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Gestational Diabetes Mellitus (GDM) is the most frequent complication during pregnancy. Pharmacological interventions, such as peptide drugs that focused on improving the insulin sensitivity might be promising in the prevention and treatment of GDM. In this study, we aimed to investigate the role and mechanism of a novel peptide, named AGDMP1 (Anti-GDM peptide 1), which we previously identified lower in the serum of GDM patients using mass spectrometry, on the adipose insulin resistance in GDM. We found that AGDMP1 had a high affinity for adipose tissues in vivo. AGDMP1 markedly improved glucose homeostasis and insulin resistance in GDM mice. This was associated with reduced inflammation and upregulated AKT/GLUT4 signaling pathway in white adipose tissue. In vitro, AGDMP1 could increase glucose uptake and insulin sensitivity of adipocytes by activating the IRS-1/AKT/GLUT4 signaling pathway under basal, insulin-stimulated, and insulin-resistant conditions, respectively. Mechanistically, we found that AGDMP1 could bind to HSP60 to dampen its effects on AKT signaling and pro-inflammatory response, which was reversed in the present of recombinant HSP60 protein. AGDMP1 ameliorated adipose insulin resistance and inflammation by targeting HSP60 and activating the IRS-1/AKT/GLUT4 signaling pathway. These data supported AGDMP1 with therapeutic potential in GDM and associated pathologies., (© 2025 Federation of American Societies for Experimental Biology.)

The high heat-producing capacity of brown and beige adipocytes, collectively known as thermogenic adipocytes, contributes to whole-body energy expenditure and is an attractive target for the management of obesity. It has been revealed that the functions of thermogenic adipocytes are important for the regulation of whole-body carbohydrate and lipid metabolism, and the activation of thermogenic adipocytes seems to have beneficial effects for the management of obesity-related metabolic disorders, such as dyslipidemia. Recent studies have showed that specific food ingredients have the potential to activate thermogenic adipocytes via various mechanisms. Some of these are effective not only in rodents, but also in humans, and effective prevention of obesity using these food ingredients is expected. In this review, we introduce the recent findings on the regulatory mechanisms of lipid metabolism by thermogenic adipocytes and food ingredients, demonstrating the potential to activate thermogenic adipocytes and their underlying mechanisms., (© The Author(s) 2024. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Oxidative stress (OS) refers to the disruption in the balance between free radical generation and antioxidant defenses, leading to potential tissue damage. Reactive oxygen species (ROS) can interact with biological components, triggering processes like protein oxidation, lipid peroxidation, or DNA damage, resulting in the generation of several volatile organic compounds (VOCs). Recently, VOCs provided new insight into cellular metabolism and can serve as potential biomarkers. The objective is to investigate the impact of OS on cell metabolism by analyzing the release or alterations of VOCs in the headspace of differentiated 3T3-L1 adipocytes. An OS model in differentiated 3T3-L1 cell lines was constructed using hydrogen peroxide (H 2 O 2 ) treatment. The effect of OS on cell metabolism was analyzed by detecting VOCs in the headspace of the cells using solid phase micro extraction (SPME) and gas chromatography-mass spectrometry (GCMS). Our findings indicate that H 2 O 2 concentrations exceeding 300 µM induce significant OS, leading to adipocyte apoptosis, as evidenced by various assays. Of the twenty VOCs identified, ten were upregulated in the cells. VOCs such as diphenyl ether, 1,3,5-trioxane, 5-methyl tridecane, 2-ethyl-1-hexanol, and 2,4-di-tert-butyl phenol emerged as potential biomarkers for OS. This study demonstrates that elevated OS alters VOC profiles in differentiated 3T3-L1 adipocytes, providing insights into the effects of OS on adipose tissue and identifying potential OS biomarkers., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Aspirin (ASA) is one of the most used medications worldwide and has shown various effects on cellular processes, including stem cell differentiation. However, the effect of ASA on adipogenesis of adipose tissue-derived stem cells (ASCs) remains largely unknown. Considering the potential application of ASCs in regenerative medicine and cell-based therapies, this study investigates the effects of ASA on adipogenic differentiation in human ASCs. ASCs were exposed to varying concentrations of ASA (0 µM, 400 µM, and 1000 µM) and evaluated for changes in morphology, migration, and adipogenic differentiation. While ASA exposure did not affect self-renewal potential, migration ability, or cell morphology, it significantly reduced lipid vacuole formation at 1000 µM after 21 days of adipogenic differentiation ( p = 0.0025). This visible inhibition correlated with decreased expression of adipogenic markers (PPARG, ADIPOQ, and FABP4) and the proliferation marker MKi67 under ASA exposure in comparison to the control (ns). Overall, the findings demonstrate that ASA inhibits adipogenic differentiation of human ASCs in a dose-dependent manner in vitro, contrasting its known role in promoting osteogenic differentiation. This research highlights ASA's complex effects on ASCs and emphasizes the need for further investigation into its mechanisms and potential therapeutic applications in obesity and metabolic diseases. The inhibitory effects of ASA on adipogenesis should be considered in cell-based therapies using ASCs.

Adipose tissue (AT) metabolism involves coordinating various cells and cellular processes to regulate energy storage, release, and overall metabolic homeostasis. Therein, macrophage and its cytokine are important in controlling tissue homeostasis. Among cytokines, the role of transforming growth factor-β1 (Tgf-β1), a cytokine abundantly expressed in CD206 + M2-like macrophage and correlated with the expansion of AT and fibrosis, in AT metabolism, remains unknown. We used CD206CreER T2 ; Tgf-β1 f/f mouse model in which the Tgf-β1 gene was conditionally deleted in CD206 + M2-like macrophages followed by tamoxifen administration, to investigate the role of the Tgf-β1 gene in glucose and insulin metabolism. Our data demonstrated that lack of CD206 + M2-like macrophages derived Tgf-β1 gene improved glucose metabolism and insulin sensitivity by enhancing adipogenesis via hyperplasia. The Tgf-β1 gene, specifically from CD206 + M2-like macrophages, deletion stimulated APs' proliferation and differentiation, leading to the generation of smaller mature adipocytes, therefore enhancing insulin sensitivity and improving glucose metabolism under normal chow conditions. Our study brings a new perspective that Tgf-β1 gene deletion specific from CD206 + M2-like macrophage promotes adipocyte hyperplasia, improving glucose homeostasis and insulin sensitivity in the lean state., Competing Interests: Competing interests: The authors declare no competing interests. Ethical approval: All procedures were conducted in accordance with ARRIVE guidelines. All experiments and procedures were performed in accordance with the relevant guidelines and regulations and were approved by the Animal Care Committee of the University of Toyama (Approved number A2023MED-16)., (© 2025. The Author(s).)

With the development of high-throughput sequencing technology, numerous unknown long noncoding RNAs (lncRNAs) have been discovered. Preliminary research found that after being subjected to low-temperature enviroment, lncRNA44154 expression in the subcutaneous fat of pigs significantly increased. In order to analyze its biological function and regulatory mechanism, qRT-PCR was used to detect its spatiotemporal expression pattern. The nucleoplasmic isolation and FISH were used to locate it subcellular. Through overexpression or interference assays discussed the effect of lncRNA44154 on adipocyte proliferation and differentiation. RNA-seq was used to screen the biological pathways that lncRNA44154 may be involved in. RNA-pull down was used to find the interaction protein and double luciferase reporter gene detection experiment was used to validate the target gene. It was found that the expression of lncRNA44154 had tissue specificity and played a role in adipocyte proliferation. It was expressed in both cytoplasm and nucleus. After overexpression of lncRNA44154 in adipocytes, the expression level of Cyclins B, D, and E were all up-regulated and the cell proliferation ability was significantly enhanced. The number of positive cells increased significantly and the DNA replication activity was significantly enhanced. LncRNA44154 can promote the proliferation of porcine preadipocytes by encouraging cells to enter the S phase of the cell cycle. The result of interfering with lncRNA44154 is the opposite. Further analysis revealed that lncRNA44154 regulates intracellular lipid metabolism, inhibits the production of intracellular lipid droplets, and inhibits preadipocyte differentiation. RNA-seq results indicate that lncRNA44154 may be involved in biological pathways such as AMPK, PPAR and cAMP signaling pathway. It may work by regulating the RPS4X gene. This research may provide a new perspective for investigating the regulation of adipose metabolism by lncRNAs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Intramuscular fat (IMF) content is a critical indicator of the beef nutritional value and flavor. In this study, we focused on bta-miR-484, a microRNA that is differentially expressed during the adipogenic differentiation of bovine intramuscular adipocytes and is negatively correlated with the IMF content across different cattle breeds. Our findings demonstrate that bta-miR-484 inhibits adipogenic differentiation without altering the fatty acid composition of bovine intramuscular adipocytes. miRNA pull-down and dual-luciferase reporter assays confirmed that MAP3K9 is a target gene of bta-miR-484. Furthermore, bta-miR-484 suppresses the JNK signaling pathway by targeting MAP3K9, leading to decreased CCND1 expression, which impedes the mitotic clonal expansion (MCE) process and inhibits intramuscular adipocyte differentiation. In summary, this study uncovers a novel mechanism by which bta-miR-484 regulates bovine IMF content and provides the first exploration of MCE during intramuscular adipocyte adipogenic differentiation. These findings offer valuable theoretical insights into beef cattle breeding and molecular improvements.

Middle-aged obesity, characterized by excessive fat accumulation and systemic energy imbalance, often precedes various health complications. Recent research has unveiled a surprising link between DNA damage response and energy metabolism. Here, we explore the role of Eepd1, a DNA repair enzyme, in regulating adipose tissue function and obesity onset. Eepd1 is primarily expressed in adipose tissue, where its downregulation or deletion accelerates obesity development. We show that Eepd1 ablation hinders PKA activation, thereby inhibiting lipolysis and thermogenesis in adipose tissue. Notably, cold exposure enhances Eepd1's myristoylation, facilitating its anchorage to adipocyte membranes and subsequent activation of PKA, while a mutation at the myristoylation site of Eepd1 disrupts this process. Moreover, individuals with obesity exhibit reduced Eepd1 expression. Pharmacological restoration of Eepd1 with Retigabine dihydrochloride effectively mitigates obesity. This study reveals Eepd1's unexpected role in promoting adipose lipolysis and thermogenesis, underscoring its potential as a promising therapeutic target to combat obesity., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Purpose of Review: Bone marrow adipose tissue is a distinctive fat depot located within the skeleton, with the potential to influence both local and systemic metabolic processes. Although significant strides have been made in understanding bone marrow adipose tissue over the past decade, many questions remain regarding their precise lineage and functional roles., Recent Findings: Recent studies have highlighted bone marrow adipose tissue's involvement in continuous cross-talk with other organs and systems, exerting both endocrine and paracrine functions that play a crucial role in metabolic homeostasis, skeletal remodeling, hematopoiesis, and the progression of bone metastases. The advancement of imaging techniques, particularly cross-sectional imaging, has profoundly expanded our understanding of the complexities beyond the traditional view of bone marrow adipose tissue as an inert depot. Notably, marrow adipocytes are anatomically and functionally distinct from brown, beige, and classic white adipocytes. Emerging evidence suggests that bone marrow adipocytes, bone marrow adipose tissue originate from the differentiation of bone marrow mesenchymal stromal cells; however, they appear to be a heterogeneous population with varying metabolic profiles, lipid compositions, secretory properties, and functional responses depending on their specific location within the bone marrow. This review provides an up-to-date synthesis of current knowledge on bone marrow adipocytes, emphasizing the relationships between bone marrow adipogenesis and factors such as aging, osteoporosis, obesity, and bone marrow tumors or metastases, thereby elucidating the mechanisms underlying musculoskeletal pathophysiology., Competing Interests: Compliance with Ethical Standards. Competing interests: The authors declare no competing interests. Human and Animal Rights and Informed Consent : This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Obesity is a critical risk factor for the development of metabolic diseases and is often associated with dysfunctional adipocytes. Prevalent treatments such as lifestyle intervention, pharmacotherapy, and bariatric surgery are often accompanied by adverse side effects and poor patient compliance. Nanotechnology and cell-based therapy offer innovative approaches for targeted obesity treatments, as they can directly target adipocytes, regulate lipid metabolism, and minimize off-target effects. Here, we provide an overview of the intricate relationship between adipocytes and obesity, highlighting the potential of nanotechnology and cell-based therapy in obesity treatment. Additionally, we discuss the advancements of adipose-derived mesenchymal stem cells (ADMSCs) in obesity progression, including the latest challenges and considerations for developing adipose-targeted treatments for obesity. The objective is to provide a perspective on the design and development of nanotechnology and cell-based therapy for treating obesity and related comorbidities., (© 2024 Wiley-VCH GmbH.)

Adipocytes play a critical role in energy storage and endocrine signaling and are associated with various diseases such as cancer and diabetes. Facile strategies to engineer adipocytes have long been pursued for elucidating adipocyte biology and developing adipocyte-based therapies. Herein, we report metabolic glycan labeling of adipocytes and subsequent targeted modulation of adipocytes via click chemistry. We show that azido tags expressed on the surface of adipocytes can persist for over 4 days. By conjugating dibenzocyclooctyne (DBCO)-cargos onto azido-labeled adipocytes via click chemistry, the cargos can be retained on the adipocyte membrane for over 12 hours. We further show that signaling molecules including adiponectin, calreticulin, mannose-binding lectin 2, and milk fat globule-EGF factor 8 protein can be conjugated to adipocytes to orchestrate their phagocytosis by macrophages. The azido-labeled adipocytes grafted into mice can also mediate targeted conjugation of DBCO-cargos in vivo . This adipocyte labeling and targeting technology will facilitate the development of adipocyte-based therapies and provides a new platform for manipulating the interaction between adipocytes and other types of cells.

Background: Obesity is becoming one of the major non-communicable diseases with increasing incidence and risks that cannot be ignored. However effective and safe clinical treatment strategies still need to be deeply explored. Increased number and volume of adipocytes lead to overweight and obesity. The aim of our work is to identify lncRNAs that have important regulatory in differentiation of human mesenchymal stem cells (MSCs) into adipocytes, and to provide effective targets for clinical prevention and treatment of obesity and related metabolic disorders., Methods: We extracted primary MSCs from human adipose tissue, and conducted expression profile analysis of lncRNAs during adipogenic differentiation of MSCs to screen changed lncRNAs. Characteristics of lncRNA were revealed mainly by RACE and RNA FISH. Loss- and gain-of function experiments in vivo and in vitro were used to analyze effects of lncRNA. Targeted metabolomics was utilized to detect levels of free fatty acids. RNA pull-down, mRNA stability tests, etc. were employed to explore mechanisms of lncRNA., Results: Human-specific lncRNA, we named it MEK6-AS1, was the most up-regulated transcript during adipogenic differentiation of MSCs. MEK6-AS1 was highly expressed in adipose tissue samples from individuals with BMI ≥ 25 and positively correlated with adipogenic marker genes in these samples. Knocking down lncRNA inhibited expression of adipogenic differentiation markers and ectopic adipogenesis, reducing contents of various free fatty acids, as well as promoting osteogenic differentiation. Overexpression of lncRNA had the opposite effects to the above processes. We also found that MEK6-AS1 was elevated during hepatic steatosis organoid generation. Mechanistically, MEK6-AS1 worked partially through stabilization of MEK6 mRNA by NAT10., Conclusions: We have identified a human-specific lncRNA (MEK6-AS1) with position information in the genomic database but has not been extensively reported. We demonstrated that MEK6-AS1 as a novel lncRNA involved in adipogenic differentiation and adipogenesis, fatty acid metabolism, and osteogenic differentiation. We found that MEK6-AS1 may exert its effect by enhancing MEK6 mRNA stability through NAT10. Our study may provide insights into implication of lncRNAs in stem cell biology and offer a new potential therapeutic target for the prevention and treatment of obesity and other related disease., Competing Interests: Declarations. Ethics approval and consent to participate: Human adipose tissues were medical waste obtained from patients undergoing liposuction. The samples are only used for scientific research. The collection of samples does not cause additional harm to the patients and does not infringe their privacy. The informed consent was exempted, which was approved by the Ethics Committee at the Chinese Academy of Medical Sciences and Peking Union Medical College. All animal experiments were carried out in accordance with guidelines of a protocol approved by the Ethics Committee of the Chinese Academy of Medical Sciences and School of Basic Medicine Peking Union Medical College (SB2023048). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. The Author(s).)

Obesity is a widespread nutritional disorder, leading to a strong predisposition toward adverse health consequences. Activating transcription factor 3 (ATF3), a stress-induced transcription factor, has been documented as a therapeutic target for obesity. The intent of this project was to characterize the detailed role of ATF3 in adipogenesis in the context of obesity and its obscure downstream mechanism. After adipogenic differentiation, RT-qPCR and western blot examined ATF3 and ubiquitin-specific peptidase 53 (USP53) mRNA levels and protein levels. Adipogenesis was identified by Oil Red O staining, triglyceride (TG) levels, and western blot analysis. JASPAR database, ChIP and luciferase reporter assays predicted and validated the transcriptional regulation of USP53 by ATF3. Western blot also examined the protein levels of Ras homolog family member A (RhoA)/Rho-associated coiled-coil kinase (ROCK) pathway-involved proteins. ATF3 mRNA and protein levels were depleted in the differentiated 3T3-L1 adipocytes, and ATF3 elevation hindered the adipogenesis of 3T3-L1 adipocytes. ATF3 suppressed the transcription of USP53 as a transcription factor and lowered USP53 expression. Eventually, USP53 upregulation partially blunted the inhibitory role of ATF3 overexpression in adipogenesis and the RhoA/ROCK pathway. Consequently, ATF3 might transcriptionally inactivate USP53 to repress adipocyte adipogenesis and downregulate the RhoA/ROCK pathway.

Obesity is a chronic disease that contributes to the development of insulin resistance, type 2 diabetes (T2D), and cardiovascular risk. Glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) and glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) co-agonism provide an improved therapeutic profile in individuals with T2D and obesity when compared with selective GLP-1R agonism. Although the metabolic benefits of GLP-1R agonism are established, whether GIPR activation impacts weight loss through peripheral mechanisms is yet to be fully defined. Here, we generated a mouse model of GIPR induction exclusively in the adipocyte. We show that GIPR induction in the fat cell protects mice from diet-induced obesity and triggers profound weight loss (∼35%) in an obese setting. Adipose GIPR further increases lipid oxidation, thermogenesis, and energy expenditure. Mechanistically, we demonstrate that GIPR induction activates SERCA-mediated futile calcium cycling in the adipocyte. GIPR activation further triggers a metabolic memory effect, which maintains weight loss after the transgene has been switched off, highlighting a unique aspect in adipocyte biology. Collectively, we present a mechanism of peripheral GIPR action in adipose tissue, which exerts beneficial metabolic effects on body weight and energy balance., Competing Interests: Declaration of interests R.J.S., V.P., K.A.C., C.J., and M.C. are current or past employees of Eli Lilly and Company. This does not alter the authors’ adherence to science journal policies on sharing data and materials., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Until two decades ago, brown adipose tissue (BAT) was studied primarily as a thermogenic organ of small rodents in the context of cold adaptation. The discovery of functional human BAT has opened new opportunities to understand its physiological role in energy balance and therapeutic applications for metabolic disorders. Significantly, the role of BAT extends far beyond thermogenesis, including glucose and lipid homeostasis, by releasing mediators that communicate with other cells and organs. The field has made major advances by using new model systems, ranging from subcellular studies to clinical trials, which have also led to debates. In this perspective, we identify six fundamental issues that are currently controversial and comprise dichotomous models. Each side presents supporting evidence and, critically, the necessary methods and falsifiable experiments that would resolve the dispute. With this collaborative approach, the field will continue to productively advance the understanding of BAT physiology, appreciate the importance of thermogenic adipocytes as a central area of ongoing research, and realize the therapeutic potential., Competing Interests: Declaration of interests D.P.B. is the GlaxoSmithKline Research Chair in Diabetes of Université de Sherbrooke. A.C.C. is the Canada Research Chair in Molecular Imaging of Diabetes. S.K. serves as a scientific advisory board member of Moonwalk Bioscience Inc., (Published by Elsevier Inc.)

Adipocyte lipolysis controls systemic energy levels and metabolic homeostasis. Lipolysis is regulated by posttranslational modifications of key lipolytic enzymes. However, less is known about the transcriptional mechanisms that regulate lipolysis. Here, we identify interferon regulatory factor-2 binding protein 2 (IRF2BP2) as a transcriptional repressor of adipocyte lipolysis. Deletion of IRF2BP2 in human adipocytes increases lipolysis without affecting glucose uptake, whereas IRF2BP2 overexpression decreases lipolysis. RNA sequencing, and chromatin immunoprecipitation sequencing analyses show that IRF2BP2 represses lipolysis-related genes, including LIPE , which encodes hormone sensitive lipase, the rate-limiting enzyme in lipolysis. Adipocyte-selective deletion of Irf2bp2 in mice increases Lipe expression and free fatty acid levels, resulting in adipose tissue inflammation and glucose intolerance. Together, these findings demonstrate that IRF2BP2 restrains adipocyte lipolysis and opens avenues to target lipolysis for the treatment of metabolic disease.

Background: Maintaining a well-developed vascular system alongside adipose tissue (AT) expansion significantly reduces the risk of metabolic complications. Although GSK3β (glycogen synthase kinase-3 beta) is known for its role in various cellular processes, its specific functions in AT and regulation of body homeostasis have not been reported., Methods: GSK3β-floxed and GSK3α-floxed mice were crossed with adiponectin-Cre mice to generate GSK3β or GSK3α adipocyte-specific knockout mice (GSK3β ADKO and GSK3α ADKO ). A comprehensive whole-body metabolism analysis was performed on obese GSK3β ADKO mice induced by a high-fat diet. RNA sequencing was conducted on AT of both obese GSK3β ADKO and GSK3α ADKO mice. Various analyses, including vessel perfusion studies, lipolysis analysis, multiplex protein assays, in vitro protein phosphorylation assays, and whole-mount histology staining, were performed on AT of obese GSK3β ADKO mice. Tube-formation experiments were performed using 3B-11 endothelial cells cultured in the conditional medium of matured adipocytes under hypoxic conditions. Chromatin precipitation and immunofluorescence studies were conducted using cultured adipocytes with GSK3 inhibition., Results: Our findings provide the first evidence that adipocyte-specific knockout of GSK3β expands AT vascularization and mitigates obesity-related metabolic disorders. GSK3β deficiency, but not GSK3α, in adipocytes activates AMPK (AMP-activated protein kinase), leading to increased phosphorylation and nuclear accumulation of HIF-2α, resulting in enhanced transcriptional regulation. Consequently, adipocytes increased VEGF (vascular endothelial growth factor) expression, which engages VEGFR2 on endothelial cells, promoting angiogenesis, expanding the vasculature, and improving vessel perfusion within obese AT. GSK3β deficiency promotes AT remodeling, shifting unhealthy adipocyte function toward a healthier state by increasing insulin-sensitizing hormone adiponectin and preserving healthy adipocyte function. These effects lead to reduced fibrosis, reactive oxygen species, and ER (endoplasmic reticulum) stress in obese AT and improve metabolic disorders associated with obesity., Conclusions: Deletion of GSK3β in adipocytes activates the AMPK/HIF-2α/VEGF/VEGFR2 axis, promoting vasculature expansion within obese AT. This results in a significantly improved local microenvironment, reducing inflammation and effectively ameliorating metabolic disorders associated with obesity., Competing Interests: None.

Purpose of Review: Review the latest data regarding the intersection of adipose tissue (AT) and iron to meet the needs of AT metabolism and the progression of related diseases., Recent Findings: Iron is involved in fundamental biological metabolic processes and is precisely fine-tuned within the body to maintain cellular, tissue and even systemic iron homeostasis. AT not only serves as an energy storage depot but also represents the largest endocrine organ in the human body, maintaining systemic metabolic homeostasis. It is involved in physiological processes such as energy storage, insulin sensitivity regulation and lipid metabolism. As a unique iron-sensing tissue, AT expresses related regulatory factors, including the classic hepcidin, ferroportin (FPN), iron regulatory protein/iron responsive element (IRP/IRE) and ferritin. Consequently, the interaction between AT and iron is intricately intertwined. Imbalance of iron homeostasis produces the potential risks of steatosis, impaired glucose tolerance and insulin resistance, leading to AT dysfunction diseases, including obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Despite the role of AT iron has garnered increasing attention in recent years, a comprehensive review that systematically organizes the connection between iron and AT remains lacking. Given the necessity of iron homeostasis, emphasizing its potential impact on AT function and metabolism regulation provides valuable insights into physiological effects such as adipocyte differentiation and thermogenesis. Futhermore, regulators including adipokines, mitochondria and macrophages have been mentioned, along with analyzing the novel perspective of iron as a key mediator influencing the fat-gut crosstalk., Competing Interests: Declarations. Ethics statement: Ethical review and approval and patient consent were not required for this study in accordance with the local legislation and institutional requirements. Competing interests: The authors declare no competing interests. Human and Animal Rights and Informed Consent: This article does not contain any studies with human or animal subjects performed by any of the authors., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

During recent decades, changes in lifestyle have led to widespread nutritional obesity and its related complications. Remodelling adipose tissue as a therapeutic goal for obesity and its complications has attracted much attention and continues to be actively explored. The endothelium lines all blood vessels and is close to all cells, including adipocytes. The endothelium has been suggested to act as a paracrine organ. We explore the role of endothelial insulin-like growth factor-1 receptor (IGF-1R), as a paracrine modulator of white adipose phenotype. We show that a reduction in endothelial IGF-1R expression in the presence of high-fat feeding in male mice leads to depot-specific beneficial white adipose tissue remodelling, increases whole-body energy expenditure and enhances insulin sensitivity via a non-cell-autonomous paracrine mechanism. We demonstrate that increased endothelial malonate may be contributory and that malonate prodrugs have potentially therapeutically relevant properties in the treatment of obesity-related metabolic disease., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background/aims: Dexamethasone (DEX) is a widely used exogenous therapeutic glucocorticoid in clinical settings. Its long-term use leads to many side effects. However, its effect on metabolic disorders in individuals on a high-fat diet (HFD) remains poorly understood., Methods: In this study, HFD-fed mice were intraperitoneally injected with DEX 2.5 mg/kg/day for 30 days. Lipid metabolism, adipocyte proliferation, and inflammation were assayed using typical approaches., Results: DEX increased the epididymal fat index and epididymal adipocyte size in HFD-fed mice. The number of epididymal adipocytes with diameters > 70 μm accounted for 0.5% of the cells in the control group, 30% of the cells in the DEX group, 19% of the cells in the HFD group, and 38% of all the cells in the D+H group. Adipocyte proliferation in the D+H group was inhibited by DEX treatment. Adipocyte enlargement in the D+H group was associated with increased the lipid accumulation but not the adipocyte proliferation. In contrast, the liver triglyceride and total cholesterol levels and their metabolism were downregulated by the same treatment, indicating the therapeutic potential of DEX for nonalcoholic fatty liver disease., Conclusion: DEX synergizes with HFD to promote lipid deposition in adipose tissues. A high risk of obesity development in patients receiving HFD and DEX treatment is suggested.

Background/aim: Obese individuals often exhibit vitamin D deficiency, potentially due to sequestration in fat cells. Little is known about how vitamin D 3 enters adipocytes and associates with the intracellular lipid droplet., Materials and Methods: Newly differentiated human and mouse (3T3-L1) adipocytes and primary mouse adipocytes were treated with vitamin D 3 covalently linked to green fluorescent BODIPY (VitD-B) or Green BODIPY (GB) as control. Cells were exposed to 10-100 nM concentrations for various lengths of time (1-48 h). Fluorescence microscopy assessed vitamin D distribution., Results: VitD-B demonstrated stable incorporation into adipocytes without enzymatic cleavage, as HPLC showed no free vitamin D 3 after 72 h. Fluorescence microscopy showed GB uptake was rapid and persisted for 48 h. VitD-B uptake was more gradual compared to GB in the human and 3T3-L1 adipocytes. Primary mouse adipocytes exhibited similar uptake patterns, with VitD-B appearing within 1 h and fluorescence intensity increasing 1.2-fold at 8 h and 5.7-fold at 24 h. GB exhibited rapid fluorescence uptake in these same cells, 29-fold higher than VitD-B at 1 h. At 24 h, some VitD-B treated cells exhibited greater fluorescence intensity around the surface of the lipid droplets, which was not observed in GB. Isolated lipid droplets exhibited rapid and immediate uptake of both VitD-B and GB, indicating a strong affinity for these lipid structures. The time-dependent accumulation of vitamin D 3 in human adipocytes mirrored VitD-B uptake., Conclusion: VitD-B is a reliable proxy for studying the dynamics of vitamin D 3 uptake in adipocytes., (Copyright © 2025 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aberrant activation of dermal fibroblasts during wound healing often leads to debilitating fibrotic changes in the skin, such as scleroderma and keloids. However, the underlying cellular and molecular mechanisms remain elusive. Here, we established a wound-induced skin fibrosis (WISF) mouse model in mature adult mice, characterised by excessive deposition of collagen bundles, loss of dermal adipocytes, and enrichment of DPP4 + Ly6A + THY1 + hypodermal interstitial adipocyte progenitors (HI-APs) and pericytes, resembling human fibrotic skin diseases. This WISF model exhibited an age-dependent gain of fibrotic characteristics, contrasting with the wound-induced hair neogenesis observed in younger mice. Through comprehensive analyses of the WISF, we delineated a trajectory of fibroblast differentiation that originates from HI-APs. These progenitors highly expressed several extracellular matrix (ECM) genes and exhibited a TGFβ pathway signature. TGFβ was identified as the key signal to inhibit the adipogenic potential and maintain the fibrogenic potential of dermal APs. Additionally, administering a TGFβ receptor inhibitor to wound scar reduced the abundance of ECM-producing APs. Finally, analysis of human scleroderma skin tissues revealed a negative correlation between the expression of AP-, ECM-, and TGFβ pathway-related genes and PPARG. Overall, this study establishes a wound-induced skin fibrosis mouse model and demonstrates that TGFβ-mediated blockage of HI-AP differentiation is crucial for driving fibrotic pathology. Targeting HI-APs and adipogenesis may provide novel avenues for developing disease-modifying therapies for fibrotic skin diseases., (© 2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.)

The sigma-1 receptor (S1R) is involved in intracellular lipid synthesis and transport. Recent studies have shown that its genetic inactivation impairs adipogenic differentiation in vitro. This study investigated the role of S1R in adipose tissue physiology and metabolic health using adult and old WT and S1R KO mice. Visceral fat mass was increased in adult, but not old S1R-KO male mice compared to that of WT mice, despite having similar body weights, food intake, and energy expenditure. The average adipocyte size was 64 % larger in adult KO mice than in adult WT mice. Adult S1R-KO mice showed reduced plasma dehydroepiandrosterone sulfate (DHEA-S) and elevated fasting plasma leptin concentrations. Lipidomic analysis revealed alterations in plasma metabolite concentrations, particularly reduced levels of sphingomyelins, ceramides, phosphatidylcholines, lysophosphatidylcholines, and cholesteryl esters in adult mice. Decreased expression of Pparγ, Adipoq, and Atgl was detected in visceral white adipose tissue (vWAT) isolated from adult KO mice. Additionally, Fabp4 and Adipoq expression levels were significantly lower in KO adipose-derived stromal cells than in WT adipose-derived stromal cells. A fivefold increase in the mitochondrial fatty acid oxidation rate and a 43 % increase in electron transfer coupling capacity were detected in adult S1R-KO vWAT. In summary, our investigation revealed an age-dependent association between increased visceral adiposity and decreased plasma levels of DHEA-S in S1R-deficient male mice. These findings underscore the potential role of S1R in regulating metabolic processes in adipose tissue and suggest that DHEA-S is a potential mediator of adiposity changes in the absence of S1R., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Visceral adipose tissue (VAT) is the primary fat reservoir and energy source in fish. Other relevant fat depots include subcutaneous adipose tissue (SAT), located under epithelial layers, and intramuscular adipose tissue (IMAT), found between the myotomes. The present study investigates the morphological, gene expression and functional characteristics of these different depots in rainbow trout (Oncorhynchus mykiss). Commercial rainbow trout of two different average weights were sampled for histology, lipid quantification and fatty acids profile. Mature adipocytes were isolated for gene expression analyses of lipid metabolic markers. Both VAT and SAT showed large adipocytes, and high total lipid content, suggesting hypertrophic growth. Adipocytes in IMAT were consistently smaller regardless of fish size. While fatty acid composition was similar across depots, SAT had lower levels of palmitic acid and higher levels of polyunsaturated fatty acids that act as precursors of phospholipids and eicosanoids such as eicosapentaenoic acid, compared to VAT and IMAT. Gene expression analyses revealed higher levels of fatty acid transporters, lipolysis and β-oxidation markers in VAT and SAT compared to IMAT, suggesting a more active lipid metabolism. These data support the role of VAT as the main energy depot, while SAT may act as a secondary reservoir, and IMAT potentially serves as an occasional energy source for muscles. This study provides valuable insights into the distinct properties of the different fat depots in fish, which may help to optimize strategies to modulate adiposity for improved health, metabolism, and product quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

DFAT cells represent an attractive source of stem cells in tissue engineering and in the potential treatment of several clinical conditions. Our objective was to determine whether DFAT cells originate from mature adipocytes and address whether contamination from the stromal vascular fraction (SVF) could be as a source for these cells. A murine adiponectin-creERT;mT/mG model was used with the excision of the cassette induced by tamoxifen injection for the cells expressing adiponectin (adipoq). This model allows distinguishing of mature adipocytes (green fluorescence) from other SVF cell types (red fluorescence) based on the fluorescent protein expressed. Mature adipocytes and SVF cells were isolated from adipose tissues by collagenase digestion. Ceiling cultures were imaged by time-lapse microscopy. Confocal microscopy was used to follow cells over 21 days. Time-lapse microscopy experiments showed liposecretion occurring in mature adipocytes displaying green fluorescence. Confocal imaging allowed the identification of a heterogeneous cell population expressing green but also red fluorescence after 21 days of culture. Asymmetrical division of mature adipocytes was not observed. In conclusion, liposecretion of mature adipocytes is a phenomenon that can be observed in vitro and DFAT cells do originate from mature adipocytes . However, the population of DFAT cells is heterogenous., Competing Interests: AT receives research funding from Johnson & Johnson, Medtronic, GI Windows and Biotwin for studies on obesity or bariatric surgery and acted as a consultant for Bausch Health, Novo Nordisk, and Biotwin.

Purpose: Adipocytes around aggressive breast cancer (BC) are less lipid different from naive adipocytes (cancer-associated adipocytes, CAAs), and peritumoral edema caused by the release of cytokines from CAAs can conduce to decrease the peritumoral fat proportion. The purpose of this study was to correlate peritumoral fat content identified by using iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) with lymph node metastasis (LNM) and recurrence-free survival (RFS) in BC patients and to compare with T2-weighted (T2WI) and diffusion-weighted images (DWI) analyses., Methods: This retrospective study consisted of 85 patients who were diagnosed with invasive carcinoma of breast and underwent breast MRI, including IDEAL before surgery. The scan time of fat fraction (FF) map imaging using IDEAL was 33s. Four regions of interest (ROIs), which are 5 mm from the tumor edge, and one ROI in the mammary fat of the healthy side were set on the FF map. Then average peritumoral FF values (TFF), average FF values on the healthy side (HFF), and peritumoral fat ratio (PTFR, which is defined as TFF/HFF) were calculated. Tumor apparent diffusion coefficient (ADC) values were measured on ADC map obtained by DWI. Peritumoral edema was classified into three grades based on the degree of signal intensity around the tumor on T2WI (T2 edema)., Results: The results of stepwise logistic regression analysis for four variables (TFF, PTFR, T2 edema, and ADC value) indicated that TFF and T2 edema were significant factors of LNM (P < 0.01). RFS was significantly associated with TFF (P = 0.016), and 47 of 49 (95.9%) patients with TFF more than 85.5% were alive without recurrence., Conclusion: Peritumoral fat content identified by using IDEAL is associated with LNM and RFS and may therefore be a useful prognostic biomarker for BC.

Background: Type 2 diabetes (T2DM) is a chronic metabolic disorder characterized by insulin resistance and chronic inflammation. Adipose tissue macrophages (ATMs), central players in mediating pro-inflammatory responses within adipose tissue, have been shown to influence insulin sensitivity through exosome secretion. While the role of macrophages-derived exosomal miRNA has been studied in various diseases, their pathogenic roles in T2DM, particularly ATMs-derived exosomal miRNA in adipose tissue inflammation, remain underexplored., Objectives: This study focuses specifically on T2DM, investigating the role of ATM-derived exosomal miRNAs in adipose tissue inflammation, a critical factor in the pathogenesis of T2DM., Methods: ATM were isolated from visceral adipose tissues in patients with or without diabetes. Differentially expressed miRNAs in ATM-derived exosomes were predicted by high-throughput RNA sequencing. The RAW264.7 macrophages and 3T3-L1 preadipocytes was selected as a model system. Quantitative RT-PCR was used to assess miR-500a-5p expression. The direct binding of miR-500a-5p to Nrf2 mRNA 3' UTR was verified by dual luciferase assay., Results: MiR-500a-5p was also enriched in the exosomes of high-glucose-treated macrophages. Furthermore, these exosomes induced high expression of miR-500a-5p and activation of the NLRP3 inflammasome in adipocytes when co-cultured with them. Additionally, the reduction of miR-500a-5p expression in macrophages by using a miR-500a-5p inhibitor ameliorated the pro-inflammatory properties of the exosomes, and co-culturing these exosomes with adipocytes resulted in decreased expression of NLRP3 inflammasome-associated proteins in adipocytes. In contrast, induction of miR-500a-5p expression led to the opposite results. Moreover, the dual-luciferase assay confirmed that miR-500a-5p directly targeted the 3' UTR of Nrf2 mRNA. Unlike miR-500a-5p, Nrf2 exhibited an anti-inflammatory response., Conclusion: The results indicate that ATM-derived exosomal miR-500a-5p promotes NLRP3 inflammasome activation and adipose tissue inflammation through down-regulation of Nrf2 in adipocytes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Caloric restriction (CR), commonly used as both a lifestyle choice and medical strategy, has been shown to adversely impact appendicular bone mass. However, its influence on alveolar bone health and the underlying mechanisms remain poorly understood. In this study, 8-week-old C57BL/6 J mice were fed with 30 % CR for 8 weeks. Micro-architecture, histologic parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. To further explore the underlying mechanisms, metabolic cages and in vitro bioenergetics were performed. Our results showed that 8 weeks of CR led to trabecular and cortical bone loss in the mandibles of female mice. CR in female mice decreased bone formation and bone resorption activities but induced adiposity in the mandibles. After CR, the adipogenesis in mesenchymal cells from orofacial bones (OMSCs) was greatly accelerated, whereas osteogenic differentiation was reduced in females. Undifferentiated CR OMSCs showed marked suppression in ATP production rates from mitochondria in female mice. ATP production rates decreased after osteogenesis but were upregulated during adipogenesis in female mice. Conversely, the generation of reactive oxygen species (ROS) was heightened during both osteoblastic and adipogenic differentiation in female CR groups. Collectively, our study indicated that CR could cause significant bone loss in the mandibles of female mice, almost certainly related to a reduced ATP supply and the unregulated generation of ROS., Competing Interests: Declaration of competing interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Cancer cells-derived extracellular vesicles can trigger the transformation of adipose-derived mesenchymal stem cells (ADMSC) into a pro-inflammatory, cancer-associated adipocyte (CAA) phenotype. Such secretome-mediated crosstalk between the adipose tissue and the tumor microenvironment (TME) therefore impacts tumor progression and metastatic processes. In addition, emerging roles of diet-derived phytochemicals, especially epigallocatechin-3-gallate (EGCG) among other polyphenols, in modulating exosome-mediated metabolic and inflammatory signaling pathways have been highlighted. Here, we discuss how selected diet-derived phytochemicals could alter the secretome signature as well as the crosstalk dynamics between the adipose tissue and the TME, with a focus on breast cancer. Their broader implication in the chemoprevention of obesity-related cancers is also discussed.

Sudden death can be the first symptom of cardiac disease, and establishing a precise postmortem diagnosis is crucial for genetic testing and follow-up of relatives. Arrhythmogenic cardiomyopathy is a structural cardiomyopathy that can be challenging to diagnose postmortem because of differences in structural findings and propagation of the disease at the time of death. Cases can have minimal or no structural findings and later be diagnosed according to genotype, known as concealed cardiomyopathy. Postmortem diagnosis often lacks clinical information, whereas antemortem diagnosis is based on paraclinical investigations that cannot be performed after death. However, the entire substrate is available, which is unique to postmortem diagnosis and research and can provide valuable insights when adding new methods. Reactive changes in the heart, such as myocardial fibrosis and fat, are significant findings. The patterns of these changes in various diseases are not yet fully understood and may be limited by sampling material and conventional microscopic diagnostics. We demonstrate an automated pipeline in QuPath for quantifying postmortem picrosirius red cardiac tissue for collagen, residual myocardium, and adipocytes by integrating Cellpose into a versatile pipeline. This method was developed and tested using cardiac tissues from autopsied individuals. Cases diagnosed with arrhythmogenic cardiomyopathy and age-matched controls were used for validation and testing. This approach is free and easy to implement by other research groups using this paper as a template. This can potentially lead to the development of quantitative diagnostic criteria for postmortem cardiac diseases, eliminating the need to rely on diagnostic criteria from endomyocardial biopsies that are not applicable to postmortem specimens. We propose that this approach serves as a template for creating a more efficient process for evaluating postmortem cardiac measurements in an unbiased manner, particularly for rare cardiac diseases., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

In this study, 39 strains of lactic acid bacteria were screened from several fermented foods. Based on the evaluation of functional and prebiotic properties, Lactiplantibacillus plantarum SDJ09 was selected as a promising candidate. It gave a 48.16% cholesterol reduction and 33.73% pancreatic lipase inhibition in cells; exhibited high resistance to acid, bile salts, and gastrointestinal fluid; and had strong antibacterial activity and high adhesion capabilities. More importantly, the lipid-lowering effect of L. plantarum SDJ09 was also investigated using 3T3-L1 mature adipocytes and HepG2 nonalcoholic fatty liver disease models. L. plantarum SDJ09 effectively decreased triglyceride accumulation by more than 50% in both cell models, in which the expression of PPARγ, C/EBPα, aP2, and LPL in 3T3-L1 cells was significantly downregulated by L. plantarum SDJ09. L. plantarum SDJ09 also improved lipid metabolism by downregulating the expression of HMGCR, SREBP-1c, ACC, and FAS and upregulating the expression of CYP7A1 in HepG2 nonalcoholic steatohepatitis cells. Therefore, L. plantarum SDJ09 has the potential to effectively decrease obesity and non-alcoholic fatty liver disease (NAFLD) by inhibiting lipid accumulation, providing a prospective probiotic agent for anti-obesity., Competing Interests: Declarations. Ethical Approval: Not applicable. Consent to Participate: Not applicable. Consent to Publish: Not applicable. Competing Interests: The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Chitosan, the deacetylated form of chitin, is considered a valuable source of compounds in the feed and food industries. However, the impact of Hermetia illucens larvae chitosan (HCS) with specific physicochemical characteristics on obesity mediated by lipid accumulation and microbiome dysbiosis has not been fully elucidated. We purified HCS with a low molecular weight (84 kDa), low crystallinity, and a high deacetylation rate, characterizing it through several analytical techniques, including gel permeation chromatography, FT-IR, 1 H NMR, FE-SEM, and XRD analysis. HCS effectively inhibited the differentiation of 3T3-L1 preadipocytes by suppressing the production of reactive oxygen species. The adipogenic signaling of preadipocytes, mediated by the phosphorylation of mTOR and PPARγ, which are essential for the expression of fatty acid synthase, was attenuated by HCS. In mouse models fed high-fat diets, the oral administration of HCS prevented changes in white adipose tissue and liver weight and reduced plasma levels of total cholesterol. Additionally, the analysis of the microbiota using 16S rRNA revealed that HCS improved dysbiosis by modulating the composition and abundance of specific bacterial genera, including F. rodentium, L. gasseri, L. reuteri, and L. murinus. These findings highlight the potential of HCS as a candidate for the treatment of obesity-related metabolic diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alcohol-associated liver disease (ALD) is one of the major chronic liver diseases and despite the dire clinical needs and extensive research efforts, no effective therapies are available for late-stages of ALD except for liver transplantation. Adipose tissue dysfunction has been implicated in the progression of ALD. Furthermore, it has been previously suggested that thermogenic fat can be activated after alcohol consumption. In this study, increased thermogenic gene expression was detected in both classical brown adipose tissue and beige adipocytes in mice that were given alcohol challenges even when housed at thermoneutrality. In particular, higher expression level of Prdm16, the key transcriptional co-component for beige fat function, was observed in the subcutaneous fat of mice after alcohol challenges. The objective of the present study is to explore the functional significance of adipocyte PRDM16 in the context of ALD. Even though Prdm16 adipocyte-specific-deleted mice (Prdm16-adKO) did not show liver defects at the basal level, following two different alcohol challenge regimens, exacerbated ALD phenotypes were observed in Prdm16-adKO mice compared to that of the control Prdm16  fl/fl mice. Mechanistic investigation suggests that adipose dysfunction after alcohol abuse, including alcohol-induced changes in adipose lipolytic activity, fatty acid oxidation and adipokine levels, may render the worsened ALD phenotype in Prdm16-adKO mice. These results indicate PRDM16-mediated signaling in fat plays a protective role against liver injury caused by alcohol abuse, suggesting it may represent a potential therapeutic target against ALD., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Preadipocytes are formed during the 14th and 16th weeks of gestation. White adipose tissue, in particular, is generated in specific areas and thereby assembles after birth, rapidly increasing following the propagation of adipoblasts, which are considered the preadipocyte cell precursors. The second trimester of gestation is a fundamental phase of adipogenesis, and in the third trimester, adipocytes, albeit small may be present within the main deposition areas. In the course of late gestation, adipose tissue develops in the foetus and promotes the synthesis of large amounts of uncoupling protein 1, in similar quantities relative to differentiated brown adipose tissue. In mammals, differentiation occurs in two functionally different types of adipose cells: white adipose cells resulting from lipid storage and brown adipose cells from increased metabolic energy consumption. During skeletogenesis, synovial joints develop through the condensation of mesenchymal cells, which forms an insertional layer of flattened cells that umlaut skeletal elements, by sharing the same origin in the development of synovium. Peri-articular fat pads possess structural similarity with body subcutaneous white adipose tissue; however, they exhibit a distinct metabolic function due to the micro-environmental cues in which they are embedded. Fat pads are an important component of the synovial joint and play a key role in the maintenance of joint homeostasis. They are also implicated in pathological states such as osteoarthritis.In this paper we explore the therapeutic potential of adipocyte tissue mesenchymal precursor-based stem cell therapy linking it back to the anatomic origin of adipose tissue., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Obesity is a widely concerned health problem. Mobilizing white adipose tissue and reducing fat synthesis are considered as effective strategies in the treatment of obesity. Here, using Connectivity Map (CMap) approach, we identified the pinocembrin (PB), a natural flavonoid primarily found in propolis, as a potential anti-obesity drug. Therefore, high-fat-diet (HFD) mice were randomly divided into two groups and fed a HFD or HFD with PB in this study. In vivo experiments showed that supplementation of PB reduced the body weight gain and ameliorated insulin resistance in HFD-induced mice. More importantly, PB did not cause side effect through detecting the levels of alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine (CRE) and blood urea nitrogen (BUN) in serum of mice. Additionally, PB reduced expansion of white adipose tissue with upregulation of genes related lipolysis and downregulation of genes related lipogenesis. Furthermore, in vitro experiments revealed that PB treatment dose-dependently inhibited lipid droplet formation with upregulation of genes related lipolysis and downregulation of genes related lipogenesis. Molecular docking analysis combined with cellular thermal shift assay (CETSA) suggested that PB has a high affinity to the G protein-coupled receptor 120 (GPR120). Meanwhile, we confirmed that PB efficiently inhibited adipogenic differentiation of preadipocytes by directly binding to GPR120 and subsequently activating the downstream phosphorylation extracellular regulated kinase 1/2 (ERK1/2). Collectively, PB exerted anti-obesity effect through GPR120-ERK1/2 signaling pathway, providing a novel and promising natural drug for the treatment of obesity., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adipose tissue regulates whole-body energy balance and is crucial for metabolic health. With energy surplus, adipose tissue expands, which may lead to local areas of hypoxia and inflammation, and consequently impair whole-body insulin sensitivity. We report that DICER, a key enzyme for miRNA maturation, is significantly lower in abdominal subcutaneous white adipose tissue of men with obesity compared with men with a lean phenotype. Furthermore, DICER is profoundly downregulated in mouse adipose tissue and liver within the first week on a high-fat diet (HFD), and remains low after prolonged HFD feeding. Downregulation of DICER in mice occurs in both mature adipocytes and stromal vascular cells. Mechanistically, chemically induced hypoxia in vitro shows DICER degradation via interaction with hypoxia-inducible factor 1-α (HIF1α). Moreover, DICER and HIF1α interact in brown adipose tissue post-HFD which may signal for DICER degradation. Finally, RNA sequencing reveals a striking time-dependent downregulation of total miRNA content in mouse subcutaneous adipose tissue after HFD feeding. Collectively, HFD in mice reduces adipose tissue DICER, likely due to hypoxia-induced interaction with HIF1α during tissue expansion, and this significantly impacts miRNA content., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest in relation to this work., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The content and composition of intramuscular fat (IMF) affect the cooked meat palatability such as tenderness and juiciness. Thus, elucidation of lipid deposition and its composition in goat IMF is necessary. Here, Jianzhou big-ear goats with higher IMF content is associated with lower mRNA level of LKB1 gene, compared with those of Chuannan black goats. Functionally, knockdown of LKB1 promoted intramuscular adipocyte lipid accumulation. Next, LC-MS/MS based pseudo target analysis found that 409 lipids existed in goat intramuscular adipocytes, of which polyunsaturated fatty acids accounted for most lipids. Compared with the control, 78 differential lipids were screened in the siLKB1 group, enriched in the triacylglycerols and fatty acids subclasses. The combined analysis between lipidomic and published transcriptomic data showed that siLKB1 enhanced polyunsaturated fatty acids synthesis through upregulation expression of HACD4. Finally, the promotion of lipid accumulation and polyunsaturated fatty acids synthesis in the LKB1 knockdown cells were partly rescued by ablation of HACD4. Collectively, these data provide a genetic target to produce PUFA enriched functional goat meat and expand new insights into improvement of meat quality., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims: Visceral adipose tissue (VAT) accumulation is essential for the occurrence and development of obesity and related metabolic diseases. Currently, the specific mechanism of VAT accumulation is still unclear., Materials and Methods: We searched the Gene Expression Omnibus database to obtain single-cell RNA sequencing (scRNAseq) data for VAT in patients with a normal body mass index (BMI), obesity, or morbid obesity. By using PCR, WB, immunofluorescence staining, and flow cytometry analysis, we validated the interactions between macrophages, endothelial cells (ECs), and adipocyte progenitor cells (APCs), as well as the underlying mechanism, in VAT. Finally, we tested the findings in obese mice using recombinant proteins and adeno-associated virus infection., Results: One study with human scRNAseq data was included. This study collected 13-VAT from 5 individuals with obesity and diabetes, 9 individuals with obesity, and 1 individual with a normal BMI. The proportion of inflammatory macrophages is substantially increased in obese and diabetic patients. ECs have the most active interactions with other cells. Notably, the activation of JAK1/STAT3 is one of the reasons for the increase in inflammatory endothelial cells and can promote the secretion of angiopoietin-2 (Angpt2) and induce APCs to transition from mesothelin (MSLN) to complement factor D (CFD) expression via integrin-α5β1 signalling. This phenotypic transition promotes APC differentiation into mature adipocytes and accelerates VAT accumulation. These observations were further validated in an in vitro model and an in vivo study using Angpt2 recombinant proteins and blocking the expression of Angpt2 by adeno-associated virus infection., Conclusions: ECs are essential for promoting VAT accumulation by facilitating APC differentiation from MSLN to CFD phenotype. This process is driven by Angpt2 from ECs upon JAK1/STAT3 signalling activation under metabolic stress., (© 2024 John Wiley & Sons Ltd.)

Adipose tissue dysfunction is one of the features of Polycystic Ovary Syndrome (PCOS) with dysregulated adipogenesis, altered functional pathways and increased inflammation. It is increasingly clear that there are also male correlates of the hormonal and metabolic features of PCOS. We hypothesised that the effects of adipose tissue dysfunction are not sex-specific but rather fat depot-specific and independent of obesity. We used a clinically realistic ovine model of PCOS where pregnant sheep are injected with 100 mg of testosterone propionate twice weekly from day 62 to day 102 of gestation. We studied control and prenatally androgenised (PA) female and male offspring during adolescence and weight-matched control and PA female sheep during adulthood. We examined subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT) and in adult female sheep bone marrow adipose tissue (BMAT). Adipogenesis related gene expression in SAT was similar in adolescent female and male controls and the reduction in adipogenesis related gene expression by PA in female adipose tissue was not observed in males. Differences in expression of genes associated with adipose tissue function in adolescence in SAT driven by PA were found in both sexes. In adulthood, the changes seen in adolescent females were absent or reversed but there was an increase in inflammatory markers that was weight independent. In addition, BMAT showed increased inflammatory markers. Adipose dysfunction evolves with time and is focussed on SAT rather than VAT and is generally sex-specific although there are also effects of prenatal androgenisation on male SAT. In female adults, the inflammation seen in SAT is also present in BMAT and the development of blood cells in an inflammatory environment may have systemic implications., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cell culture plays a crucial role in addressing fundamental research questions, particularly in studying insulin resistance (IR) mechanisms. Multiple in vitro models are utilized for this purpose, but their technical distinctions and relevance to in vivo conditions remain unclear. This study aims to assess the effectiveness of existing in vitro models in inducing IR and their ability to replicate in vivo IR conditions., Background: Insulin resistance (IR) is a cellular condition linked to metabolic disorders. Despite the utility of cell culture in IR research, questions persist regarding the suitability of various models. This study seeks to evaluate these models' efficiency in inducing IR and their ability to mimic in vivo conditions. Insights gained from this research could enhance our understanding of model strengths and limitations, potentially advancing strategies to combat IR and related disorders., Objective: 1- Investigate the technical differences between existing cell culture models used to study molecular mediators of insulin resistance (IR). 2- Compare the effectiveness of present in vitro models in inducing insulin resistance (IR). 3- Assess the relevance of the existing cell culture models in simulating the in vivo conditions and environment that provoke the induction of insulin resistance (IR)., Methods and Material: In vitro , eight sets of 3T3-L1 cells were cultured until they reached 90% confluence. Subsequently, adipogenic differentiation was induced using a differentiation cocktail (media). These cells were then divided into four groups, with four subjected to normal conditions and the other four to hypoxic conditions. Throughout the differentiation process, each cell group was exposed to specific factors known to induce insulin resistance (IR). These factors included 2.5 nM tumor necrosis factor-alpha (TNFα), 20 ng/ml interleukin-6 (IL-6), 10 micromole 4-hydroxynonenal (4HNE), and high insulin (HI) at a concentration of 100 nM. To assess cell proliferation, DAPI staining was employed, and the expression of genes associated with various metabolic pathways affected by insulin resistance was investigated using Real-Time PCR. Additionally, insulin signaling was examined using the Bio-plex Pro cell signaling Akt panel., Results: We induced insulin resistance in 3T3-L1 cells using IL-6, TNFα, 4HNE, and high insulin in both hypoxic and normoxic conditions. Hypoxia increased HIF1a gene expression by approximately 30% (P<0.01). TNFα reduced cell proliferation by 10-20%, and chronic TNFα treatment significantly decreased mature adipocytes due to its cytotoxicity. We assessed the impact of insulin resistance (IR) on metabolic pathways, focusing on genes linked to branched-chain amino acid metabolism, detoxification, and chemotaxis. Notably, ALDH6A1 and MCCC1 genes, related to amino acid metabolism, were significantly affected under hypoxic conditions. TNFα treatment notably influenced MCP-1 and MCP-2 genes linked to chemotaxis, with remarkable increases in MCP-1 levels and MCP-2 expression primarily under hypoxia. Detoxification-related genes showed minimal impact, except for a significant increase in MAOA expression under acute hypoxic conditions with TNFα treatment. Additional genes displayed varying effects, warranting further investigation. To investigate insulin signaling's influence in vitro by IRinducing factors, we assessed phospho-protein levels. Our results reveal a significant p-Akt induction with chronic high insulin (10%) and acute TNFα (12%) treatment under hypoxia (both P<0.05). Other insulin resistance-related phospho-proteins (GSK3B, mTOR, PTEN) increased with IL-6, 4HNE, TNFα, and high insulin under hypoxia, while p-IRS1 levels remained unaffected., Conclusion: In summary, different in vitro models using inflammatory, oxidative stress, and high insulin conditions under hypoxic conditions can capture various aspects of in vivo adipose tissue insulin resistance (IR). Among these models, acute TNFα treatment may offer the most robust approach for inducing IR in 3T3-L1 cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This study employs single-cell RNA sequencing (scRNA-seq) and assay for transposase-accessible chromatin with high-throughput sequencing technologies (scATAC-seq) to perform joint sequencing on cells at various time points during the induction of adipose-derived stem cells (ADSCs) into astrocytes. We applied bioinformatics approaches to investigate the differentiation trajectories of ADSCs during their induced differentiation into astrocytes. Pseudotemporal analysis was used to infer differentiation trajectories. Additionally, we assessed chromatin accessibility patterns during the differentiation process. Key transcription factors driving the differentiation of ADSCs into astrocytes were identified using motif and footprint methods. Our analysis revealed significant shifts in gene expression during the induction process, with astrocyte-related genes upregulated and stem cell-related genes downregulated. ADSCs first differentiated into neural stem cell-like cells with high plasticity, which further matured into astrocytes via two distinct pathways. Marked changes in chromatin accessibility were observed during ADSC-induced differentiation, affecting transcription regulation and cell function. Transcription factors analysis identified NFIA/B/C/X and CEBPA/B/D as key regulators in ADSCs differentiation into astrocytes. We observed a correlation between chromatin accessibility and gene expression, with ADSCs exhibiting broad chromatin accessibility prior to lineage commitment, where chromatin opening precedes transcription initiation. In summary, we found that ADSCs first enter a neural stem cell-like state before differentiating into astrocytes. ADSCs also display extensive chromatin accessibility prior to astrocyte differentiation, although transcription has not yet been initiated. These findings offer a theoretical framework for understanding the molecular mechanisms underlying this process., (© 2024 International Society for Neurochemistry.)

Obesity is a widespread prevailing health concern with multifactorial causes. Among the various defined molecular targets associated with obesity, peroxisome proliferator activated receptor gamma, leptin, ghrelin, and adiponectin play crucial roles in fundamental processes including energy balance, adipose tissue biology, and metabolic health, making them particularly significant in the study of obesity.Capsaicin and orange peel exhibit promising anti-obesity properties through their thermogenic, metabolic, and anti-inflammatory effects. Potential pathways for therapeutic approaches in the management of obesity are provided by these targets. The lipid-lowering and anti-obesity benefits of specific plant species have been highlighted in Asian medicine. Due to the potential anti-obesity qualities, capsaicin, which is derived from chilli peppers, and orange peel extract has been focused in this review. Capsaicin causes apoptosis in preadipocytes and adipocytes and suppresses adipogenesis. Citrus fruits are a significant source of bioactive substances, primarily flavonoids. Due to their ability to reduce adipocyte development and cellular lipid content, citrus polyphenols are helpful in the control of obesity. This extensive analysis offers insights into new treatment approaches for the prevention and management of obesity and metabolic syndrome by examining the interactions of molecular variables in obesity as well as the possible anti-obesity advantages of capsaicin and orange peel extract., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: All authors offer their consent towards publication. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Decellularized adipose matrix (DAM) is considered to be the most potential biological scaffold for soft tissue repair and reconstruction, as it is able to induce the regeneration of adipose tissue in situ in adulthood. But how does this adipose tissue regeneration happen and develop in vivo? Is it the same as the original autologous one? Temporary existence or long-term survival? These are the key questions that will determine the future applications of DAM. In this study, we investigated the composition, structure and biomechanical properties of DAM before implanting it into the subcutaneous back of immunodeficient mice. The entire regeneration process in vivo was closely monitored histologically from 3 days to 1 year after implantation, including fat regeneration, vascular growth, inflammatory responses, and matrix degradation and remodeling. Transcriptome sequencing was used to analyze the difference in gene expression between regenerated fat and autologous fat at different periods. The results showed that the DAM-induced regenerated fat first appeared at 1 w and remained stable over 6 m, indicating remarkable similarity to autologous fat at the later stages of implantation. And about (18.3 ± 29.3) % of the regenerated adipocytes were still viable after one year. The process of adipogenesis was enhanced by the decrease in inflammatory infiltration and proceeded in parallel with angiogenesis. STATEMENT OF SIGNIFICANCE: The decellularized adipose matrix (DAM) is the only biological scaffold that can spontaneously generate adipocytes in vivo without the need to add exogenous cells. However, in the previous studies, the longest DAM-related animal experiments were about 3 months. The different stages and characteristics of DAM implantation cannot be fully captured. Comprehensive preclinical researches on the initiation, characteristics, and long-term outcomes of DAM-induced adipose tissue regeneration in adulthood is crucial. In this study, we closely observed various aspects of the entire process in vivo from 3 days to 1 year after implantation including fat regeneration, vascular growth, inflammatory reactions as well as matrix degradation and remodeling. The thorough research will contribute to the understanding of stability and dynamic remodeling of DAM regeneration models., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Protein kinase CK2 is a highly conserved enzyme implicated in the pathogenesis of various human illnesses including obesity. Despite compelling evidence for the involvement of this kinase in the pathophysiology of obesity, the molecular mechanisms by which CK2 might regulate fat metabolism are still poorly understood., Methods and Results: In this study, we aimed to elucidate the role of CK2 on lipid metabolism by employing both in vitro and in vivo approaches using mouse pre-adipocytes and a mouse model of diet-induced obesity. We show that pharmacological inhibition of CK2 by CX-4945 results in premature upregulation of p27 KIP1 preventing the progression of cells into mature adipocytes by arresting their development at the intermediate phase of adipogenic differentiation. Consistent with this, we show that in vivo, CK2 regulates the expression levels and ERK-mediated phosphorylation of C/EBPβ, which is one of the earliest transcription factors responsive to adipogenic stimuli. Furthermore, we demonstrate the functional implication of CK2 in the expression of late markers of adipogenesis and factors regulating lipogenesis in liver and white adipose tissue. Finally, we show that while mice subjected to high-fat diet increased their body weight, those additionally treated with CX-4945 gained considerably less weight. NMR-based body composition analysis revealed that this is linked to significant differences in body fat mass., Conclusions: Taken together, our study provides novel insights into the role of CK2 in fat metabolism in response to chronic lipid overload and confirms CK2 pharmacological targeting as a potentially powerful strategy for body weight control and/or the treatment of obesity and related metabolic disorders., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Objective: To investigate the role of N-glycosylation modification of proteins in adipocyte differentiation during the adipogenic process., Methods: SVF cells and adipocytes were analyzed for proteomics and intact N-glycopeptide modificationomics.Differential expression of proteins, glycoforms, and sites between the two groups was screened and subjected to Gene Ontology (GO) functional enrichment analysis, KEGG pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. The top 20 most significantly differentially expressed adipogenic differentiation-related proteins were identified, and the most pronouncedly altered proteins were analyzed for glycoforms, glycan chains, and sites., Results: Proteomics analysis identified 39,392 peptides and 5208 proteins, while intact N-glycopeptide modification profiling identified 3293 intact glycopeptides, 426 proteins, and 161 glycan chains. Proteomics identified 2510 differentially expressed proteins, with CD36 (Cluster of Differentiation 36, CD36) significantly upregulated. In adipocytes, CD36 had 4 N-glycosylation sites: N79, N220, N320, N417, with N320 being a newly identified site. GO enrichment results indicated that CD36 is associated with fatty acid oxidation, lipid oxidation, and fatty acid uptake into cells., Conclusion: Multiple proteins undergo N-glycosylation modification during adipocyte differentiation, with CD36, a fatty acid translocase, being significantly expressed in adipocytes. This suggests that N-glycosylation modification of CD36 may play a crucial role in adipocyte differentiation, providing a foundation for further investigation into the function of CD36 N-glycosylation in adipocyte differentiation., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In the broiler industry, intensive genetic selection has been placed on muscle growth which has undesirably led to increased fat accretion. Models of chicken preadipocyte differentiation in vitro have conventionally used incubators without the ability to control oxygen (O 2 ) tension; thus, the cells are exposed to atmospheric (∼20-21%) O 2 , which is supraphysiological compared to the O 2 tension within adipose tissue. The objective of this study was to investigate embryonic broiler preadipocyte differentiation at different O 2 tensions, including atmospheric (20%), physiological (5%), and hypoxic (1%). Culture at 1% O 2 resulted in increased abundance of HIF1α, a canonical protein stabilized during hypoxia, thus confirming effectiveness of the treatment. Increased accumulation of lipid was observed in preadipocytes cultured in adipogenic differentiation medium compared to the control medium. When considering oxygen tension, lipid accumulation was increased in preadipocytes that were cultured in differentiation medium at 20% O 2 compared to 5% or 1% O 2 . Furthermore, abundance of transcripts related to fatty acid transport and adipogenesis, fatty acid binding protein 4 (FABP4) and peroxisome proliferator-activated receptor gamma (PPARγ), were increased in differentiated preadipocytes cultured at 20% O 2 compared to 5% or 1% O 2 . Abundance of transcripts related to lipid synthesis and oxidation, acyl-CoA synthetase long chain family member 1 (ACSL1) and carnitine palmitoyltransferase 1A (CPT1A), were increased in the differentiation cultures compared to the control cultures. Abundance of glutathione peroxidase 4 (GPX4) was increased in all the differentiation cultures compared to the controls, regardless of oxygen tension; however, differences in the abundance of other antioxidant enzymes were not observed. Overall, exposure to atmospheric oxygen tension promotes lipid accumulation within chicken preadipocytes, which may need to be considered when developing in vitro models of this process., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists., (Copyright © 2024. Published by Elsevier Inc.)

Type 2 diabetes increases the risk of developing obesity. Although fulvic acid alleviates back fat thickness in pigs, the mechanism underlying its anti-obesity effect remains unclear. Therefore, we investigated the anti-obesity mechanism of fulvic acid using 3T3-L1 adipocytes. We examined the effects of fulvic acid on adipocyte differentiation, cell viability, and lipid accumulation using molecular techniques. Fulvic acid treatment significantly decreased intracellular lipid accumulation in 3T3-L1 cells during the differentiation compared with that in the control group. Western blotting revealed fulvic acid-induced downregulated expression of the adipocyte differentiation-related markers peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein alpha, and sterol regulatory element-binding protein 1. The fulvic acid treatment decreased the expression of the lipid uptake-related markers fatty acid-binding protein 4 and the cluster of differentiation 36 in 3T3-L1 cells. Moreover, fulvic acid significantly increased cytosolic Ca 2+ concentration via Ca 2+ sequestration from the endoplasmic reticulum, enhanced Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) activity, and upregulated AMP-activated protein kinase (AMPK), thereby reducing adipocyte differentiation. Conclusively, fulvic acid attenuates adipocyte differentiation by activating the Ca 2+ /CaMKⅡ/AMPK pathway, suggesting its anti-obesity potential., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the mechanism of liraglutide affecting lipid metabolism by regulating lipolysis and lipogenesis in cells and ob/ob mice., Methods: 3 T3-L1 cells were treated with liraglutide in vitro, and differentially expressed genes were screened by RNA sequencing. Gene Ontology (GO) and KEGG (Kvoto Encyclopedia of Genes and Genomes) enrichment analyses identified target genes for lipid regulation of liraglutide. 3 T3-L1 preadipocytes were induced to differentiate into adipocytes using a "cocktail method". Western blot and immunofluorescence were used to detect the expression of target genes and the lipid regulatory effect of liraglutide. 3 T3-L1 preadipocytes were transfected with lentivirus overexpressing Zbtb20 to study its role in adipogenesis, and gene expression was analyzed by RT-qPCR and Western blot. In vivo, ob/ob mice were subcutaneously injected with liraglutide or saline for 4 weeks. Blood lipids, adipose tissue volume and adipocyte size were detected. Immunohistochemical analysis and RT-qPCR were used to detect the expression of target genes in adipose tissue., Results: Liraglutide reduced lipid droplets and TG levels and altered the expression of genes related to fatty acid metabolism, lipogenesis, fatty acid oxidation, and adipocyte browning. The results of PCR, Western blot and immunofluorescence confirmed that liraglutide could regulate the adipogenesis by downregulating the transcriptional suppressor ZBTB20, and overexpression of Zbtb20 inhibited the expression of LPL, the key enzyme for lipohydrolysis., Conclusions: Liraglutide regulates lipid metabolism through ZBTB20-LPL pathway to reveal its molecular mechanism., Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims/hypothesis: Metabolic disorders associated with abdominal obesity, dyslipidaemia, arterial hypertension and hyperglycaemia are risk factors for the development of insulin resistance. Extracellular vesicles (EVs) may play an important role in the regulation of metabolic signalling pathways in insulin resistance and associated complications., Methods: Circulating large EVs (lEVs) and small EVs (sEVs) from individuals with (IR group) and without insulin resistance (n-IR group) were isolated and characterised. lEVs and sEVs were administered by i.v. injection to mice and systemic, adipose tissue and liver insulin signalling were analysed. The role of phosphatases was analysed in target tissues and cells., Results: Injection of lEVs and sEVs from IR participants impaired systemic, adipose tissue and liver insulin signalling in mice, while EVs from n-IR participants had no effect. Moreover, lEVs and sEVs from IR participants brought about a twofold increase in adipocyte size and adipogenic gene expression. EVs from IR participants expressed two types of phosphatases, phosphotyrosine 1 phosphatase (PTP1B) and protein phosphatase 2 (PP2A), IR lEVs being enriched with the active form of PTP1B while IR sEVs mainly carried active PP2A. Blockade of PTP1B activity in IR lEVs fully restored IRS1 and Akt phosphorylation in adipocytes and blunted insulin-induced Akt phosphorylation by inhibition of the macrophage secretome in hepatocytes. Conversely, blockade of PP2A activity in IR sEVs completely prevented insulin resistance in adipocytes and hepatocytes., Conclusions/interpretation: These data demonstrate that inhibition of phosphatases carried by EVs from IR participants rescues insulin signalling in adipocytes and hepatocytes and point towards PTP1B and PP2A carried by IR EVs as being novel potential therapeutic targets against insulin resistance in adipose tissue and liver and the development of obesity., Competing Interests: Acknowledgements: We thank the SCAHU staff of Angers University for taking care of the animals, the SCIAM platform, especially F. Manero, for technical assistance in electron microscopy imaging, and the staff of University Hospital Centre of Angers for analysis of clinical data of NUMEVOX cohort. Additionally, we thank the Department of Pathology of University Hospital Centre of Angers for help with the histological analyses. Data availability: All data generated or analysed during this study are available on request from the authors. Funding: Open access funding provided by Université d'Angers. This work was supported by Institut National de la Santé et de la Recherche Médicale, Université d’Angers, Centre Hospitalo-Universitaire d’Angers and Fondation de France (no. 00096290). SA was a recipient of a doctoral fellowship from Conseil Départemental de Mayotte. XVG was supported by Fondation pour la Recherche Médicale (SPF201809006985). Authors’ relationships and activities: The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: SA, XV-G, MP, LV, PP and SK-S conducted the experiments and acquired and analysed the data. GS, SD, SH and FG provided the human samples and acquired and analysed the clinical data. P-HD and MD contributed critically to the discussion and interpretation of data. MD and PP provided reagents. RA and MCM conceived and supervised the study. SA and MCM designed the experiments and wrote the manuscript. All authors edited and approved the final version of the manuscript. MCM is responsible for the integrity of this work as a whole., (© 2024. The Author(s).)

Objective: A biallelic missense mutation in mitofusin 2 (MFN2) causes multiple symmetric lipomatosis and partial lipodystrophy, implicating disruption of mitochondrial fusion or interaction with other organelles in adipocyte differentiation, growth and/or survival. In this study, we aimed to document the impact of loss of mitofusin 1 (Mfn1) or 2 (Mfn2) on adipogenesis in cultured cells., Methods: We characterised adipocyte differentiation of wildtype (WT), Mfn1-/- and Mfn2-/- mouse embryonic fibroblasts (MEFs) and 3T3-L1 preadipocytes in which Mfn1 or 2 levels were reduced using siRNA., Results: Mfn1-/- MEFs displayed striking fragmentation of the mitochondrial network, with surprisingly enhanced propensity to differentiate into adipocytes, as assessed by lipid accumulation, expression of adipocyte markers (Plin1, Fabp4, Glut4, Adipoq), and insulin-stimulated glucose uptake. RNA sequencing revealed a corresponding pro-adipogenic transcriptional profile including Pparg upregulation. Mfn2-/- MEFs also had a disrupted mitochondrial morphology, but in contrast to Mfn1-/- MEFs they showed reduced expression of adipocyte markers. Mfn1 and Mfn2 siRNA mediated knockdown studies in 3T3-L1 adipocytes generally replicated these findings., Conclusions: Loss of Mfn1 but not Mfn2 in cultured pre-adipocyte models is pro-adipogenic. This suggests distinct, non-redundant roles for the two mitofusin orthologues in adipocyte differentiation., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)