bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–03–23
fourteen papers selected by
Xiong Weng, University of Edinburgh
  1. Identification of lysosomal lipolysis as an essential noncanonical mediator of adipocyte fasting and cold-induced lipolysis.
  2. Eva1 deficiency prevents obesity-induced metabolic disorders by reducing visceral adipose dysfunction.
  3. m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice.
  4. DNA methylation entropy is a biomarker for aging.
  5. IL-27 alleviates high-fat diet-induced obesity and metabolic disorders by inhibiting adipogenesis via activating HDAC6.
  6. Acute diacylglycerol production activates critical membrane-shaping proteins leading to mitochondrial tubulation and fission.
  7. SIRT5 slows skeletal muscle ageing by alleviating inflammation.
  8. Adipose progenitor cell-derived extracellular vesicles suppress macrophage M1 program to alleviate midlife obesity.
  9. Defining lipedema's molecular hallmarks by multi-omics approach for disease prediction in women.
  10. Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.
  11. ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis.
  12. Interplay of somatic mutations and epigenetic aging clocks.
  13. Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1.
  14. Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control.
  1. 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
  2. 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
  3. Cell Stem Cell. 2025 Mar 12. pii: S1934-5909(25)00079-7. [Epub ahead of print]
    m6A deficiency impairs hypothalamic neurogenesis of feeding-related neurons in mice and human organoids and leads to adult obesity in mice.
    Yachen Shen, Samuel Zheng Hao Wong, Tong Ma, Feng Zhang, Qing Wang, Riki Kawaguchi, Daniel H Geschwind, Jeremy Wang, Chuan He, Guo-Li Ming, Hongjun Song.
      N6-methyladenosine (m6A), the most prevalent internal modification on mRNAs, plays important roles in the nervous system. Whether neurogenesis in the hypothalamus, a region critical for controlling appetite, is regulated by m6A signaling, especially in humans, remains unclear. Here, we showed that deletion of m6A writer Mettl14 in the mouse embryonic hypothalamus led to adult obesity, with impaired glucose-insulin homeostasis and increased energy intake. Mechanistically, deletion of Mettl14 leads to hypothalamic arcuate nucleus neurogenesis deficits with reduced generation of feeding-related neurons and dysregulation of neurogenesis-related m6A-tagged transcripts. Deletion of m6A writer Mettl3 or m6A reader Ythdc1 shared similar phenotypes. METTL14 or YTHDC1 knockdown also led to reduced generation of feeding-related neurons in human brain subregion-specific arcuate nucleus organoids. Our studies reveal a conserved role of m6A signaling in arcuate nucleus neurogenesis in mice and human organoids and shed light on the developmental basis of epitranscriptomic regulation of food intake and energy homeostasis.
    Keywords:  METTL3; Mettl14; POMC neuron; RNA modification; Ythdc1; Ythdf2; arcuate nucleus; brain organoids; feeding-related neurons; hypothalamus; neurogenesis; obesity
    DOI:  https://doi.org/10.1016/j.stem.2025.02.011
  4. Aging (Albany NY). 2025 Mar 12. 17
    DNA methylation entropy is a biomarker for aging.
    Jonathan Chan, Liudmilla Rubbi, Matteo Pellegrini.
      The dynamic nature of epigenetic modifications has been leveraged to construct epigenetic clocks that accurately predict an individual's age based on DNA methylation levels. Here we explore whether the accumulation of epimutations, which can be quantified by Shannon's entropy, changes reproducibly with age. Using targeted bisulfite sequencing, we analyzed the associations between age, entropy, and methylation levels in human buccal swab samples. We find that epigenetic clocks based on the entropy of methylation states predict chronological age with similar accuracy as common approaches that are based on methylation levels of individual cytosines. Our approach suggests that across many genomic loci, methylation entropy changes reproducibly with age.
    Keywords:  DNA methylation; aging; entropy; epigenetic clocks; epigenetics
    DOI:  https://doi.org/10.18632/aging.206220
  5. Commun Biol. 2025 Mar 19. 8(1): 460
    IL-27 alleviates high-fat diet-induced obesity and metabolic disorders by inhibiting adipogenesis via activating HDAC6.
    Yinsheng Zhong, Shujun Yang, Shuangmei Li, Sijun Yuan, Xuxiang Chen, Huibao Long, Haidong Wu, Yajie Guo, Tong Wang.
      Obesity arises from an imbalance between adipogenesis and adipocyte thermogenesis. Interleukin-27 (IL-27), a heterodimer cytokine, is known to promote thermogenesis in brown adipose tissue. However, its role in adipogenesis remains unclear. This study aims to investigate the effects of IL-27 on adipogenesis both in vitro and in vivo, and to elucidate the underlying mechanisms. In vitro, an adipogenic differentiation model of adipose-derived mesenchymal stem cells (ADSCs) demonstrate that IL-27 is non-cytotoxic to ADSCs and inhibits ADSCs adipogenic differentiation. In vivo, using a high-fat diet (HFD)-induced obese mouse model and a targeted adipose tissue-specific IL-27 overexpression adeno-associated viral (AAV) vector, we confirm that IL-27 suppresses adipogenesis, prevents weight gain, and improves glucose and lipid metabolic homeostasis in obese mice. Additionally, the inhibition of adipogenesis by IL-27 is mediated through HDAC6 activation of the TGFβ/Smad3 signaling pathway. Our study suggests that IL-27 is a potential therapeutic target for obesity and metabolic disorders.
    DOI:  https://doi.org/10.1038/s42003-025-07918-y
  6. 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
  7. Nat Metab. 2025 Mar 14.
    SIRT5 slows skeletal muscle ageing by alleviating inflammation.
    Vera Gorbunova, Andrei Seluanov.
      
    DOI:  https://doi.org/10.1038/s42255-025-01228-7
  8. Nat Commun. 2025 Mar 20. 16(1): 2743
    Adipose progenitor cell-derived extracellular vesicles suppress macrophage M1 program to alleviate midlife obesity.
    Qing Zhou, Jia Gao, Guorao Wu, Chenwei Wang, Yan Yang, Teng Huang, Yi Wang, Tiantian Yue, Zhichao Gao, Hao Xie, Fei Xiong, Ke Xiang, Tuying Yong, Wanguang Zhang, Tongtong Zhang, Wen Kong, Cai Chen, Shu Zhang, Qilin Yu, Xuemei Fan, Shiwei Liu, Yanjun Liu, Cong-Yi Wang.
      Among different age groups, middle-aged individuals are particularly susceptible to obesity, with a 22% higher risk of all-cause mortality. However, the underlying mechanisms remain unclear. In this study, we identify adipose progenitor cells (APCs) in the white adipose tissue (WAT) of middle-aged subjects as potential causes of midlife obesity. Specifically, the extracellular vesicles (EVs) derived from APCs display an impaired ability to mitigate the inflammaging of adipose tissue macrophages (ATMs) in middle-aged individuals. Mechanistically, these EVs, lacking miR-145-5p, fail to suppress the expression of L-selectin in ATMs, thereby facilitating their M1 program via the NF-κB signaling pathway. In contrast, EVs from young APCs effectively inhibit M1 macrophage polarization. Accordingly, targeted liposomes are designed to deliver miR-145-5p mimics to ATMs, which effectively prevent the obesity in middle-aged mice. Collectively, our findings highlight the role of APC-derived EVs in midlife obesity and propose miR-145-5pas a promising therapeutic target for clinical applications.
    DOI:  https://doi.org/10.1038/s41467-025-57444-y
  9. Metabolism. 2025 Mar 15. pii: S0026-0495(25)00060-5. [Epub ahead of print] 156191
    Defining lipedema's molecular hallmarks by multi-omics approach for disease prediction in women.
    Leon G Straub, Jan-Bernd Funcke, Nolwenn Joffin, Chanmin Joung, Sara Al-Ghadban, Shangang Zhao, Qingzhang Zhu, Ilja L Kruglikov, Yi Zhu, Paul R Langlais, Ruth Gordillo, Karen L Herbst, Philipp E Scherer.
      Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial organization were upregulated. Measuring a cytokine and chemokine panel in the serum of non-menopausal women, we observed little systemic changes in inflammatory markers, but a trend towards increased VEGF. Metabolomic and lipidomic analyses highlighted altered circulating glutamic acid, glutathione, and sphingolipid levels, suggesting a broader dysregulation of metabolic and inflammatory processes. We subsequently benchmarked a set of models to accurately predict lipedema using serum factor measurements (sLPM). Our study of the molecular signature of lipedema thus provides not only potential targets for therapeutic intervention, but also candidate markers of disease development and progression.
    Keywords:  Adipose tissue; Complement; Disease prediction; ElasticNet; Inflammation; Lipedema; Machine learning; Multi-omics; Random Forest classifier; Support vector machine
    DOI:  https://doi.org/10.1016/j.metabol.2025.156191
  10. Nat Commun. 2025 Mar 15. 16(1): 2569
    Heterogeneous effects of genetic variants and traits associated with fasting insulin on cardiometabolic outcomes.
    Magdalena Sevilla-González, Kirk Smith, Ningyuan Wang, Aubrey E Jensen, Elizabeth M Litkowski, Hyunkyung Kim, Daniel A DiCorpo, Sarah Hsu, Jinrui Cui, Ching-Ti Liu, Chenglong Yu, John J McNeil, Paul Lacaze, Kenneth E Westerman, Kyong-Mi Chang, Philip S Tsao, Lawrence S Phillips, Mark O Goodarzi, Rob Sladek, Jerome I Rotter, Josée Dupuis, Jose C Florez, Jordi Merino, James B Meigs, Jin J Zhou, Sridharan Raghavan, Miriam S Udler, Alisa K Manning.
      Elevated fasting insulin levels (FI), indicative of altered insulin secretion and sensitivity, may precede type 2 diabetes (T2D) and cardiovascular disease onset. In this study, we group FI-associated genetic variants based on their genetic and phenotypic similarities and identify seven clusters with distinct mechanisms contributing to elevated FI levels. Clusters fall into two types: "non-diabetogenic hyperinsulinemia," where clusters are not associated with increased T2D risk, and "diabetogenic hyperinsulinemia," where T2D associations are driven by body fat distribution, liver function, circulating lipids, or inflammation. In over 1.1 million multi-ancestry individuals, we demonstrated that diabetogenic hyperinsulinemia cluster-specific polygenic scores exhibit varying risks for cardiovascular conditions, including coronary artery disease, myocardial infarction (MI), and stroke. Notably, the visceral adiposity cluster shows sex-specific effects for MI risk in males without T2D. This study underscores processes that decouple elevated FI levels from T2D and cardiovascular risk, offering new avenues for investigating process-specific pathways of disease.
    DOI:  https://doi.org/10.1038/s41467-025-57452-y
  11. 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
  12. Nat Aging. 2025 Mar 19.
    Interplay of somatic mutations and epigenetic aging clocks.
    Wolfgang Wagner.
      
    DOI:  https://doi.org/10.1038/s43587-025-00846-w
  13. Cell Rep. 2025 Mar 16. pii: S2211-1247(25)00197-4. [Epub ahead of print]44(3): 115426
    Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1.
    Penghui Hu, Xiao Shan, Hongyuan Dong, Sujun Yu, Baochen Wang, Hui Xiong, Zemin Ji, Weijia Jing, Yan Cui, Zihan Li, Yanzhao Zhou, Zhe Wang, Jinrong Wang, Jiuzhou Tang, Ting Wang, Keliang Xie, Qiujing Yu.
      Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive disease with only one approved treatment currently available. Hepatic phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine biosynthesis pathway, regulates MAFLD development. However, the role of macrophage PHGDH in MAFLD progression remains unclear. Here, we demonstrate that the lipotoxicity inducer palmitic acid (PA) significantly increases macrophage PHGDH expression and that PHGDH deficiency in macrophages promotes PA-induced inflammatory responses. Myeloid-specific PHGDH deficiency exacerbates MAFLD in mice. Mechanistically, tetrameric PHGDH binds to transforming growth factor-β-activated kinase 1 (TAK1) to inhibit its interaction with TAK1 binding protein 1 (TAB1), sequentially suppressing the activation of TAK1 and downstream NF-κB and MAPK signaling. Inhibition of TAK1 activation slows the development of metabolic dysfunction-associated steatohepatitis (MASH) caused by myeloid PHGDH knockout. Importantly, adeno-associated virus-mediated PHGDH overexpression in liver macrophages alleviates MAFLD in mice. Collectively, these results identify macrophage PHGDH as a promising therapeutic agent for MAFLD.
    Keywords:  CP: Immunology; CP: Metabolism; macrophage; metabolic dysfunction-associated fatty liver disease; phosphoglycerate dehydrogenase; transforming growth factor-β-activated kinase 1
    DOI:  https://doi.org/10.1016/j.celrep.2025.115426
  14. Nat Metab. 2025 Mar 14.
    Human gut microbial aromatic amino acid and related metabolites prevent obesity through intestinal immune control.
    Zengliang Jiang, Liuqing He, Diyin Li, Laibao Zhuo, Lingjun Chen, Rui-Qi Shi, Jianhua Luo, Yuhui Feng, Yuhui Liang, Danyang Li, Xiao Congmei, Yuanqing Fu, Yu-Ming Chen, Ju-Sheng Zheng, Liang Tao.
      Obesity affects millions of people in the world. The gut microbiome influences body fat accumulation, but the mechanisms remain to be investigated. Here, we show an association between microbial aromatic amino acid metabolites in serum and body fat accumulation in a large Chinese longitudinal cohort. We next identify that 4-hydroxyphenylacetic acid (4HPAA) and its analogues effectively protect male mice from high-fat-diet-induced obesity. These metabolites act on intestinal mucosa to regulate the immune response and control lipid uptake, which protects against obesity. We further demonstrate that T cells and B cells are not vital for 4HPAA-mediated obesity prevention, and innate lymphoid cells have antagonistic roles. Together, these findings reveal specific microbial metabolites as pivotal molecules to prohibit obesity through immune control, establishing mechanisms of host modulation by gut microbial metabolites.
    DOI:  https://doi.org/10.1038/s42255-025-01246-5
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