bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–10–19
eleven papers selected by
Xiong Weng, University of Edinburgh
  1. Adipose m6A reader YTHDF2 promotes obesity, insulin resistance, and liver steatosis by suppressing β-adrenergic signaling and lipolysis.
  2. Aged mice exhibit widespread metabolic changes but preserved major fluxes.
  3. CCL26 and CXCL12 preserve insulin-sensitizing macrophages in subcutaneous adipose tissue in obesity.
  4. Fat talks first: how adipose tissue sets the pace of aging?
  5. A framework of biomarkers for adipose tissue aging: a consensus statement by the Aging Biomarker Consortium.
  6. Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
  7. Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism.
  8. Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
  9. Interleukin-18 in obesity and obesity-related metabolic diseases.
  10. EMito-Metrix enables automated evaluation of mitochondrial morphology across species.
  11. METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease.
  1. Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01216-1. [Epub ahead of print]44(10): 116445
    Adipose m6A reader YTHDF2 promotes obesity, insulin resistance, and liver steatosis by suppressing β-adrenergic signaling and lipolysis.
    Ruoyu Zhou, Liping Ju, Qianqian Kang, Qiantao Zheng, Decheng Ren, Liangyou Rui.
      RNA N6-methyladenosine (m6A) modification induces catecholamine resistance and lipolysis inhibition in white adipose tissue (WAT), contributing to obesity pathogenesis; however, the responsible m6A readers remain elusive. Here, we identify YTHDF2 as a key m6A reader governing both β-adrenergic signaling and lipolytic machinery. YTHDF2 binds to m6A-marked mRNAs encoding β3-adrenergic receptor (Adrb3), adipose triacylglycerol lipase (Atgl), and comparative gene identification-58 (Cgi-58), promoting their degradation and thereby suppressing β-adrenergic signaling and lipolysis. Deletion of adipose Ythdf2 enhances lipolysis in vivo, in WAT explants ex vivo, and in cultured adipocytes. Conversely, YTHDF2 overexpression suppresses adipocyte lipolysis. High-fat diet feeding upregulates adipose YTHDF2 and increases its binding to Adrb3, Atgl, and Cgi-58 mRNAs. Adipocyte-specific deletion of Ythdf2 protects against diet-induced obesity, insulin resistance, and liver steatosis. Moreover, deletion of adipose Mettl14-but not Ythdf2-disrupts brown adipose tissue development. These results unveil an adipose-intrinsic METTL3/METTL14/m6A/YTHDF2 pathway that drives catecholamine resistance and lipolysis suppression in obesity.
    Keywords:  CP: Metabolism; MAFLD; METTL14; YTHDF2; adipocytes; brown adipose tissue; insulin resistance; lipolysis; m(6)A; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2025.116445
  2. Cell Metab. 2025 Oct 16. pii: S1550-4131(25)00394-8. [Epub ahead of print]
    Aged mice exhibit widespread metabolic changes but preserved major fluxes.
    Connor S R Jankowski, Laith Z Samarah, Michael R MacArthur, Sarah J Mitchell, Daniel R Weilandt, Craig J Hunter, Xianfeng Zeng, Melanie R McReynolds, Joshua D Rabinowitz.
      Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.
    Keywords:  aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.009
  3. Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01221-5. [Epub ahead of print]44(10): 116450
    CCL26 and CXCL12 preserve insulin-sensitizing macrophages in subcutaneous adipose tissue in obesity.
    Ishtiaq Jeelani, Flavia Franco da Cunha, Theresa V Rohm, Chanond A Nasamran, Letian Wang, Jae-Su Moon, Sruthika Prakash, Justin Oswari, Roi Isaac, Cairo Murphy, Christopher K Glass, Jerrold M Olefsky, Yun Sok Lee.
      Unlike visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) can protect against insulin resistance and metabolic dysfunction in obesity. Here, we show that, in obesity, subcutaneous adipose tissue macrophages (ATMs) release small extracellular vesicles (sEVs) that can improve insulin sensitivity, opposite to the effect of visceral ATM sEVs. This functional difference is associated with an increase in the proportion of insulin-sensitizing, resident ATMs in SAT. In vivo and in vitro measurements of ATM growth and trafficking combined with single-cell RNA sequencing revealed that higher resident ATM survival and lower blood monocyte immigration along with decreased transition to pro-inflammatory ATMs collectively lead to the relative abundance of resident ATMs in SAT in obesity. These changes are mediated by CCL26 derived from subcutaneous adipocytes and adipocyte progenitors and CXCL12 secreted from resident ATMs. Our results elucidate previously unknown mechanisms for how SAT retains protective functions against metabolic dysfunction in obesity.
    Keywords:  CCL26; CP: Metabolism; CXCL12; T2DM; adipose tissue macrophages; exosome; inflammation; insulin resistance; obesity; resident vs. recruited macrophages; sEVs; small extracellular vesicles; type 2 diabetes mellitus
    DOI:  https://doi.org/10.1016/j.celrep.2025.116450
  4. Life Med. 2025 Oct;4(5): lnaf028
    Fat talks first: how adipose tissue sets the pace of aging?
    Juanhong Liu, Qinlei Huang, Feng Liu.
      Once viewed primarily as an energy reservoir, adipose tissue (AT) is now recognized as a key endocrinal organ in regulating systemic aging. With age, AT undergoes significant remodeling, marked by altered fat distribution, visceral fat expansion, impaired thermogenesis, and chronic low-grade inflammation, which disrupts metabolic and immune homeostasis. Emerging insights from single-cell and spatial transcriptomics highlight the critical roles of adipose progenitors, immune cells, and senescent cells in driving local dysfunction and systemic decline. Through inflammatory and metabolic signaling, dysfunctional AT actively contributes to age-related pathologies. This review explores how AT functions as both an early sensor and driver of aging and discusses therapeutic opportunities targeting adipose dysfunction to promote healthy aging.
    Keywords:  adipose tissue; aging; cell senescent; inflammation; metabolic dysfunction
    DOI:  https://doi.org/10.1093/lifemedi/lnaf028
  5. Life Med. 2025 Oct;4(5): lnaf027
    A framework of biomarkers for adipose tissue aging: a consensus statement by the Aging Biomarker Consortium.
    Aging Biomarker Consortium
      Adipose tissue serves as a crucial energy storage and metabolic organ in the human body. With the surging of elderly population in China comes significant challenges in preventing and managing age-associated diseases, while adipose tissue aging represents one of the pivotal initiating events for multi-organ senescence. To address these challenges, the Aging China Biomarkers Consortium (ABC) has established an expert consensus on biomarkers of adipose tissue aging by digesting literature and collecting insights from scientists and clinicians. This consensus provides a comprehensive evaluation of the key changes and characteristics, as well as biomarkers related to adipose tissue aging and proposes a systematic framework categorizing these biomarkers into functional, structural and humoral dimensions. Within each dimension, the ABC recommends clinically and empirically validated biomarkers and parameters for assessing both physiological and pathological changes in adipose tissue during aging, which aims to establish a foundation for future prediction, diagnosis, early warning and treatment for adipose tissue aging and its related diseases, with the ultimate goal of improving adipose tissue health and promoting healthy aging in elderly populations both in China and worldwide.
    DOI:  https://doi.org/10.1093/lifemedi/lnaf027
  6. Cell Metab. 2025 Oct 10. pii: S1550-4131(25)00434-6. [Epub ahead of print]
    Machine-learning-guided discovery of SLC25A45 as a mediator of mitochondrial methylated amino acid import and carnitine synthesis.
    Artem Khan, Frederick S Yen, Gokhan Unlu, Nicole L DelGaudio, Ranya Erdal, Michael Xiao, Khando Wangdu, Kevin Cho, Eric R Gamazon, Gary J Patti, Kıvanç Birsoy.
      Solute carriers (SLCs) regulate cellular and organismal metabolism by transporting small molecules and ions across membranes, yet the physiological substrates of ∼20% remain elusive. To address this, we developed a machine-learning platform to predict gene-metabolite associations. This approach identifies UNC93A and SLC45A4 as candidate plasma membrane transporters for acetylglucosamine and polyamines, respectively. Additionally, we uncover SLC25A45 as a mitochondrial transporter linked to serum levels of methylated basic amino acids, products of protein catabolism. Mechanistically, SLC25A45 is necessary for the mitochondrial import of methylated basic amino acids, including ADMA and TML, the latter serving as a precursor for carnitine synthesis. In line with this observation, SLC25A45 loss impairs carnitine synthesis and blunts upregulation of carnitine-containing metabolites under fasted conditions. By facilitating mitochondrial TML import, SLC25A45 connects protein catabolism to carnitine production, sustaining β-oxidation during fasting. Altogether, our study identifies putative substrates for three SLCs and provides a resource for transporter deorphanization.
    Keywords:  SLC25A45; SLC45A4; UNC93A; acetylglucosamine; carnitine synthesis; fasting; metabolomic GWAS; mitochondrial metabolism; polyamines; solute carrier transporters
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.015
  7. Nat Metab. 2025 Oct 17.
    Human genetics of steatotic liver disease: insights into insulin resistance and lipid metabolism.
    Rosellina M Mancina, Luca Valenti, Stefano Romeo.
      Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease or NAFLD) is a prevalent and heterogeneous condition affecting nearly 30% of the global population. MASLD is defined as excessive hepatic lipid accumulation with at least one feature of insulin resistance, with potential progression to metabolic dysfunction-associated steatohepatitis, cirrhosis and hepatocellular carcinoma. The disease often coexists with insulin resistance and cardiovascular and chronic kidney diseases. Human genetics has shed light on MASLD predisposition and its causal association with type 2 diabetes and insulin resistance, enabling the field to progress towards precision-medicine therapeutics. Convergent selection of somatic mutations in genes involved in glucose and lipid metabolism in cirrhotic livers suggests adaptive responses to gluco-lipotoxicity that influence end-stage liver disease. Recently, two distinct types of MASLD, with specific clinical trajectories, were identified on the basis of partitioned polygenic risk scores. Future studies are needed to integrate this knowledge, enabling earlier detection, risk stratification and targeted therapies.
    DOI:  https://doi.org/10.1038/s42255-025-01394-8
  8. Nat Med. 2025 Oct 16.
    Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
    Stefanie Zorn, Rebecca Bounds, Alice Williamson, Katherine Lawler, Ruth Hanssen, Julia Keogh, Elana Henning, Miriam Smith, Barbara A Fielding, A Margot Umpleby, Summaira Yasmeen, Maria Marti-Solano, Claudia Langenberg, Martin Wabitsch, Tinh-Hai Collet, I Sadaf Farooqi.
      Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.
    DOI:  https://doi.org/10.1038/s41591-025-03976-1
  9. Nat Rev Endocrinol. 2025 Oct 17.
    Interleukin-18 in obesity and obesity-related metabolic diseases.
    Christian Stoess, Janset Onyuru, Phillipp Hartmann, Hal M Hoffman, Lori Broderick, Ariel E Feldstein.
      
    DOI:  https://doi.org/10.1038/s41574-025-01199-5
  10. Nat Metab. 2025 Oct 15.
    EMito-Metrix enables automated evaluation of mitochondrial morphology across species.
    Eléna Morin, Emmanuel Doumard, Lisa M Hartnell, Beñat Salegi Ansa, Jean-Philippe Leduc-Gaudet, Aurélie Quillien, Jean Nakhle, Séverine Ethuin, Dominique Goudounèche, Bruno Payré, Vanessa Soldan, Stéphanie Balor, Anna Mattout, Jacques Rouquette, Laurence Dubois, Coralie Sengenès, Valérie Planat, Louis Casteilla, Armelle Yart, Cédric Dray, Julien Aligon, Luigi Ferrucci, Élise Duchesne, Sabah N A Hussain, Gilles Gouspillou, Laura Formentini, Arnaud Mourier, Olivier R Baris, Philippe Valet, Harold Parpex, Paul Monsarrat, Mathieu Vigneau, Jean-Philippe Pradère.
      
    DOI:  https://doi.org/10.1038/s42255-025-01400-z
  11. Metabolism. 2025 Oct 14. pii: S0026-0495(25)00289-6. [Epub ahead of print] 156420
    METTL1-mediated m7G methylation of FoxO1 regulates lipid metabolism in metabolic dysfunction-associated fatty liver disease.
    Jiang Du, Yujie Li, Xinxing Zhu, Jingwen Gao, Yuxuan Zhang, Chiheng Wang, Di Han, Liang Qiao, Beilin Kou, Rui Guo, Hongen Zhang, Juntang Lin.
      Metabolic dysfunction-associated fatty liver disease (MASLD) is characterized by the accumulation and degeneration of lipids in hepatocytes, presenting a complex pathogenesis that complicates drug development. In this study, we found that methyltransferase-like 1 (METTL1) is upregulated in the livers of both MASLD mice and clinical samples. Hepatocyte-specific depletion of METTL1 inhibits lipid synthesis and promotes lipid oxidation, alleviating metabolic disorders in high-fat diet (HFD)-induced MASLD mice. Conversely, overexpression of METTL1 enhances lipid synthesis while suppressing lipid oxidation. Mechanistically, METTL1 regulates the stability and protein expression levels of FoxO1 mRNA by methylating the Exon1 region of FoxO1, as demonstrated by m7G sequencing. Additionally, we found that overexpression of FoxO1 counteracts the protective effects of METTL1 deficiency on metabolic disorders in MASLD mice. Moreover, we identified a potent small-molecule inhibitor of METTL1, specifically Homatropine Methylbromide (HtMBm), which significantly ameliorated HFD-induced MASLD. Overall, our study suggests that METTL1 plays a crucial role in the progression of MASLD and highlights the therapeutic potential of targeting METTL1 to modulate fatty acid metabolism in this condition.
    Keywords:  Fatty acid metabolism; FoxO1; Hepatocyte; METTL1; Metabolic dysfunction-associated fatty liver disease
    DOI:  https://doi.org/10.1016/j.metabol.2025.156420
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