bims-mimead 2025-03-23 papers

bims-mimead

Biomed News

on Adipose tissue and metabolic disease

Issue of 2025–03–23
eight papers selected by
Rachel M. Handy, University of Guelph

Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity.
Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction.
Absence of intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.
ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis.
Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKα2 signaling.
Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
Injectable Skeletal Muscle Constructs Overexpressing GLUT4 for Type 2 Diabetes Intervention.

EBioMedicine. 2025 Mar 20. pii: S2352-3964(25)00097-0. [Epub ahead of print]114 105653

Chromatin landscape in paired human visceral and subcutaneous adipose tissue and its impact on clinical variables in obesity.

Sadia Saeed, Lars la Cour Poulsen, Tina Visnovska, Anne Hoffmann, Adhideb Ghosh, Christian Wolfrum, Torunn Rønningen, Mai Britt Dahl, Junbai Wang, Akin Cayir, Tom Mala, Jon A Kristinsson, Marius Svanevik, Jøran Hjelmesæth, Jens Kristoffer Hertel, Matthias Blüher, Tone Gretland Valderhaug, Yvonne Böttcher.

   BACKGROUND: Obesity is a global health challenge and adipose tissue exhibits distinct depot-specific characteristics impacting differentially on the risk of metabolic comorbidities.
METHODS: Here, we integrate chromatin accessibility (ATAC-seq) and gene expression (RNA-seq) data from intra-individually paired human subcutaneous (SAT) and omental visceral adipose tissue (OVAT) samples to unveil depot-specific regulatory mechanisms.
FINDINGS: We identified twice as many depot-specific differentially accessible regions (DARs) in OVAT compared to SAT. SAT-specific regions showed enrichment for adipose tissue enhancers involving genes controlling extracellular matrix organization and metabolic processes. In contrast, OVAT-specific regions showed enrichment in promoters linked to genes associated with cardiomyopathies. Moreover, OVAT-specific regions were enriched for bivalent transcription start site and repressive chromatin states, suggesting a "lingering" regulatory state. Motif analysis identified CTCF and BACH1 as most significantly enriched motifs in SAT and OVAT-specific DARs, respectively. Distinct gene sets correlated with important clinical variables of obesity, fat distribution measures, as well as insulin, glucose, and lipid metabolism.
INTERPRETATION: We provide an integrated analysis of chromatin accessibility and transcriptional profiles in paired human SAT and OVAT samples, offering new insights into the regulatory landscape of adipose tissue and highlighting depot-specific mechanisms in obesity pathogenesis.
FUNDING: SS received EU-Scientia postdoctoral Fellowship and project funding from the European Union's Horizon 2020 Research and Innovation program under the Marie Skłodowska-Curie Grant, (agreement No. 801133). LlCP and TR were supported by Helse Sør-Øst grants to Y.B (ID 2017079, ID 278908). MB received funding from grants from the DFG (German Research Foundation)-Projekt number 209933838-SFB 1052 (project B1) and by Deutsches Zentrum für Diabetesforschung (DZD, Grant: 82DZD00601).

Keywords:  Adipose tissue; Chromatin accessibility; Gene expression; Obesity

DOI:  https://doi.org/10.1016/j.ebiom.2025.105653
Metabolism. 2025 Mar 19. pii: S0026-0495(25)00104-0. [Epub ahead of print] 156235

Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction.

You Lee Son, Jiahui Hou, Mira Kato-Suzuki, Yuko Okamatsu-Ogura, Megumi Watase, Hiroshi Kiyonari, Toru Kondo.

   AIMS: Epithelial V-like antigen 1 (Eva1) is a highly specific marker for brown adipose tissue (BAT) in both mice and humans, but its metabolic function remains unclear. We investigated the impact of Eva1 deletion on the development of obesity.
METHODS: To assess the metabolic role of Eva1, we generated whole-body and adipocyte-specific Eva1knockout (KO) mice, which were subjected to a high-fat diet (HFD) for 12 weeks and characterized metabolic phenotypes. To further elucidate the depot-dependent impact of Eva1 deficiency, we performed histological analysis and 3' mRNA-seq of BAT and epididymal visceral white adipose tissue (eWAT). To investigate the role of macrophage-derived Eva1 in obesity development, we transplanted wild-type (WT) or Eva1KO macrophages into Eva1KO mice fed an HFD.
RESULTS: We found that whole-body Eva1KO mice are resistant to HFD-induced obesity, insulin resistance and visceral adipose inflammation. However, Eva1 deletion in adipocytes, both brown and white, did not phenocopy these protective effects. Notably, whole-body Eva1 deficiency triggers functional changes in eWAT, but not in BAT. These results led us to investigate a possible involvement of macrophages in Eva1-mediated obesity regulation. We found that Eva1 is expressed in macrophages and plays a role in lipopolysaccharide (LPS)-induced inflammatory responses, possibly through the direct interaction with toll-like receptor 4 (TLR4). Moreover, Eva1KO mice exhibited improved survival rates in the face of severe sepsis induced by LPS. Importantly, transplantation of WT macrophages to Eva1KO mice abolished the beneficial effects of whole-body Eva1 deletion against obesity and visceral adipose inflammation.
CONCLUSION: Our findings highlight macrophage-derived Eva1 as an important mediator in obesity-induced eWAT remodeling, suggesting that targeting Eva1 could offer a novel therapeutic strategy for obesity-related metabolic disorders.

Keywords:  BAT; Eva1; Inflammation; Macrophage; Obesity; eWAT

DOI:  https://doi.org/10.1016/j.metabol.2025.156235
J Clin Invest. 2025 Mar 18. pii: e181754. [Epub ahead of print]

Absence of intracellular lipolytic inhibitor G0S2 enhances intravascular triglyceride clearance and abolishes diet-induced hypertriglyceridemia.

Yongbin Chen, Scott M Johnson, Stephanie D Burr, Davide Povero, Aaron M Anderson, Cailin E McMahon, Jun Liu.

  The interplay between intracellular and intravascular lipolysis is crucial for maintaining circulating lipid levels and systemic energy homeostasis. Adipose triglyceride lipase (ATGL) and lipoprotein lipase (LPL), the primary triglyceride (TG) lipases responsible for these two spatially separate processes, are highly expressed in adipose tissue. Yet, their coordinated regulation remains undetermined. Here, we demonstrate that genetic ablation of G0S2, a specific inhibitory protein of ATGL, completely abolishes diet-induced hypertriglyceridemia and significantly attenuates atherogenesis in mice. These effects are attributed to enhanced whole-body TG clearance, not altered hepatic TG secretion. Specifically, G0S2 deletion increases circulating LPL concentration and activity, predominantly through LPL production from white adipose tissue (WAT). Strikingly, transplantation of G0S2-deficient WAT normalizes plasma TG levels in mice with hypertriglyceridemia. In conjunction with improved insulin sensitivity and decreased ANGPTL4 expression, the absence of G0S2 enhances the stability of LPL protein in adipocytes, a phenomenon that can be reversed upon ATGL inhibition. Collectively, these findings highlight the pivotal role of adipocyte G0S2 in regulating both intracellular and intravascular lipolysis, and the possibility of targeting G0S2 as a viable pharmacological approach to reduce circulating TGs.

Keywords:  Adipose tissue; Atherosclerosis; Endocrinology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI181754
J Clin Invest. 2025 Mar 17. pii: e184740. [Epub ahead of print]135(6):

ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis.

Aaron L Slusher, Nicola Santoro, Alla Vash-Margita, Alfonso Galderisi, Pamela Hu, Fuyuze Tokoglu, Zhongyao Li, Elena Tarabra, Jordan Strober, Daniel F Vatner, Gerald I Shulman, Sonia Caprio.

  BACKGROUNDThis study examined the underlying cellular mechanisms associated with insulin resistance (IR) and metabolic disease risk within subcutaneous adipose tissue (SAT) in youth with obesity and IR compared with those without IR.METHODSThirteen adolescents who were insulin sensitive (IS) and 17 adolescents with IR and obesity underwent a 3-hour oral glucose tolerance test and MRI to measure abdominal fat distribution and liver fat content. Lipolysis was determined by glycerol turnover ([2H5]-glycerol infusion) and adipose triglyceride lipase (ATGL) phosphorylation (Western blot) from SAT samples biopsied prior to and 30-minutes following insulin infusion during a hyperinsulinemic-euglycemic clamp (HEC).RESULTSGlycerol turnover suppression during the HEC (first step) was lower in participants with IR compared with those with IS. Prior to insulin infusion, activated ATGL (reflected by the p-ATGL (Ser406)-to-ATGL ratio) was greater in participants with IR compared with those with IS and suppressed in response to a 30-minute insulin exposure in participants with IS, but not in those with IR. Lastly, greater ATGL inactivation is associated with greater glycerol suppression and lower liver fat.CONCLUSIONSInsulin-mediated inhibition of adipose tissue lipolysis via ATGL is dysregulated among adolescents with IR compared with those with IS, thereby serving as a vital mechanism linking glucose and insulin dysregulation and ectopic lipid storage within the liver.FUNDINGThis work was supported by funding from the NIH (R01-HD028016-25A1, T32- DK-007058, R01-DK124272, RO1-DK119968, R01MD015974, RO1-DK113984, P3-DK045735, RO1-DK133143, and RC2-DK120534) and the Robert E. Leet and Clara Guthrie Patterson Trust Mentored Research Award.

Keywords:  Adipose tissue; Diabetes; Endocrinology; Metabolism; Obesity

DOI:  https://doi.org/10.1172/JCI184740
J Clin Invest. 2025 Mar 17. pii: e185340. [Epub ahead of print]135(6):

Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.

Yu-Sheng Yeh, Trent D Evans, Mari Iwase, Se-Jin Jeong, Xiangyu Zhang, Ziyang Liu, Arick Park, Ali Ghasemian, Borna Dianati, Ali Javaheri, Dagmar Kratky, Satoko Kawarasaki, Tsuyoshi Goto, Hanrui Zhang, Partha Dutta, Francisco J Schopfer, Adam C Straub, Jaehyung Cho, Irfan J Lodhi, Babak Razani.

  Adipose tissue lipolysis is the process by which triglycerides in lipid stores are hydrolyzed into free fatty acids (FFAs), serving as fuel during fasting or cold-induced thermogenesis. Although cytosolic lipases are considered the predominant mechanism of liberating FFAs, lipolysis also occurs in lysosomes via lysosomal acid lipase (LIPA), albeit with unclear roles in lipid storage and whole-body metabolism. We found that adipocyte LIPA expression increased in adipose tissue of mice when lipolysis was stimulated during fasting, cold exposure, or β-adrenergic agonism. This was functionally important, as inhibition of LIPA genetically or pharmacologically resulted in lower plasma FFAs under lipolytic conditions. Furthermore, adipocyte LIPA deficiency impaired thermogenesis and oxygen consumption and rendered mice susceptible to diet-induced obesity. Importantly, lysosomal lipolysis was independent of adipose triglyceride lipase, the rate-limiting enzyme of cytosolic lipolysis. Our data suggest a significant role for LIPA and lysosomal lipolysis in adipocyte lipid metabolism beyond classical cytosolic lipolysis.

Keywords:  Adipose tissue; Endocrinology; Lysosomes; Metabolism; Obesity; Therapeutics

DOI:  https://doi.org/10.1172/JCI185340
Cell Metab. 2025 Mar 12. pii: S1550-4131(25)00065-8. [Epub ahead of print]

Dietary timing enhances exercise by modulating fat-muscle crosstalk via adipocyte AMPKα2 signaling.

Jianghui Chen, Jing Xiang, Meiyu Zhou, Rongfeng Huang, Jianxin Zhang, Yuanting Cui, Xiaoqing Jiang, Yang Li, Runchao Zhou, Haoran Xin, Jie Li, Lihua Li, Sin Man Lam, Jianfang Zhu, Yanxiu Chen, Qingyuan Yang, Zhifu Xie, Guanghou Shui, Fang Deng, Zhihui Zhang, Min-Dian Li.

  Feeding rhythms regulate exercise performance and muscle energy metabolism. However, the mechanisms regulating adipocyte functions remain unclear. Here, using multi-omics analyses, involving (phospho-)proteomics and lipidomics, we found that day-restricted feeding (DRF) regulates diurnal rhythms of the mitochondrial proteome, neutral lipidome, and nutrient-sensing pathways in mouse gonadal white adipose tissue (GWAT). Adipocyte-specific knockdown of Prkaa2 (the gene encoding AMPKα2) impairs physical endurance. This defect is associated with altered rhythmicity in acyl-coenzyme A (CoA) metabolism-related genes, a loss of rhythmicity in the GWAT lipidome, and circadian remodeling of serum metabolites-in particular, lactate and succinate. We also found that adipocyte Prkaa2 regulates muscle clock genes during DRF. Notably, oral administration of the AMPK activator C29 increases endurance and muscle functions in a time-of-day manner, which requires intact adipocyte AMPKα2 signaling. Collectively, our work defines adipocyte AMPKα2 signaling as a critical regulator of circadian metabolic coordination between fat and muscle, thereby enhancing exercise performance.

Keywords:  AMPK; adipocyte; adipose tissue; chrono-medicine; circadian clock; circadian rhythm; day-restricted feeding; exercise physiology; feeding rhythm; multi-omics

DOI:  https://doi.org/10.1016/j.cmet.2025.02.007
Nat Commun. 2025 Mar 19. 16(1): 2685

Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.

Joshua G Pemberton, Krishnendu Roy, Yeun Ju Kim, Tara D Fischer, Vijay Joshi, Elizabeth Ferrer, Richard J Youle, Thomas J Pucadyil, Tamas Balla.

Mitochondrial dynamics are orchestrated by protein assemblies that directly remodel membrane structure, however the influence of specific lipids on these processes remains poorly understood. Here, using an inducible heterodimerization system to selectively modulate the lipid composition of the outer mitochondrial membrane (OMM), we show that local production of diacylglycerol (DAG) directly leads to transient tubulation and rapid fragmentation of the mitochondrial network, which are mediated by isoforms of endophilin B (EndoB) and dynamin-related protein 1 (Drp1), respectively. Reconstitution experiments on cardiolipin-containing membrane templates mimicking the planar and constricted OMM topologies reveal that DAG facilitates the membrane binding and remodeling activities of both EndoB and Drp1, thereby independently potentiating membrane tubulation and fission events. EndoB and Drp1 do not directly interact with each other, suggesting that DAG production activates multiple pathways for membrane remodeling in parallel. Together, our data emphasizes the importance of OMM lipid composition in regulating mitochondrial dynamics.

DOI: https://doi.org/10.1038/s41467-025-57439-9
Acta Biomater. 2025 Mar 15. pii: S1742-7061(25)00202-8. [Epub ahead of print]

Injectable Skeletal Muscle Constructs Overexpressing GLUT4 for Type 2 Diabetes Intervention.

Hagit Shoyhet, Yifat Herman Bachinsky, Margarita Bekerman, Lior Debbi, Gali Guterman Ram, Dina Safina, Eddy Karnieli, Shulamit Levenberg.

  Skeletal muscle tissue engineering aims to repair tissue defects caused by injury, cancer, metabolic or neuromuscular disease. The need for invasive implantation techniques often limits the implantation of large tissue constructs or repeated treatments. Recent studies have reported on the development of injectable scaffolds for tissue engineering; however, fabrication of skeletal muscle tissue is particularly challenging due to the large size of human myotubes and the required mechanical properties. This work developed a collagen-based shape-memory scaffold supportive of skeletal muscle tissue growth and differentiation in vitro and maintained shape post-injection in vivo. The injectable engineered muscle construct was intramuscularly delivered via a syringe needle and integrated successfully with the native muscle tissue. We demonstrated the system's potential on a Type 2 diabetes mouse model. A prominent early sign of type 2 diabetes is the reduction in GLUT4 expression and translocation in skeletal muscle; therefore, based on a previous work published by our group, we created injectable GLUT4-overexpressing muscle constructs. Following injection, GLUT4 overexpressing skeletal muscle tissue retained its shape-memory properties and viability and improved glucose homeostasis in the diabetic mice. This work demonstrated successful minimally invasive delivery of engineered muscle tissue and potential treatment for chronic muscle-related conditions. STATEMENT OF SIGNIFICANCE: Type 2 diabetes is a widespread metabolic disorder characterized by insulin resistance and impaired glucose regulation. This study offers a minimally invasive approach to treatment through the development of an injectable skeletal muscle construct overexpressing GLUT4 to improve glucose homeostasis. Unlike traditional surgical methods, this minimally invasive system employs a collagen-based scaffold with shape-memory properties, enabling effective tissue delivery and integration. Existing therapies are limited in addressing chronic metabolic disorders that require repeated interventions. Our work fills that gap by enhancing muscle function and glucose regulation. The scaffold's unique ability to retain its structure post-injection and support muscle differentiation presents a significant advancement with broad implications for treating metabolic diseases and advancing regenerative medicine.

Keywords:  Injectable scaffold; Shape-memory scaffold; Tissue Engineering; Type II Diabetes; skeletal muscle

DOI:  https://doi.org/10.1016/j.actbio.2025.03.029