bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–01–18
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function.
  2. YAP/TAZ-VGLL3 governs adipocyte fate via epigenetic reprogramming of PPARγ and its target enhancers.
  3. Identification of a thermogenic target in the dorsal raphe nucleus for weight management in mice.
  4. Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
  5. Cytoarchitectural multi-depot profiling reveals immune-metabolic crosstalk in human colon-associated adipose tissue.
  6. Ablation of Prdm16 and beige fat identity causes vascular remodeling and elevated blood pressure.
  7. Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
  8. Lipid-induced granules in hepatocytes alleviate liver fibrosis.
  9. Precision phenotyping of type 2 diabetes in chinese populations using a variational autoencoder-informed tree model.
  10. Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
  11. Simultaneous epigenomic profiling and regulatory activity measurement using e2MPRA.
  12. AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.
  13. Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss.
  1. Cell Metab. 2026 Jan 09. pii: S1550-4131(25)00540-6. [Epub ahead of print]
    DGAT-driven futile lipid cycling has a pronounced, yet concealed, thermogenic function.
    Anand Kumar Sharma, Radhika Khandelwal, Jelena Zurkovic, Fen Long, Tongtong Wang, Revati S Dewal, Chunyan Wu, Adhideb Ghosh, Klug Manuel, Alaa Othman, Chandramohan Chitraju, Robert V Farese, Tobias C Walther, Miroslav Balaz, Christoph Thiele, Christian Wolfrum.
      Thermoregulation is an essential yet incompletely understood homeostatic process in mammals. UCP1-mediated thermogenesis, while efficient, is dispensable, suggesting the existence of alternative mechanisms. Using a pharmacogenetic approach, we show that the adipose tissue futile lipid cycling (FLC) contributes to UCP1-independent thermogenesis, with DGATs being involved in the regulation of FLC. The loss of DGAT-driven FLC-mediated thermogenesis is compensated for by the hierarchical recruitment of alternative mechanisms such as shivering and enhanced lipid catabolism mediated by AMPK activation. Consistently, pharmacological inhibition of muscle shivering or AMPK in FLC-deficient mice leads to an acute reduction in energy expenditure and hypothermia. These findings demonstrate a substantial thermogenic potential of FLC and suggest previously unappreciated flexibility and adaptability in regulating the core body temperature through adaptive changes in adipocyte metabolism.
    Keywords:  AMPK; DGAT; adipose tissue; energy homeostasis; futile cycles; futile lipid cycling; lipid metabolism; shivering; thermal homeostasis; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.009
  2. Sci Adv. 2026 Jan 16. 12(3): eaea7235
    YAP/TAZ-VGLL3 governs adipocyte fate via epigenetic reprogramming of PPARγ and its target enhancers.
    Taejun Seol, Ju-Gyeong Kang, Kwangmin Ryu, Woojae Kim, Daehee Hwang, Suhyeon Cho, Daeun Song, Bomin Ku, Yen T H Tran, Sun-Hye Jeong, Won-Ki Cho, Dae-Sik Lim.
      Adipocyte differentiation from mesenchymal stem cells is governed by tightly regulated transcriptional and epigenetic programs. The Hippo pathway effectors YAP and TAZ impede this process, yet the underlying molecular mechanisms remain unclear. Here, we demonstrate how YAP/TAZ regulate transcription of the adipocyte lineage specification factor PPARγ and its target genes at the chromatin level. TAZ represses PPARγ-bound target enhancers as evidenced by a markedly reduced histone H3 acetylated at lysine-27 occupancy, resulting in the transcriptional repression of adipogenic genes, including Pparg2. Single-nucleus genomic analyses of mouse adipose tissue further revealed that YAP/TAZ activation drives extensive epigenetic modulation. Notably, the repressive effect of TAZ on adipogenic enhancers requires TEAD-dependent transcriptional activity, but not a direct interaction with PPARγ through the WW domain as previously reported. Last, we identified Vestigial-like 3 (Vgll3) as a transcriptional target of TAZ critical for repressing adipogenic enhancers. These findings reveal that the YAP/TAZ-VGLL3 axis regulates adipocyte fate by repressing the PPARγ program at its target enhancers.
    DOI:  https://doi.org/10.1126/sciadv.aea7235
  3. Nat Commun. 2026 Jan 13.
    Identification of a thermogenic target in the dorsal raphe nucleus for weight management in mice.
    Alexandre Moura-Assis, Kaja Plucińska, David Meseguer, Aiste Baleisyte, Bandy Chen, Kyle Pellegrino, Luca Parolari, Jordan T Shaked, Keith J Page, Douglas W Barrows, Thomas S Carroll, Jose G Grajales-Reyes, Daxiang Na, Amanda Rodriguez-Diaz, Jessica Furtado, Juan Uribe Isaza, Hans H Schiffer, Yun Chen, Huikai Sun, Nidhi Kaushal, Holger Monenschein, Daniel F Barker, María José Ortuño, Nicolas Renier, Paul Cohen, Mark Carlton, Nathaniel Heintz, Nicola L Brice, Jeffrey M Friedman, Marc Schneeberger.
      Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, which ultimately disrupt body weight homeostasis1. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the dorsal raphe nucleus and ventrolateral periaqueductal gray (DRN/vlPAGVGAT) reduces body weight in diet-induced obese (DIO) male mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRN/vlPAGVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly prevented weight gain in male mice exposed to a high-fat diet by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study integrates transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a candidate to treat obesity.
    DOI:  https://doi.org/10.1038/s41467-025-68056-x
  4. Science. 2026 Jan 15. 391(6782): eadq9006
    Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity.
    Danhui Liu, Chuanli Zhou, Xiaochen Wang, Zhou Luo, Ruiyao Xu, Shanshan Huo, Lina Guo, Xuemei Luo, Shuhan Yang, Arielle Click, Janiece Vancil, Paola Barajas, Victor Mijares, Hamid Baniasadi, Nan Yan, Jan Rehwinkel, Dustin C Hancks, Elizabeth H Chen, Shuang Liang, Zhenyu Zhong.
      Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.
    DOI:  https://doi.org/10.1126/science.adq9006
  5. Cell Metab. 2026 Jan 13. pii: S1550-4131(25)00539-X. [Epub ahead of print]
    Cytoarchitectural multi-depot profiling reveals immune-metabolic crosstalk in human colon-associated adipose tissue.
    Jutta Jalkanen, Jiawei Zhong, Pamela A Nono Nankam, Nayanika Bhalla, Merve Elmastas, Jiaxin Luo, Sophie Weinbrenner, Scott Frendo-Cumbo, Benedek Pesti, William Gourash, Anita Courcoulas, Zinger Yang Loureiro, Arne Dietrich, Jesper Bäckdahl, Anders Thorell, Marcus Buggert, Joanna Kalucka, Margo P Emont, Evan D Rosen, Matthias Blüher, Peter Kovacs, Patrik L Ståhl, Lucas Massier, Mikael Rydén, Niklas Mejhert.
      While it is well established that the cellular composition of white adipose tissue (WAT) varies between depots, the functional relevance of this heterogeneity remains unclear. By combining spatial and single-nucleus RNA sequencing, we provide a comprehensive map of subcutaneous and visceral (omental, mesenteric, mesocolic, and epiploic) WAT in both men and women. Our analyses reveal shared features, such as the spatial organization of adipogenesis, alongside depot-specific characteristics, including distinct cell-type enrichments and unique cell-cell communication routes. Epiploic WAT stands out by harboring high proportions of serum amyloid A expressing fat cells (encoded by SAA1/SAA2) and several leukocyte populations. Through mechanistic studies, we demonstrate that adipocyte SAA1/SAA2 expression is induced by inflammatory signals, including lipopolysaccharide, and that SAA1 activates immune responses in adipose-resident myeloid cells. Collectively, our findings suggest that visceral WAT exhibits distinct cytoarchitectural properties, with those located near the colon adapting by developing specialized adipocytes and immune cell populations.
    Keywords:  adipocyte subtypes; adipose depots; cell-cell communication; cellular heterogeneity; inflammation; insulin resistance; microbiome; obesity; transcriptomics
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.008
  6. Science. 2026 Jan 15. 391(6782): 306-313
    Ablation of Prdm16 and beige fat identity causes vascular remodeling and elevated blood pressure.
    Mascha Koenen, Tobias Becher, Giulia Pagano, Ilaria Del Gaudio, Jorge A Barrero, Augusto C Montezano, Jenelys Ruiz Ortiz, Zeran Lin, Nicolás Gómez-Banoy, Rose Amblard, Daniel Schriever, Meltem E Kars, Luisa Rubinelli, Sarah J Halix, Zhen Fang Huang Cao, Xing Zeng, Scott D Butler, Yuval Itan, Rhian M Touyz, Annarita Di Lorenzo, Paul Cohen.
      Excess adiposity is a major risk factor for hypertension and heart disease. Brown fat is associated with protection from cardiovascular pathology, but whether this relationship is causal remains unknown. In this work, we investigate the role of mouse beige fat, as a model of human inducible brown fat, in adipocyte-vascular cross-talk. Using adipocyte-specific Prdm16 knockout mice with a loss of beige adipocyte identity, we discovered marked remodeling of perivascular adipose tissue, increased vascular reactivity, and elevated blood pressure. We show that the circulating enzyme QSOX1 is derepressed in Prdm16-deficient adipocytes, and deletion of Qsox1 in Prdm16 conditional knockout mice prevented vascular fibrosis and normalized vascular reactivity. These results demonstrate a key role for beige adipocytes in blood pressure regulation and identify QSOX1 as an important mediator of adipocyte-vascular cross-talk.
    DOI:  https://doi.org/10.1126/science.ady8644
  7. Nat Aging. 2026 Jan 16.
    Metformin inhibits nuclear egress of chromatin fragments in senescence and aging.
    Takuya Kumazawa, Yanxin Xu, Yu Wang, Ji-Won Lee, Tara C O'Brien, Chia-Kang Ho, Murat Cetinbas, Aaron Weiner, Konrad Hochedlinger, Ruslan I Sadreyev, Nabeel Bardeesy, Chia-Wei Cheng, Bin He, Zhixun Dou.
      Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.
    DOI:  https://doi.org/10.1038/s43587-025-01048-0
  8. Cell Metab. 2026 Jan 09. pii: S1550-4131(25)00546-7. [Epub ahead of print]
    Lipid-induced granules in hepatocytes alleviate liver fibrosis.
    Yunhui Li, Ting Lei, Wen Nie, Mingrui Ma, Wei Zhao, Ye Zhou, Yanfang Liu, Minjun Wang, Kaiwei Jia, Shanrong Liu, Yuanyuan Wang, Yiwen Fan, Long Chen, Xing He, Jihang Yuan, Xuetao Cao, Jin Hou.
      Intracellular membraneless organelles, including granules, bodies, speckles, etc., play critical roles in physiological and pathological processes. The discovery of new membraneless organelles has generated significant attention. DEAD-box helicase (DDX) family members possess the potential to undergo liquid-liquid phase separation (LLPS), the foundation for the assembly of membraneless organelles. Here, to identify new granules assembled in steatotic hepatocytes, we screened DDX family members and found that lipids, especially arachidonic acid (AA) metabolites, induced LLPS of DDX49 in hepatocytes, forming an assembled granule named as lipid-induced granule (LIG). The assembled LIGs by DDX49 feedback restrained metabolic dysfunction-associated steatotic liver disease (MASLD)-associated fibrosis. Mechanistically, C5-methylcytosine (m5C)-modified mRNA of pro-fibrotic hepatokine tissue inhibitor of metalloproteinase 2 (Timp2) and its reader Y-box binding protein 1 (YBX1) were recruited into LIGs, thereby inhibiting Timp2 mRNA translation and consequently feedback suppressing liver fibrosis. Moreover, LIGs were identified in human MASLD livers and exhibited reverse correlation with fibrosis progression. Therefore, we identified a new granule in steatotic hepatocytes and elucidated its role in restraining liver fibrosis.
    Keywords:  C5-methylcytosine; DEAD-box helicase 49; liquid-liquid phase separation; membraneless organelle; metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.015
  9. Nat Commun. 2026 Jan 14.
    Precision phenotyping of type 2 diabetes in chinese populations using a variational autoencoder-informed tree model.
    Tong Yue, Wenhao Zhang, Yu Ding, Xueying Zheng, Yunjie Ma, Juliana C N Chan, Eric S H Lau, Juliana N M Lui, Guoxi Jin, Wen Xu, Yan Bi, Zuocheng Wang, Sheng Nie, Mengchun Gong, Ewan R Pearson, Sihui Luo, Jianping Weng.
      Type 2 diabetes (T2D) exhibits clinical heterogeneity, yet most existing classification models are derived from European populations and face challenges in clinical application. Here, we evaluate the generalizability of a tree-like graph structure from Scottish data to 32,501 newly diagnosed T2D patients from a multi-center Chinese cohort comprising over 8.6 million individuals. We observe similar distribution between the Scottish and Chinese individuals in heart and kidney outcomes, but diabetic retinopathy varies across ancestries even within similar phenotypes. To capture T2D Chinese-specific heterogeneity, we apply a variational autoencoder (VAE) framework to identify key clinical features and construct a tree structure using the Discriminative Dimensionality Reduction Tree (DDRTree) algorithm. This Chinese tree model is validated in two independent external cohorts and revealed longitudinal phenotypic shifts trending toward higher-risk branches. Our findings emphasize the need for population-specific classification frameworks to advance precision diabetology through individualized risk prediction and specialized treatment guidelines.
    DOI:  https://doi.org/10.1038/s41467-025-68211-4
  10. Nat Med. 2026 Jan 14.
    Circulating metabolites, genetics and lifestyle factors in relation to future risk of type 2 diabetes.
    Jun Li, Jie Hu, Huan Yun, Zhendong Mei, Xingyan Wang, Kai Luo, Marta Guasch-Ferré, Xikun Han, Buu Truong, Jordi Merino, Chengyong Jia, Miguel Ruiz-Canela, Casey M Rebholz, Eun Hye Moon, Taryn Alkis, Guning Liu, Jie Yao, Xiyuan Zhang, Bianca C Porneala, Jordi Salas-Salvadó, Thomas J Wang, Josée Dupuis, Elizabeth Selvin, Xiuqing Guo, Shilpa N Bhupathiraju, Jennifer A Brody, Yongmei Liu, Alexis C Wood, Kari E North, Su Yon Jung, Ching-Ti Liu, Nona Sotoodehnia, Simin Liu, Lesley F Tinker, A Heather Eliassen, JoAnn E Manson, Jose C Florez, Robert E Gerszten, Clary B Clish, Liming Liang, Rozenn N Lemaitre, Katherine L Tucker, Stephen S Rich, Jerome I Rotter, Miguel Angel Martínez-González, Kathryn M Rexrode, James B Meigs, Eric Boerwinkle, Robert C Kaplan, Frank B Hu, Bing Yu, Qibin Qi.
      The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.
    DOI:  https://doi.org/10.1038/s41591-025-04105-8
  11. Nat Commun. 2026 Jan 14.
    Simultaneous epigenomic profiling and regulatory activity measurement using e2MPRA.
    Zicong Zhang, Ilias Georgakopoulos-Soares, Guillaume Bourque, Nadav Ahituv, Fumitaka Inoue.
      Using various biochemical assays that identify transcription factor (TF) binding and histone modifications, cis-regulatory elements (CREs) can be annotated in a genome-wide manner. However, these assays are descriptive and require functional validation. To the best of our knowledge, no technology can simultaneously analyze the regulatory function and epigenomic modifications of a specific sequence. Here, we develop an enrichment followed by epigenomic profiling massively parallel reporter assay (e2MPRA). This technique uses lentivirus to enrich for the integration of specific CREs into the genome and applies MPRA, Cut&Tag or ATAC-seq on them enabling simultaneous, high-throughput analysis of regulatory activity, protein binding, and epigenetic modification. We demonstrate that e2MPRA can dissect the epigenetic functions of TF motifs arranged within synthetic enhancers and evaluate the effects of sequence perturbation on epigenetic states. In summary, e2MPRA advances our understanding of the regulatory code, its effect on the epigenome and how its alteration leads to phenotypic effects.
    DOI:  https://doi.org/10.1038/s41467-026-68422-3
  12. Nat Metab. 2026 Jan 12.
    AMPK at the interface of nutrient sensing, metabolic flux and energy homeostasis.
    Tyler K T Smith, Logan K Townsend, William J Smiles, Jonathan S Oakhill, Morgan D Fullerton, Gregory R Steinberg.
      The orchestration of cellular metabolism requires the integration of signals related to energy stores and nutrient availability through multiple overlapping mechanisms. AMP-activated protein kinase (AMPK) is a pivotal energy sensor that responds to reductions in adenylate charge; however, studies over the past decade have also positioned AMPK as a key integrator of nutrient-derived signals that coordinate metabolic function. This Review highlights recent advances in our understanding of how AMPK senses nutrients and regulates metabolic activity across tissues, timescales and cell types. These effects are mediated through the phosphorylation of substrates involved in metabolite trafficking, mitochondrial function, autophagy, transcription, ubiquitination, proliferation and cell survival pathways, including ferroptosis. Particular attention is given to the role of AMPK in the pathophysiology of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, cardiovascular and renal diseases, neurodegenerative disorders and cancer. Collectively, these findings reinforce AMPK as a central metabolic node that aligns cellular behaviour with energetic demand. Continued investigation into its nutrient-sensing mechanisms holds promise for identifying new strategies to restore metabolic balance in disease.
    DOI:  https://doi.org/10.1038/s42255-025-01442-3
  13. Nat Metab. 2026 Jan 12.
    Single-cell-resolved transcriptional dynamics of human subcutaneous adipose tissue during lifestyle- and bariatric surgery-induced weight loss.
    Anne Loft, Rasmus Rydbirk, Ellen Gammelmark Klinggaard, Elvira Laila Van Hauwaert, Charlotte Wilhelmina Wernberg, Andreas Fønss Møller, Trine Vestergaard Dam, Mohamed Nabil Hassan, Babukrishna Maniyadath, Ronni Nielsen, Aleksander Krag, Joanna Kalucka, Søren Fisker Schmidt, Mette Enok Munk Lauridsen, Jesper Grud Skat Madsen, Susanne Mandrup.
      Human white adipose tissue undergoes major remodelling during sustained weight gain that may compromise tissue function and drive cardiometabolic comorbidities. Although weight loss reverses many of these complications, the cellular and molecular adaptations of adipose tissue to different weight loss interventions are poorly understood. Here we show how abdominal subcutaneous adipose tissue (SAT) in men and women with severe obesity adapts to modest lifestyle-induced (8-10%) weight loss followed by substantial bariatric surgery-induced (20-45%) weight loss, using single-nucleus RNA sequencing (snRNA-seq) combined with bulk RNA-seq, and three-dimensional light-sheet fluorescence microscopy. To enable interactive exploration, all snRNA-seq data are available in a browsable format on the Single Cell Portal ( SCP2849 ). Lifestyle-induced weight loss activated proadipogenic gene programmes in progenitor cells, indicating early beneficial effects on SAT. Subsequent surgery-induced weight loss drove profound compositional and transcriptional remodelling of SAT, including increased vascularization and marked reduction of myeloid cell populations. Collectively, our study indicates that following major and sustained weight loss, SAT from individuals with severe obesity has the capacity to return to a state comparable to that observed in lean individuals.
    DOI:  https://doi.org/10.1038/s42255-025-01433-4
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