bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–08–10
25 papers selected by
Xiong Weng, University of Edinburgh
  1. Adipose tissue thermogenesis is not proportional to temperature.
  2. A DEL-1/αvβ3 integrin axis promotes brown adipocyte progenitor proliferation and cold-induced brown adipose tissue adaptation.
  3. Defective Olfactomedin-2 connects adipocyte dysfunction to obesity.
  4. A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.
  5. NADH reductive stress drives metabolic reprogramming.
  6. Exosome Trafficking Is a Key Regulator of Adipocyte Thermogenesis.
  7. IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells.
  8. DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation.
  9. Circulating epigenetic signatures classifying brain insulin resistance in humans.
  10. Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.
  11. Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
  12. Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species.
  13. Urinary Complement proteome strongly linked to diabetic kidney disease progression.
  14. CRISPR-Cas9 screening reveals microproteins regulating adipocyte proliferation and lipid metabolism.
  15. HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes.
  16. Brain control of energy homeostasis: Implications for anti-obesity pharmacotherapy.
  17. Foam cell-derived exosomes: Messengers between atherosclerosis and microglia.
  18. Effects of β-catenin deficiency on adipose tissue physiology.
  19. Tirzepatide Heralds the Hope of Chronic Disease Eradication.
  20. Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience.
  21. The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling.
  22. Molecular Mechanisms of Cardiomyocyte Aging.
  23. Noncatalytic telomerase function in inflammation.
  24. Refining the generation, interpretation and application of multi-organ, multi-omics biological aging clocks.
  25. Identification of gut microbial bile acid metabolic enzymes via an AI-assisted pipeline.
  1. Nat Rev Endocrinol. 2025 Aug 07.
    Adipose tissue thermogenesis is not proportional to temperature.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-025-01163-3
  2. Mol Metab. 2025 Aug 01. pii: S2212-8778(25)00136-X. [Epub ahead of print] 102229
    A DEL-1/αvβ3 integrin axis promotes brown adipocyte progenitor proliferation and cold-induced brown adipose tissue adaptation.
    Kyoung-Jin Chung, Antonios Chatzigeorgiou, Jong-Hyung Lim, Xiaofei Li, Ismini Marava, Dong-Young Kim, Anke Witt, Janine Gebler, Sylvia Grossklaus, Bettina Gercken, Irakli Kopaliani, Pallavi Subramanian, Matthias Blüher, Khalil Bdeir, Vasileia Ismini Alexaki, George Hajishengallis, Triantafyllos Chavakis.
      Cold-triggered adaptation of the brown adipose tissue (BAT) promotes increased non-shivering thermogenesis and helps maintain body temperature. Here, we demonstrate that the secreted protein developmental endothelial locus-1 (DEL-1) acts as a regulator of cold-induced BAT adaptation. DEL-1 was expressed in the vascular endothelium of the BAT and its expression was upregulated upon cold exposure. By interacting with αvβ3 integrin on brown adipocyte progenitor cells, DEL-1 promoted their proliferation in a manner dependent on AKT signaling and glycolysis activation. Compared to DEL-1-sufficient mice, DEL-1-deficient mice or mice expressing a non-integrin-binding mutant of DEL-1 carrying an Asp-to-Glu substitution in its RGD motif, displayed decreased cold tolerance. This phenotype was associated with impaired BAT adaptation to cold and reduced brown adipocyte progenitor cell proliferation. Conversely, endothelial-specific DEL-1 overexpression in DEL-1-deficient mice restored the BAT thermogenic response to cold. Together, the DEL-1/αvβ3 integrin-dependent endothelial-brown adipocyte progenitor cell crosstalk promotes cold-stimulated BAT adaptation. This knowledge could be potentially harnessed therapeutically for promoting BAT expansion towards improving systemic metabolism.
    Keywords:  Developmental endothelial locus-1; brown adipocyte progenitor proliferation; brown adipose tissue; cold-induced brown adipose tissue adaptation; integrins; thermogenesis
    DOI:  https://doi.org/10.1016/j.molmet.2025.102229
  3. Nat Commun. 2025 Aug 04. 16(1): 7154
    Defective Olfactomedin-2 connects adipocyte dysfunction to obesity.
    Aina Lluch, Jèssica Latorre, Isabel Espadas, Núria Oliveras-Cañellas, José M Moreno-Navarrete, Estefanía Caballano-Infantes, Gitalee Sarker, Nicolás F Malvido, Pablo Garrido-Gil, José L Labandeira-García, Naoki Nakaya, Silvia Mora, Eduardo Chicano, Jaime López-Alcalá, María M Malagón, Alejandro Martín-Montalvo, Birong Zhang, You Zhou, Ana I Domingos, Miguel López, Johanna Pörschke, María Gómez-Serrano, Witold Szymanski, Johannes Graumann, Stanislav I Tomarev, Ismael González-García, José M Fernández-Real, Francisco J Ortega.
      Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity.
    DOI:  https://doi.org/10.1038/s41467-025-62430-5
  4. Metabolism. 2025 Aug 05. pii: S0026-0495(25)00227-6. [Epub ahead of print]172 156358
    A key role of polyamine metabolism in adipose tissue homeostasis that regulates obesity.
    Christine Mund, Anupam Sinha, Anika Aderhold, Ivona Mateska, Eman Hagag, Sofia Traikov, Bettina Gercken, Andres Soto, Jonathan Pollock, Lilli Arndt, Michele Wölk, Natalie Werner, Georgia Fodelianaki, Pallavi Subramanian, Kyoung-Jin Chung, Sylvia Grossklaus, Mathias Langner, Mohamed Elgendy, Tatyana Grinenko, Ben Wielockx, Andreas Dahl, Martin Gericke, Matthias Blüher, Ünal Coskun, David Voehringer, Maria Fedorova, Mirko Peitzsch, Peter J Murray, Triantafyllos Chavakis, Vasileia Ismini Alexaki.
       BACKGROUND AND AIMS: Adipose tissue function is integral to systemic metabolic homeostasis. Excessive adipose tissue growth is associated with development of chronic low-grade inflammation and whole body dysmetabolism. The cell metabolic pathways regulating adipose tissue growth and homeostasis are little understood. Here we studied the role of polyamine metabolism in adipose tissue (patho)physiology.
    METHODS: We generated mice with global and adipocyte progenitor (AP)-specific Antizyme inhibitor 2 (AZIN2) deficiency and performed diet-induced obesity studies. APs were isolated from the subcutaneous and gonadal adipose tissue of mice and cultured.
    RESULTS: Polyamine metabolism components, including AZIN2, were highly expressed in APs and their expression in the adipose tissue was downregulated with obesity. IL4 induced Azin2 expression in APs. AZIN2 facilitated polyamine synthesis and acetylation, and regulated total acetyl-CoA levels in APs. AZIN2 deficiency upregulated histone acetylation in genes related to lipid metabolism. Azin2-/- APs committed more efficiently to adipogenesis in vivo and in vitro, and were more prone to senescence compared to wild-type counterparts. Upon diet-induced obesity, global and AP-specific AZIN2 deficiency in mice provoked AP depletion, adipocyte hypertrophy, obesity, inflammation, glucose intolerance and insulin resistance. In human adipose tissue, AZIN2 expression strongly correlated with expression of progenitor markers.
    CONCLUSIONS: Altogether, we identified AZIN2 as a novel AP marker that regulates AP fate and preserves adipose tissue health.
    Keywords:  AZIN2; Adipocyte progenitors; Adipose tissue; Obesity; Polyamine metabolism
    DOI:  https://doi.org/10.1016/j.metabol.2025.156358
  5. Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]
    NADH reductive stress drives metabolic reprogramming.
    Ronghui Yang, Zihao Guo, Binghui Li.
      Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.
    Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
  6. bioRxiv. 2025 Jul 31. pii: 2025.07.20.665768. [Epub ahead of print]
    Exosome Trafficking Is a Key Regulator of Adipocyte Thermogenesis.
    Devesh Kesharwani, Michele Karolak, Chad Doucette, Rachelle Mendola, Summer Pray, Raghu Bhardwaj, Su Su, Anne Harrington, Victoria DeMambro, Clifford Rosen, Lucy Liaw, Aaron C Brown.
      Activation of beige adipocytes enhances energy expenditure and promotes metabolic health, presenting a promising approach for combating obesity and diabetes. As part of this process, thermogenesis, fueled in part by uncoupled mitochondrial respiration, plays a central role in converting calories into thermal energy, thereby preventing their storage as fat. Here, we identify a role for exosome trafficking as an intrinsic regulator of beige adipocyte thermogenesis. Exosomes are small extracellular vesicles that mediate cell-cell and intracellular communication by transporting regulatory cargo, including microRNAs, proteins, and lipids. Using both human cells and mouse models, we show that thermogenic activation of beige adipocytes promotes the rapid release of exosomes enriched in microRNAs known to suppress thermogenic programs. Genetic or pharmacological blockade of exosome secretion attenuates thermogenesis, whereas enhancing exosome release amplifies thermogenic output. Mice deficient in the exosome secretion regulator Rab27a exhibit reduced energy expenditure in response to both cold exposure and β3-adrenergic stimulation. These findings establish exosome trafficking as a key contributor to beige adipocyte thermogenic capacity, highlighting an intracellular mechanism that may be leveraged to enhance energy expenditure and treat obesity-related metabolic diseases.
    Significance Statement: Thermogenic adipocytes, including beige fat cells, help maintain energy balance by converting excess nutrients into heat, thereby reducing fat storage and supporting metabolic function. Although these cells are known to promote energy expenditure, the intracellular processes that enable their full thermogenic response are not well defined. Here, we show that exosome secretion is required for beige adipocytes to reach their full thermogenic potential. Blocking exosome release dampens this response, while boosting it amplifies thermogenic output. These findings point to exosome release as an essential part of thermogenic regulation and a potential target for improving metabolic health.
    DOI:  https://doi.org/10.1101/2025.07.20.665768
  7. Nat Commun. 2025 Aug 06. 16(1): 7248
    IRX3 controls a SUMOylation-dependent differentiation switch in adipocyte precursor cells.
    Jan-Inge Bjune, Samantha Laber, Laurence Lawrence-Archer, Patrizia M C Nothnagel, Shuntaro Yamada, Xu Zhao, Pouda Panahandeh Strømland, Niyaz Al-Sharabi, Kamal Mustafa, Pål R Njølstad, Melina Claussnitzer, Roger D Cox, Pierre Chymkowitch, Gunnar Mellgren, Simon N Dankel.
      IRX3 is linked to predisposition to obesity through the FTO locus and is upregulated during early adipogenesis in risk-allele carriers, shifting adipocyte fate toward fat storage. However, how this elevated IRX3 expression influences later developmental stages remains unclear. Here we show that IRX3 regulates adipocyte fate by modulating epigenetic reprogramming. ChIP-sequencing in preadipocytes identifies over 300 IRX3 binding sites, predominantly at promoters of genes involved in SUMOylation and chromatin remodeling. IRX3 knockout alters expression of SUMO pathway genes, increases global SUMOylation, and inhibits PPARγ activity and adipogenesis. Pharmacological SUMOylation inhibition rescues these effects. IRX3 KO also reduces SUMO occupancy at Wnt-related genes, enhancing Wnt signaling and promoting osteogenic fate in 3D cultures. This fate switch is partially reversible by SUMOylation inhibition. We identify IRX3 as a key transcriptional regulator of epigenetic programs, acting upstream of SUMOylation to maintain mesenchymal identity and support adipogenesis while suppressing osteogenesis in mouse embryonic fibroblasts.
    DOI:  https://doi.org/10.1038/s41467-025-62361-1
  8. EMBO Rep. 2025 Aug 04.
    DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation.
    Jessica Leismann, Styliani-Eirini Kanta, Ishita Amar, Anna Szczepińska, Monika Mielnicka, Giuseppe Petrosino, Anke Busch, Marion Scheibe, Pengxiang Wang, Yuan Wang, Falk Butter, Matthieu Boulard, Joan Barau.
      Silencing evolutionary young retrotransposons by cytosine DNA methylation is essential for spermatogenesis, as failure to methylate their promoters leads to reactivation, meiotic failure, and infertility. How retrotransposons reactivate in the absence of DNA methylation is poorly understood. We show that upon defective DNA methylation, distinct retrotransposon families display unique expression patterns and chromatin landscapes during mouse spermatogenesis. We find that their reactivation in meiotic spermatocytes correlates with the loss of bivalent H3K4me3-H3K27me3 chromatin marks. Through proteomics and chromatin profiling, we identify NRF1 as a DNA methylation-sensitive transcription factor that transactivates unmethylated retrotransposons. Conditional germline knockout of Nrf1 in the absence of DNA methylation rescues the silencing of the most mutagenic retrotransposon in mice, namely Intracisternal A-particle or IAP. Our findings reveal that chromatin modifications together with a DNA methylation-sensitive transcription factor regulate retrotransposon expression in the absence of DNA methylation in spermatogenesis, revealing a mechanism by which retrotransposons proliferate in the germline after evading DNA methylation-based silencing.
    Keywords:  Chromatin Modifications; DNA Methylation; Germline; NRF1; Transposable Elements
    DOI:  https://doi.org/10.1038/s44319-025-00526-1
  9. Sci Transl Med. 2025 Aug 06. 17(810): eadv7834
    Circulating epigenetic signatures classifying brain insulin resistance in humans.
    Stephanie Kullmann, Amandeep Singh, Ratika Sehgal, Fabian Eichelmann, Leontine Sandforth, Britta Wilms, Markus Jähnert, Andreas Peter, Svenja Meyhöfer, Dirk Walther, Hubert Preissl, Hans-Ulrich Häring, Matthias B Schulze, Martin Heni, Andreas L Birkenfeld, Annette Schürmann, Meriem Ouni.
      Brain insulin action plays an important role in metabolic and cognitive health, but there is no biomarker available to assess brain insulin resistance in humans. Here, we developed a machine learning framework based on blood DNA methylation profiles of participants who did not have type 2 diabetes with and without brain insulin resistance and detailed metabolic phenotyping. We identified 540 DNA methylation sites (CpGs) as classifiers of brain insulin resistance in a discovery cohort (n = 167), results that were validated in two replication cohorts (n = 33 and 24) with high accuracy (83 to 94%). All 540 CpGs were differentially methylated and annotated to 445 genes mapping to neuronal development and axonogenesis processes. Methylation patterns of 98 of 540 CpGs exhibited a strong and significant (P < 0.05) blood-brain correlation, indicating that blood cells are a reliable proxy to capture brain-specific DNA methylation changes. These blood-based epigenetic signatures could potentially serve in the future for the early detection of individuals with brain insulin resistance in a broad clinical setting.
    DOI:  https://doi.org/10.1126/scitranslmed.adv7834
  10. Mol Metab. 2025 Aug 01. pii: S2212-8778(25)00137-1. [Epub ahead of print] 102230
    Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue.
    Ayushi Mittal, Paul Buscaglia, Dhiraj Srivastava, Nikolai O Artemyev, Julien A Sebag.
       OBJECTIVE: A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown.
    METHODS: Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis.
    RESULTS: We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1.
    CONCLUSION: Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking and identifies the mechanism of action of a new class of insulin sensitizers.
    Keywords:  Diabetes; GLUT4 translocation; Rac1; Unc119b; glucose tolerance; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102230
  11. Mol Med. 2025 Aug 04. 31(1): 273
    Preclinical evaluation of candidate "kill or cure" strategies to treat MFN2-related lipodystrophy.
    Ineke Luijten, Xiong Weng, Ula Kibildyte, Jana Buchan, Ami Onishi, Jake Mann, Eleanor McKay, David Savage, Robert K Semple.
       BACKGROUND: The mitofusin 2 (MFN2) R707W mutation causes debilitating human lipodystrophy featuring lower body adipose loss, upper body adipose hyperplasia, and dyslipidaemic insulin resistance. Mechanical complications include airway compromise due to head and neck adipose overgrowth. This condition, sometimes called Multiple Symmetrical Lipomatosis (MSL), is also seen in sporadic form strongly associated with excess ethanol consumption. Mitigating the cellular pathology, or, conversely, exacerbating it, inducing selective death of affected adipocytes, are potential therapeutic strategies.
    METHODS: Candidate exacerbating and mitigating approaches to MFN2-MSL were tested in human MFN2R707W/R707W fibroblasts, and in Mfn2R707W/R707W mice and derived preadipocytes. Cell survival, mitochondrial network morphology and integrated stress response markers were assessed in cells, and body composition and metabolic indices in mice.
    RESULTS: Forcing galactose metabolism in human MFN2R707W/R707W dermal fibroblasts did not replicate the overt adipose mitochondrial phenotype. 50mmol ethanol had little effect on Mfn2R707W/R707W white preadipocytes, but increased mitochondrial content and blunted mitolysosome formation in Mfn2R707W/R707W brown preadipocytes. 20% EtOH consumption increased brown adipose tissue in female Mfn2R707W/R707W mice, and serum lactate in males. Rapamycin - a candidate mitigating treatment - increased size and mitolysosome content of WT preadipocytes, and to a lesser degree of Mfn2R707W/R707W preadipocytes. In male Mfn2R707W/R707W mice, rapamycin reduced weight gain, brown adipose mass, and increased serum Fgf21. Finally, a panel of mitochondrial stressors solicited no selective death or ISR in Mfn2R707W/R707W preadipocytes.
    CONCLUSIONS: Ethanol mildly exacerbates murine MFN2-related MSL, while rapamycin is tolerated. MFN2-related MSL may not be solely attributable to compromised oxidative phosphorylation.
    Keywords:  Alcohol; Lipodystrophy; MFN2; Mitofusin; Multiple symmetrical lipomatosis; Rapamycin; Sirolimus
    DOI:  https://doi.org/10.1186/s10020-025-01314-2
  12. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2505217122
    Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species.
    Jongsun Lee, Bora Lee, Hyein Lee, Eun Ji E Kim, Sieun S Kim, Hyunwoo C Kwon, Hanseul Lee, Gee-Yoon Lee, Woojin Hong, Seokjin Ham, Jae Won Yang, Heeju Park, Tatiana M Moreno, Michelle E Brown, Hae-Eun H Park, Eunah Kim, Yoonji Jung, Eunseok Kang, Sangsoon Park, Yeo Jin Shin, Seokjun G Ha, Sujeong Kwon, Seungjae Hwang, Hyemin Min, Caroline Kumsta, Chunghun Lim, Chanhee Kang, Jinsoo Seo, Kwang-Pyo Lee, Seung-Jae V Lee.
      Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode Caenorhabditis elegans. We show that Pelota mitigates premature senescence in cultured human cells, muscle aging in mice, and neuropathology in cellular and organoid models of Alzheimer's disease. Mechanistically, we demonstrate that Pelota maintains autophagy-mediated proteostasis, by preventing the hyperactivation of mechanistic target of rapamycin signaling. Overall, our work highlights the conserved functional significance of RQC, regulated by Pelota, in extending lifespan and protecting diverse species against age-associated disease phenotypes.
    Keywords:  C. elegans; RNA quality control (RQC); aging
    DOI:  https://doi.org/10.1073/pnas.2505217122
  13. Nat Commun. 2025 Aug 07. 16(1): 7291
    Urinary Complement proteome strongly linked to diabetic kidney disease progression.
    Zaipul I Md Dom, Salina Moon, Eiichiro Satake, Daigoro Hirohama, Nicholette D Palmer, Heather Lampert, Linda H Ficociello, Amin Abedini, Karen Fernandez, Xiujie Liang, Sara Pickett, Jonathan Levinsohn, Kristina O'Neil, Simon T Dillon, Michael Mauer, Andrzej T Galecki, Barry I Freedman, Katalin Susztak, Alessandro Doria, Andrzej S Krolewski, Monika A Niewczas.
      Diabetic kidney disease (DKD) progression is not well understood. Using high-throughput proteomics, biostatistical, pathway and machine learning tools, we examine the urinary Complement proteome in two prospective cohorts with type 1 or 2 diabetes and advanced DKD followed for 1,804 person-years. The top 5% urinary proteins representing multiple components of the Complement system (C2, C5a, CL-K1, C6, CFH and C7) are robustly associated with 10-year kidney failure risk, independent of clinical covariates. We confirm the top proteins in three early-to-moderate DKD cohorts (2,982 person-years). Associations are especially pronounced in advanced kidney disease stages, similar between the two diabetes types and far stronger for urinary than circulating proteins. We also observe increased Complement protein and single cell/spatial RNA expressions in diabetic kidney tissue. Here, our study shows Complement engagement in DKD progression and lays the groundwork for developing biomarker-guided treatments.
    DOI:  https://doi.org/10.1038/s41467-025-62101-5
  14. Proc Natl Acad Sci U S A. 2025 Aug 12. 122(32): e2506534122
    CRISPR-Cas9 screening reveals microproteins regulating adipocyte proliferation and lipid metabolism.
    Victor J Pai, Huanqi Shan, Cynthia J Donaldson, Joan M Vaughan, Eduardo V De Souza, Carolyn O'Connor, Michelle Liem, Antonio F M Pinto, Jolene Diedrich, Alan Saghatelian.
      Small open reading frames (smORFs) encode microproteins that play crucial roles in various biological processes, yet their functions in adipocyte biology remain largely unexplored. In a previous study, we identified thousands of smORFs in white and brown adipocytes derived from the stromal vascular fraction of mice using ribosome profiling. Here, we expand on this work by identifying additional smORFs related to adipocytes using the in vitro 3T3-L1 preadipocyte model. To systematically investigate the functional relevance of these smORFs, we designed a custom CRISPR/Cas9 single guide RNA (sgRNA) library and screened for smORFs influencing adipocyte proliferation and differentiation. Through a dropout screen and fluorescence-assisted cell sorting of lipid droplets, we identified dozens of smORFs that regulate either cell proliferation or lipid accumulation. The smORFs on the 5'- and 3'-untranslated regions (i.e., upstream smORFs (uORFs) and downstream smORFs (dORFs)) of functional genes can exert activity through cis-regulatory effects of the main ORF on these messenger RNAs (mRNAs), such as uORFs of MDM2 that impact proliferation. However, other smORFs, especially those from mRNAs with no other ORFs, point to a functional microprotein. Indeed, we tested a candidate smORF 1183 from a long noncoding RNA 923011K14Rik and demonstrated that the microprotein regulates adipocyte differentiation. These findings highlight the potential of CRISPR/Cas9-based screening to uncover functional smORFs and provide a framework for further exploration of microproteins in adipocyte biology and metabolic regulation.
    Keywords:  CRISPR; adipogenesis; lipid; microprotein; smORF
    DOI:  https://doi.org/10.1073/pnas.2506534122
  15. Cell Metab. 2025 Aug 06. pii: S1550-4131(25)00334-1. [Epub ahead of print]
    HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes.
    Edgar Bernardo, Matías Gonzalo De Vas, Diego Balboa, Mirabai Cuenca-Ardura, Sílvia Bonàs-Guarch, Mercè Planas-Fèlix, Fanny Mollandin, Miquel Torrens-Dinarès, Miguel Angel Maestro, Javier García-Hurtado, Sonia Moratinos, Philippe Ravassard, Haiqiang Dou, Holger Heyn, Alexander van Oudenaarden, Nathalie Groen, Eelco de Koning, Christian Conrad, Roland Eils, Santiago Vernia, Patrik Rorsman, Jorge Ferrer.
      Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. HNF1A also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of A1CF, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.
    Keywords:  HNF1 homeobox A; HNF1A; MODY-3; RNA splicing; gene regulatory networks; gene transcription; genetics of diabetes; human embryonic stem cell-derived islets; human genetics; pancreatic beta cells; pancreatic islets; splicing factor networks; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.007
  16. Cell. 2025 Aug 07. pii: S0092-8674(25)00677-4. [Epub ahead of print]188(16): 4178-4212
    Brain control of energy homeostasis: Implications for anti-obesity pharmacotherapy.
    Valdemar Brimnes Ingemann Johansen, Jonas Petersen, Jens Lund, Cecilie Vad Mathiesen, Henning Fenselau, Christoffer Clemmensen.
      Despite the evolution of hardwired homeostatic mechanisms to balance food intake with energy needs, the obesity epidemic continues to escalate globally. However, recent breakthroughs in delineating the molecular signaling pathways by which neural circuits regulate consummatory behaviors, along with transformative advances in peptide-based pharmacotherapy, are fueling the development of a new generation of safe and effective treatments for obesity. Here, we outline our current understanding of how the central nervous system controls energy homeostasis and examine how emerging insights, including those related to neuroplasticity, offer new perspectives for restoring energy balance and achieving durable weight loss. Together, these advances provide promising avenues for treating obesity and managing cardiometabolic disease.
    Keywords:  anti-obesity pharmacotherapy; appetite regulation; body weight regulation; energy homeostasis; food reward; gut-brain axis; hunger; neuroendocrine control; neuroplasticity; obesity
    DOI:  https://doi.org/10.1016/j.cell.2025.06.010
  17. Cell Metab. 2025 Aug 05. pii: S1550-4131(25)00332-8. [Epub ahead of print]37(8): 1626-1628
    Foam cell-derived exosomes: Messengers between atherosclerosis and microglia.
    Yan Yue, Shiping Li, Dezhi Mu.
      Atherosclerosis (AS) is an independent risk factor for vascular cognitive impairment (VCI). Zhang et al.1 revealed that foam cell-derived exosomes transmit redox imbalance and metabolic defects to microglia via the miR-101-3p-Nrf2-Slc2a1 axis, causing microglial dysfunction and exacerbating VCI, uncovering a peripheral-brain link and potential therapeutic targets for AS-induced VCI.
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.005
  18. Mol Metab. 2025 Aug 02. pii: S2212-8778(25)00133-4. [Epub ahead of print] 102226
    Effects of β-catenin deficiency on adipose tissue physiology.
    Romina M Uranga, Akira Nishii, Jessica N Maung, Hiroyuki Mori, Brian Desrosiers, Jannis Jacobs, Keegan S Hoose, Rebecca L Schill, Devika P Bagchi, Hannah Guak, Clair Crewe, Ivo D Dinov, Erin D Giles, Carey N Lumeng, Ormond A MacDougald.
       OBJECTIVE: Compelling evidence from investigation of preclinical models and humans links canonical Wnt/β-catenin signaling to regulation of many aspects of white adipose tissue development and physiology. Dysregulation of this ancient pathway alters adiposity and metabolic homeostasis. Herein we explore how disruption of adipocyte Wnt/β-catenin signaling affects gene expression and crosstalk between cell types within adipose tissue.
    METHODS: To investigate mechanisms through which adipose tissue attempts to maintain homeostasis in the absence of β-catenin in adipocytes, we employed standard methods of metabolic phenotyping as well as bulk RNA sequencing, flow cytometry, single-cell RNA sequencing, and isolation of secreted extracellular vesicles.
    RESULTS: Our experiments reveal that male, but not female adipocyte-specific β-catenin knockout mice, Ctnnb1AdKO, have an increase in adiposity and insulin resistance. Whereas metabolic processes including fatty acid metabolism were suppressed in adipocytes, mitochondrial metabolism of immune cells was made more efficient, resulting in reduced reactive oxygen species in macrophages and dendritic cells. Deficiency of β-catenin in adipocytes altered the transcriptome of numerous stromal-vascular cell populations including adipose stem and progenitor cells, macrophages, and other immune cells. Homeostasis in white adipose tissue of Ctnnb1AdKO mice is maintained in part by elevated expression of Ctnnb1 mRNA in endothelial cells and in secreted small extracellular vesicles.
    CONCLUSIONS: Our studies demonstrate the importance of adipocyte Wnt signaling for regulation of lipid and mitochondrial metabolic processes in stromal-vascular cells and adipocytes in adipose tissues. This research provides further support for an intercellular Wnt signaling network with compensatory capability to maintain homeostasis, and underscores importance of Wnt/β-catenin signaling for understanding adipose tissue physiology and pathophysiology.
    Keywords:  Wnt signaling; adipocyte; adipose; extracellular vesicles; macrophages; mitochondria; reactive oxygen species; β-catenin
    DOI:  https://doi.org/10.1016/j.molmet.2025.102226
  19. J Clin Endocrinol Metab. 2025 Aug 04. pii: dgaf444. [Epub ahead of print]
    Tirzepatide Heralds the Hope of Chronic Disease Eradication.
    Beverly G Tchang, Sarah Barenbaum, Louis J Aronne.
      
    DOI:  https://doi.org/10.1210/clinem/dgaf444
  20. Cell. 2025 Jul 29. pii: S0092-8674(25)00733-0. [Epub ahead of print]
    Single-cell multiregion epigenomic rewiring in Alzheimer's disease progression and cognitive resilience.
    Zunpeng Liu, Shanshan Zhang, Benjamin T James, Kyriaki Galani, Riley J Mangan, Stuart Benjamin Fass, Chuqian Liang, Manoj M Wagle, Carles A Boix, Yosuke Tanigawa, Sukwon Yun, Yena Sung, Xushen Xiong, Na Sun, Lei Hou, Martin Wohlwend, Mufan Qiu, Xikun Han, Lei Xiong, Efthalia Preka, Lei Huang, William F Li, Li-Lun Ho, Amy Grayson, Julio Mantero, Alexey Kozlenkov, Hansruedi Mathys, Tianlong Chen, Stella Dracheva, David A Bennett, Li-Huei Tsai, Manolis Kellis.
      Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, yet its epigenetic underpinnings remain elusive. Here, we generate and integrate single-cell epigenomic and transcriptomic profiles of 3.5 million cells from 384 postmortem brain samples across 6 regions in 111 AD and control individuals. We identify over 1 million candidate cis-regulatory elements (cCREs), organized into 123 regulatory modules across 67 cell subtypes. We define large-scale epigenomic compartments and single-cell epigenomic information and delineate their dynamics in AD, revealing widespread epigenome relaxation and brain-region-specific and cell-type-specific epigenomic erosion signatures during AD progression. These epigenomic stability dynamics are closely associated with cell-type proportion changes, glial cell-state transitions, and coordinated epigenomic and transcriptomic dysregulation linked to AD pathology, cognitive impairment, and cognitive resilience. This study provides critical insights into AD progression and cognitive resilience, presenting a comprehensive single-cell multiomic atlas to advance the understanding of AD.
    Keywords:  Alzheimer's disease; cognitive resilience; epigenomic erosion; epigenomic information; epigenomic stability; epigenomics; exhaustion; microglial activation; regulatory network; single-cell multiomics
    DOI:  https://doi.org/10.1016/j.cell.2025.06.031
  21. Nat Commun. 2025 Aug 05. 16(1): 7214
    The RING finger E3 ligase RNF25 protects DNA replication forks independently of its canonical roles in ubiquitin signaling.
    Lilly F Chiou, Gaith N Droby, Deepika Jayaprakash, Jay R Anand, Xingyuan Zhang, Yang Yang, C Allie Mills, Thomas S Webb, Natalie K Barker, Jialiu Xie, Di Wu, Laura E Herring, Junya Tomida, Jessica L Bowser, Cyrus Vaziri.
      The DNA damage response (DDR) mechanisms that allow cells to tolerate DNA replication stress are critically important for genome stability and cell viability. Using an unbiased genetic screen, we identify a role for the RING finger E3 ubiquitin ligase RNF25 in promoting DNA replication stress tolerance. In response to DNA replication stress, RNF25-deficient cells generate aberrantly high levels of single-stranded DNA (ssDNA), accumulate in S-phase and show reduced mitotic entry. Using single-molecule DNA fiber analysis, we show that RNF25 protects reversed DNA replication forks generated by the fork remodeler HLTF from nucleolytic degradation by MRE11 and CtIP. Mechanistically, RNF25 interacts with the replication fork protection factor REV7 and recruits REV7 to nascent DNA after replication stress. The role of RNF25 in protecting replication forks is fully separable from its canonical functions in ubiquitin conjugation. This work reveals the RNF25-REV7 signaling axis as an important protective mechanism in cells experiencing replication stress.
    DOI:  https://doi.org/10.1038/s41467-025-62368-8
  22. bioRxiv. 2025 Aug 01. pii: 2025.07.29.666777. [Epub ahead of print]
    Molecular Mechanisms of Cardiomyocyte Aging.
    Dogacan Yucel, Michael A Trembley, Qingen Ke, Zexuan Wu, Peter Kang, William T Pu.
      Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced representation bisulfite sequencing to delineate the cellular and molecular landscape of CM aging in mice. Our analysis revealed significant age-associated changes in CM physiology, including hypertrophy, fibrosis, and diastolic dysfunction. We uncovered dramatic epigenetic remodeling in aged CMs, characterized by increased chromatin accessibility and altered DNA methylation patterns. Overexpression of the DNA methylase DNMT3A in young adult mouse hearts recapitulated key features of the aged heart phenotype, establishing DNA hypermethylation as a significant regulator of age-related CM function. Furthermore, ESRRG, an orphan nuclear receptor, functions as a mediator of diastolic function in the heart. Its overexpression significantly improved diastolic function and reduced expression of a non-coding RNA that is upregulated in aged CMs. These novel insights into the molecular mechanisms underlying cardiac aging identify molecular regulators involved in age-associated cardiac remodeling.
    DOI:  https://doi.org/10.1101/2025.07.29.666777
  23. Nat Cell Biol. 2025 Aug 06.
    Noncatalytic telomerase function in inflammation.
    Jing Ye, Eric Gilson.
      
    DOI:  https://doi.org/10.1038/s41556-024-01497-6
  24. Nat Aging. 2025 Aug 05.
    Refining the generation, interpretation and application of multi-organ, multi-omics biological aging clocks.
    Junhao Wen.
      Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi-organ proteome-based biological age gaps (ProtBAGs) using 2,448 plasma proteins from 43,498 participants in the UK Biobank. Here I highlight methodological and clinical considerations for developing and using these clocks, including correction for age bias, organ specificity of proteins, sample size and underlying pathologies in the training data, which can affect model generalizability and clinical interpretability. In addition, I integrated 11 ProtBAGs with previously developed nine multi-organ phenotype-based biological age gaps to investigate genetic overlap and causal associations with disease endpoints. Finally, I show that incorporating features across organs improves predictions for systemic disease categories and all-cause mortality. These analyses provide methodological and clinical insights for developing and interpreting these clocks and highlight future avenues toward a multi-organ, multi-omics biological aging clock framework.
    DOI:  https://doi.org/10.1038/s43587-025-00928-9
  25. Cell. 2025 Jul 31. pii: S0092-8674(25)00806-2. [Epub ahead of print]
    Identification of gut microbial bile acid metabolic enzymes via an AI-assisted pipeline.
    Yong Ding, Xi Luo, Jiasheng Guo, Baiying Xing, Haoyu Lin, Haohan Ma, Yicun Wang, Meng Li, Chuan Ye, Sen Yan, Kangjie Lin, Jinxin Zhang, Yingying Zhuo, Qixing Nie, Donghui Yang, Zhipeng Zhang, Yanli Pang, Kai Wang, Ming Ma, Luhua Lai, Changtao Jiang.
      The modifications of bile acids (BAs) are fundamental to their role in host physiology and pathology. Identifying their synthetases is crucial for uncovering the diversity of BAs and developing targeted interventions, yet it remains a significant challenge. To address this hurdle, we developed an artificial intelligence (AI)-assisted workflow, bile acid enzyme announcer unit tool (BEAUT), which predicted over 600,000 candidate BA metabolic enzymes that we compiled into the human generalized microbial BA metabolic enzyme (HGBME) database (https://beaut.bjmu.edu.cn). We identified a series of uncharacterized BA enzymes, including monoacid acylated BA hydrolase (MABH) and 3-acetoDCA synthetase (ADS). Notably, ADS can produce an unreported skeleton BA, 3-acetoDCA, with a carbon-carbon bond extension. After determining its bacterial source and catalytic mechanism, we found that 3-acetoDCA is widely distributed among populations and regulates the microbial interactions in the gut. In conclusion, our work offers alternative insights into the relationship between microbial BAs and the host from an enzymatic perspective.
    Keywords:  3-acetoDCA; ADS; MABH; artificial intelligence; bile acid; biosynthesis enzyme; gut microbiota
    DOI:  https://doi.org/10.1016/j.cell.2025.07.017
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