bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–04–26
ten papers selected by
Xiong Weng, University of Edinburgh
  1. IDH3A Deficiency Compromises Adaptive Thermogenesis and Exacerbates Obesity-Induced Metabolic Dysfunction via Impaired BCKDHA-Dependent BCAA Catabolism.
  2. A conserved hormonal signalling-H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis.
  3. The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.
  4. Adipose single cell epigenome and transcriptome localize genetic risk for cardiometabolic disease and accelerated aging.
  5. EBF2 condensates enable adipose thermogenesis through ZFP423 sequestration and epigenetic remodeling.
  6. Glycerol-driven TNAP activation in thermogenesis and mineralization.
  7. Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
  8. White adipose atrophy exacerbates cold stress and accelerates aging in male mice.
  9. Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.
  10. Dynamics of genetic and somatic trade-offs in ageing and mortality.
  1. Diabetes. 2026 May 01. 75(5): 772-786
    IDH3A Deficiency Compromises Adaptive Thermogenesis and Exacerbates Obesity-Induced Metabolic Dysfunction via Impaired BCKDHA-Dependent BCAA Catabolism.
    Xuhong Lu, Ningning Bai, Jialu Lyu, Jingjing Sun, Yingying Su, Yafen Ye, Tingting Hu, Tianwen Liu, Wenfei Li, Xiaoya Li, Xiaojing Ma, Ying Yang, Yuqian Bao.
      Adaptive thermogenesis in beige adipocytes is essential for maintaining energy homeostasis and preventing obesity. Emerging evidence suggests that human visceral adipose tissue harbors adipocytes with beige-like thermogenic features, enabling analysis of thermogenic gene regulation in humans. Isocitrate dehydrogenase 3A (IDH3A) is a rate-limiting enzyme of the tricarboxylic acid cycle, yet its function in adipocytes remains poorly defined. In this study, we examined IDH3A expression in human visceral adipose tissue and generated adipocyte-specific IDH3A knockout mice to investigate its role in beige adipocyte thermogenesis and metabolic regulation. IDH3A expression in human visceral fat was inversely associated with adiposity and adverse metabolic traits. Moreover, IDH3A expression was induced in human and mouse adipocytes following thermogenic stimulation. Adipocyte-specific IDH3A deletion in mice impaired beige fat thermogenic capacity, led to cold intolerance, and exacerbated diet-induced metabolic dysfunction. Mechanistically, IDH3A deficiency increased DNA methylation at the Bckdha promoter, resulting in the repression of this key branched-chain amino acid (BCAA) catabolic gene and impaired BCAA catabolism. Notably, restoring BCKDHA in IDH3A-deficient adipocytes rescued respiration and thermogenic function. Together, in addition to its canonical enzymatic role, our findings identify IDH3A as a critical regulator of BCAA catabolism that facilitates adaptive thermogenesis under metabolic stress conditions.
    ARTICLE HIGHLIGHTS: IDH3A expression in human visceral fat exhibits a negative correlation with metabolic dysfunction indicators. IDH3A is induced during thermogenic activation, yet its role in adipose tissue is not well characterized. Adipocyte-specific deletion of IDH3A impairs adaptive thermogenesis and metabolic homeostasis by disrupting BCKDHA-mediated BCAA catabolism. Overexpression of BCKDHA restores the thermogenic program in IDH3A-deficient beige adipocytes.
    DOI:  https://doi.org/10.2337/db25-0789
  2. Nat Metab. 2026 Apr 21.
    A conserved hormonal signalling-H2A.Z axis rapidly reorganizes 3D chromatin interactions in adipocyte thermogenesis.
    Yang Zhang, Rongbin Zheng, Tadataka Tsuji, Chih-Hao Wang, Xiang-Yu Liu, Yu-Hang Xing, Justin Darcy, Matthew D Lynes, Morten Lundh, Rini Arianti, Ferenc Győry, Rui Dong, Brice Emanuelli, Sarah E Johnstone, Miguel N Rivera, Endre Kristóf, C Ronald Kahn, Kaifu Chen, Yu-Hua Tseng.
      Three-dimensional genome organization underlies gene regulation, yet how acute hormonal signalling reshapes chromatin structure to control metabolism remains unclear. β3-adrenergic receptor (β3-AR) hormonal signalling drives adipocyte thermogenesis. Here, we show three-dimensional genome maps of mouse and primary human brown adipocytes during thermogenesis using Micro-C. We find that β3-AR signalling rapidly reorganizes chromatin loops within 4 h, with dynamically gained loops coupled to thermogenic gene activation in both species. Mechanistically, β3-AR stimulation promotes histone variant H2A.Z deposition to enhance chromatin accessibility at loop anchors, facilitating the recruitment of bridging factor MED1. Loss of H2A.Z compromises loop formation and thermogenic gene activation across species. Brown fat-specific H2A.Z deficiency in mice impairs thermogenic activity and glucose tolerance. Integration with genome-wide association studies links H2A.Z-occupied loops to genetic variants associated with obesity and related metabolic disorders. Together, our findings uncover a cross-species conserved β3-AR signalling-H2A.Z axis that rapidly reorganizes chromatin interactions in adipocyte thermogenesis, providing mechanistic and translational insights into metabolic regulation.
    DOI:  https://doi.org/10.1038/s42255-026-01510-2
  3. Aging Cell. 2026 May;25(5): e70509
    The Mitochondrial NAD Transporter SLC25A51 in Adipocytes Regulates Adipose Tissue Mitochondrial Function and Systemic Metabolism During Aging.
    Daiki Kojima, Keisuke Yaku, Shotaro Kosugi, Ryunosuke Mitsuno, Kenji Kaneko, Yoshinaga Kawano, Akihito Hishikawa, Seiya Mizuno, Manami Katoh, Akiko Satoh, Shinya Toyokuni, Tatsuhiko Azegami, Kenichiro Kinouchi, Shintaro Yamaguchi, Hiroshi Itoh, Takeshi Kanda, Toshimasa Yamauchi, Takashi Nakagawa, Kaori Hayashi, Jun Yoshino.
      Nicotinamide adenine dinucleotide (NAD) is a classical coenzyme regulating cellular energy metabolism. Emerging evidence demonstrates the causal relationship between defective NAD metabolism and various age-associated diseases. The major purpose of the present study was to investigate the role of adipocyte mitochondrial NAD biology in age-associated metabolic diseases. To this end, we focused on solute carrier family 25 member 51 (SLC25A51), a recently identified mitochondrial NAD transporter. We found that aging was associated with decreased adipose tissue SLC25A51 expression in both humans and mice. We next generated and analyzed novel knockout and overexpression models, which we have named adipocyte-specific Slc25a51 knockout (ASKO) and Slc25a51 overexpressing (ASLO) mice. ASKO mice had a marked decrease in adipose tissue mitochondrial NAD levels and exhibited age-associated systemic metabolic complications, such as obesity, glucose intolerance, insulin resistance, hyperinsulinemia, metabolic inflexibility, dyslipidemia, and hepatosteatosis. Mechanistically, loss of Slc25a51 reduced mitochondrial respiratory function, fatty acid oxidation capacity, and adiponectin production in adipose tissue, likely contributing to the development of systemic metabolic complications. Conversely, ASLO mice were protected from obesity and insulin resistance caused by aging. In conclusion, our results provide novel mechanistic and therapeutic insights into understanding the critical role of adipocyte mitochondrial NAD transporter SLC25A51 in the pathophysiology of age-associated metabolic diseases, particularly obesity and insulin resistance.
    Keywords:  NAD; adipocyte; aging; insulin resistance; obesity
    DOI:  https://doi.org/10.1111/acel.70509
  4. Nat Commun. 2026 Apr 20.
    Adipose single cell epigenome and transcriptome localize genetic risk for cardiometabolic disease and accelerated aging.
    Seung Hyuk T Lee, Asha Kar, Kyla Z Gelev, Zeyuan Johnson Chen, Sankha Subhra Das, Sini Heinonen, Tuure Saarinen, Maija Vaittinen, Dorota Kaminska, Hilkka Peltoniemi, Chongyuan Luo, Anne Juuti, Ville Männistö, Jussi Pihlajamäki, Minna U Kaikkonen, Kirsi H Pietiläinen, Brunilda Balliu, Päivi Pajukanta.
      Obesity impairs subcutaneous adipose tissue function, which predisposes to chronic cardiometabolic comorbidities and accelerated biological aging. However, regulatory variants, their target genes and epigenomic landscape underlying this predisposition in each subcutaneous adipose tissue cell-type remain elusive. Our subcutaneous adipose tissue cell-type level cis-expression quantitative trait and colocalization analyses reveal cis-expression quantitative trait locus variants, regulating 279 genes for 33 cardiometabolic disease and aging traits. Most of these genes are cell-type-specific (90%), led by adipocytes (55%), and missed in previous bulk tissue colocalization studies. Conducting subcutaneous adipose tissue cell-type level epigenome analysis, we discover that the vast majority (81%) of these colocalized cardiometabolic disease and aging risk variants map to the active chromatin compartments that comprise only 45% of the human genome, revealing three-dimensional epigenome in the center of cardiometabolic disease and aging risk. These findings uncover genetic and epigenomic regulation of genes underlying 33 cardiometabolic disease and aging traits in subcutaneous adipose tissue cell-types and offer critical insights into the principal role of three-dimensional chromatin in disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-72248-4
  5. Nat Commun. 2026 Apr 23.
    EBF2 condensates enable adipose thermogenesis through ZFP423 sequestration and epigenetic remodeling.
    Xianju Wang, Chen Li, Zongzheng Gui, Yubei Jin, Sijian Xia, Han Zhao, Yifei Wang, Minxian Dai, Suhua He, Yihang Zhong, Xiaozhi Lin, Qiang Xu, Wei Peng, Hongtu Zhao, Jinsai Shang, Haoyue Zhang, Wenxiang Hu.
      Brown adipose tissue (BAT) dissipates energy through non-shivering thermogenesis and holds promise as a therapeutic target for obesity. The transcription factor Early B Cell Factor 2 (EBF2) is a key regulator of the thermogenic gene program, yet its underlying transcriptional regulatory mechanisms and potential for pharmacological targeting remain incompletely defined. Here, we identify a low-complexity C-terminal domain (CTD) within EBF2 that drives biomolecular condensation critical for thermogenic activation. Deletion of the CTD (ΔCTD) or mutation of conserved proline residues disrupts EBF2 phase separation without affecting genomic occupancy, thereby impairing brown adipocyte differentiation and thermogenic capacity both in vitro and in male mice. Remarkably, fusion of the intrinsically disordered region (IDR) of FUS to the EBF2 ΔCTD mutant fully rescues its function, whereas fusion with the MED1-IDR produces distinct transcriptional and phenotypic outcomes. Mechanistically, EBF2 condensates sequester the transcriptional repressor ZFP423 while excluding HDAC1, creating a permissive chromatin environment that promotes thermogenic gene expression. Finally, a phenotypic small-molecule screen targeting phase separation identifies compounds that modulate EBF2 condensate dynamics and thermogenic programming. Together, our findings reveal phase separation as an emerging regulatory mechanism underlying brown fat determination and suggest that targeting biomolecular condensation offers a potential therapeutic strategy for obesity.
    DOI:  https://doi.org/10.1038/s41467-026-72233-x
  6. Nature. 2026 Apr 22.
    Glycerol-driven TNAP activation in thermogenesis and mineralization.
    Mohammed Faiz Hussain, Shreya S Krishnan, Brittany L Carroll, Bozena Samborska, Aisha Mousa, Alice Williamson, Maria Delgado-Martin, Bindu Y Srinivasu, Jakub Bunk, Janane F Rahbani, Abel Oppong, Anna Roesler, Zafir Kaiser, Mina Ersin, Qiaoqiao Zhang, Maria Guerra Martinez, Abhirup Shaw, Jonathan Cheng, Hannah Klemets, Katalin Kocsis Illes, Victoria E DeMambro, Clifford J Rosen, José Luis Millán, Thomas E Wales, Claudia Langenberg, Marc D McKee, Alba Guarné, Lawrence Kazak.
      Tissue-nonspecific alkaline phosphatase (TNAP) promotes skeletal mineralization by hydrolysing pyrophosphate1 and has been linked to uncoupling protein 1 (UCP1)-independent adipocyte thermogenesis through the futile creatine cycle through phosphocreatine hydrolysis2,3. Despite TNAP's broad physiological roles, endogenous regulators of its activity have not been defined. Furthermore, the activation mechanism of UCP1-independent thermogenesis has remained unresolved. Here we identify glycerol as an allosteric activator of TNAP. Glycerol binds to a surface pocket distal to the active site, which we term the glycerol pocket, to enhance TNAP activity. Using biophysical, structural, bioenergetic and physiological approaches, we show that the glycerol pocket is required for TNAP-driven thermogenesis. Through this mechanism, TNAP activates the futile creatine cycle, acting as a physiological complement to UCP1. The glycerol pocket is likewise required for optimal osteoblast-regulated mineralization. Human missense variants in this site reduce TNAP-dependent mineralization in vitro and are associated with lower alkaline phosphatase activity and bone mineral density, providing genetic evidence that its disruption impairs skeletal physiology.
    DOI:  https://doi.org/10.1038/s41586-026-10396-9
  7. Cell Metab. 2026 Apr 22. pii: S1550-4131(26)00111-7. [Epub ahead of print]
    Cav3.1 is a neuronal leucine sensor that mediates satiety and weight loss in response to dietary protein.
    Anthony H Tsang, Nicholas Heeley, Constanza Alcaino, Eunsang Hwang, Brian Y Lam, Taufiq Rahman, Tamana Darwish, Danae Nuzzaci, Richard G Kay, Amar Sarkar, Ruiyan Wang, Nihal Basha, Austin Punnoose, Peter Kirwan, Marcella Ma, Giles S Yeo, Florian T Merkle, Fiona M Gribble, Frank Reinmann, Kevin W Williams, Clémence Blouet.
      Dietary protein promotes satiety and weight loss, yet how appetite-regulating neurons sense dietary protein remains poorly understood. Here, we show that Cacna1g, which encodes the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates neuronal leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of pro-opiomelanocortin (POMC) neurons in cultured neurons and brain slices, thereby suppressing the anorectic response to hypothalamic leucine in vivo. Genetic deletion of Cacna1g in POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, leucine binds a hydrophobic pocket of Cav3.1 and lowers its threshold for voltage-dependent activation. Finally, pharmacological activation of mediobasal hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates responses to anorectic agents, including liraglutide. Together, these findings establish hypothalamic Cav3.1 as a neuronal leucine sensor and nominate it as a tractable target for anti-obesity therapy.
    Keywords:  POMC neurons; appetite; arcuate nucleus; dietary proteins; hypothalamus; leucine; metabolic diseases; nutrient sensing; obesity; voltage-gated calcium channel
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.017
  8. Nat Commun. 2026 Apr 18.
    White adipose atrophy exacerbates cold stress and accelerates aging in male mice.
    Zuojun Liu, Wenjing Hu, Xiaoqing Tan, Shimin Sun, Xin Huang, Yuan Meng, Nan Zhao, Ming Wang, Weiwei Wu, Minxian Qian, Xiaolong Tang, Qiuxiang Pang, Zimei Wang, Wen Su, Baohua Liu.
      Adipose tissues are highly dynamic in response to environmental temperature changes. During aging, subcutaneous white adipose tissues (WAT) decreases, yet whether this atrophy exacerbates cold stress and triggers systemic aging remains unclear. Here we show that adipocyte-specific expression of the LmnaG609G mutation in male mice leads to progressive WAT atrophy, accelerates aging, and shortens lifespan, whereas female mice remain unaffected. This lipoatrophy exacerbates cold stress, triggering cyclooxygenase-2 (COX-2) upregulation in WAT, and increased prostaglandin E2 production, which mediates the elevation of core body temperature (CBT). Inhibiting COX-2 by celecoxib or thermotherapy by housing the lipoatrophic mice at 26 °C (normally 22 °C) ameliorates cold stress, restores CBT, reduces aging features, and extends lifespan. Our findings reveal that subcutaneous WAT atrophy and subsequent CBT elevation induced by chronic mild cold stress are drivers of systemic aging in male mice, identifying thermotherapy as a potential regimen for progeria.
    DOI:  https://doi.org/10.1038/s41467-026-71857-3
  9. Adv Sci (Weinh). 2026 Apr 21. e01083
    Cell Cycle Control of Nuclear Metabolism Couples Phosphatidylinositol Signaling to Histone Methylation.
    Antoni Gañez-Zapater, Savvas Kourtis, Camilla Reiter Elbæk, Lorena Espinar, Carolina Toro-Márquez, Albert Coll-Manzano, Alfredo Smiriglia, Laura García-López, Laura Wiegand, Maria Guirola, Frédéric Fontaine, Andrea Morandi, André C Müller, Sara Sdelci.
      Progression through the cell cycle requires coordinated regulation of transcription, chromatin state, and cellular metabolism. While metabolic enzymes are known to localize the nucleus and influence chromatin states, how nuclear metabolism itself oscillates during the cell cycle remains unexplored. Here, we combine a customized FUCCI-3 reporter with chromatome mass spectrometry and high-throughput imaging to systematically resolve nuclear and chromatin-associated metabolic changes across cell cycle phases. We identify phosphatidylinositol metabolism as a nuclear pathway that oscillates with the cell cycle, with PIP5K1A, PLCD3, and PLD2 showing phase-specific nuclear and chromatin dynamics. Nuclear PIP2 levels redistribute within the nucleus depending on cell cycle stage. Downregulation of PIP5K1A reduces nuclear PIP2 levels, whereas nuclear enrichment of PIP5K1A increases PIP2 abundance in the nucleus and nucleolus, functionally linking PIP5K1A nuclear localization to nuclear PIP2 synthesis. Moreover, perturbation of nuclear PIP2 synthesis alters chromatin methylation, with a pronounced impact on H4K20 monomethylation. Together, our results reveal that nuclear phosphatidylinositol metabolism is cell cycle regulated and functionally linked to chromatin methylation, establishing nuclear lipid metabolism as a previously unrecognized layer of cell cycle control.
    Keywords:  cell cycle; chromatin; epigenetics; nuclear metabolism; proteomics
    DOI:  https://doi.org/10.1002/advs.202501083
  10. Nature. 2026 Apr 22.
    Dynamics of genetic and somatic trade-offs in ageing and mortality.
    Danny Arends, David G Ashbrook, Suheeta Roy, Lu Lu, Zachary Sloan, Arthur G Centeno, Kurt H Lamour, João Pedro de Magalhães, Pjotr Prins, Karl W Broman, Saunak Sen, Sarah J Mitchell, Michael R MacArthur, Özlem Altintas Akin, Xiaoxu Li, Amandeep Bajwa, Vivian Diaz, David E Harrison, Randy Strong, James F Nelson, Khyobeni Mozhui, Johan Auwerx, Evan G Williams, Richard A Miller, Robert W Williams.
      DNA variants modulate mortality risks across an entire lifespan but their dynamic age-dependent effects have not been resolved in any species for either sex. Here we mapped variants that shape mortality using an actuarial approach, starting with a base population of 6,438 pubescent mice and ending with 559 survivors that lived beyond 1,100 days of age. Twenty-nine Vita loci influence lifespan with strong age- and sex-specific effects. Most act during distinct stages with polarities that often invert with age, but a minority have consistent age-dependent effects in one or both sexes. A separate set of 30 Soma loci influence correlations between body mass and life expectancy. Nineteen Soma loci mediate higher mortality in larger young mice, whereas 11 mediate lower mortality in larger old mice. All effects are stronger in male mice than in female mice. Vita and Soma loci form epistatic networks split strictly by sex. These findings provide a genetic bridge between evolutionary theories of ageing and molecular mechanisms that can guide interventions to extend healthy lifespan.
    DOI:  https://doi.org/10.1038/s41586-026-10407-9
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