor intracellular FFA concentrations, indicating that the elevated extracellular FFA accumulation was not due to reduced intracellular consumption. Conversely, isoproterenol blunted FFA uptake into adipocytes to a significantly higher extent at 40°C compared to 37°C. Hence, an acute temperature rise to 40°C reduces FFA uptake into white adipocytes, thereby increasing extracellular FFA availability.
Stem cell-based therapies are emerging as a promising treatment for diabetes by differentiating these cells into insulin-producing cells (IPCs). However, using growth factors for differentiation has always been challenging. Physical differentiation of stem cells presents a promising approach to reduce reliance on chemical growth factors. One method of physical cell differentiation is cell imprinting. This study aimed to physically induce the differentiation of rat adipose-derived mesenchymal stem cells (rADSCs) into β-like cells using the cell-imprinting technique. For this purpose, RIN-5F cells were used to transfer their geometry and cell-specific topographies to a polydimethylsiloxane (PDMS) substrate. After cell imprinting, the rADSCs were seeded on the substrate, and their differentiation into β-like cells was evaluated after 14 and 21 days by assessing insulin production using dithizone staining and ELISA, as well as real-time PCR and immunocytochemistry (ICC) for expression analysis of the genes effective in cell differentiation into β-like cells, including PDX1, NKX6.1, NGN3, and insulin. The results of dithizone staining and ELISA confirmed insulin secretion by differentiated cells compared to stem cells (p ≤ 0.05). Real-time PCR and ICC results showed that after 21 days, the differentiated cells expressed key β-cell genes significantly more than stem cells (p ≤ 0.05).
The receptor for advanced glycation end products (RAGE) and its ligands are critical drivers of adipose tissue inflammation. While RAGE expression increases in ageing cells and pathological conditions, its specific role in high-fat diet (HFD)-induced adipose tissue senescence remains to be fully elucidated. In this study, we investigated the function of RAGE in the development of adipose tissue senescence associated with obesity. We observed that HFD-fed RAGE-deficient (RAGE-/-) mice exhibited significantly reduced body weight and adipocyte hypertrophy compared to wild-type (WT) controls. At the molecular level, RAGE-/- mice displayed lower mRNA expression of cell cycle regulators and markers of the senescence-associated secretory phenotype. This anti-senescent phenotype was accompanied by decreased reactive oxygen species (ROS) production and elevated expression of anti-oxidant genes. Mechanistically, the lack of RAGE resulted in the upregulation of silent information regulator type 1 (SIRT1) in adipose tissues. Notably, the inhibition of SIRT1 reversed these anti-senescent effects and attenuated anti-oxidant gene expression in RAGE-deficient mice. Furthermore, while antioxidant treatment with N-acetylcysteine (NAC) reduced p53 in WT mice, it failed to fully suppress p16 and p21, whereas NAC treatment in RAGE-/- mice significantly downregulated all senescence markers, suggesting a synergistic protective effect. In conclusion, our results demonstrated that RAGE deficiency improved anti-oxidant properties and prevents adipocyte senescence via the SIRT1 signalling pathway, highlighting a potential therapeutic target for obesity-associated tissue dysfunction.
Brown and beige adipose tissue represent evolutionary adaptations in mammals, functioning as specialized thermogenic organs to maintain body temperature. Over the past two decades, researches have demonstrated that white adipose tissue (WAT) browning is an effective strategy to enhance energy expenditure. However, a growing body of evidence indicates that the browning process frequently occurs in a variety of chronic disease states, though its pathophysiological significance remains unclear. This review summarized evidence of pathological browning observed in human diseases and animal models, including breast cancer, colorectal cancer (CRC), clear cell renal cell carcinoma (ccRCC), kidney health, burn injury, atherosclerotic, SARS-CoV-2 and sepsis. Despite distinct pathological contexts, adipose tissue browning is consistently observed. This suggests that browning may not simply serve its classical metabolically protective role, but instead reflect an atypical response to pathological stress. It is currently unclear whether this is a compensatory mechanism by the organism in a diseased state or merely a byproduct of the disease process. Whether this response is adaptive or a cause of disease progression remains unresolved. Future research should therefore focus on identifying the triggers and functional outcomes of pathological browning to better understand adipocyte plasticity and its role in disease progression.
