bims-obesme Biomed News
on Obesity metabolism
Issue of 2026–06–14
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.
  2. Charting human cellular senescence in aging and disease.
  3. Mitochondria-ER contacts function as an iron supply hub.
  4. A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
  5. SenCat: Cataloging human cell senescence through multi-omic profiling of multiple senescent primary cell types.
  6. Role of autophagy in adipose tissue: Implications for metabolic health.
  7. SUMOylation-driven nuclear translocation of HSF2BP alleviates MASLD via COX6A1-dependent mitochondrial reprogramming.
  8. Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is reversed by metformin.
  9. Genetics of MASLD: a diabetes perspective.
  10. Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
  11. A damage accumulation model identifies distinct aging regimes across species.
  12. Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.
  13. Cell-to-cell variability and gain of methylation at polycomb CpG islands as a hallmark of aging.
  1. Sci Adv. 2026 Jun 12. 12(24): eaec8873
    SUCNR1 coordinates metabolic flux, mitochondrial function, and nutrient-dependent adaptation in hepatocytes.
    Anna Marsal-Beltran, Laura Salmerón-Pelado, Aleix Ribas-Latre, Maria Repollés-de-Dalmau, M-Mar Rodríguez-Peña, Catalina Núñez-Roa, Joan Badia, Ana Madeira, Eva Novoa, Marc Beltrà, Ana Belén Plata-Gómez, Jordi Capellades, Joan Carles Escolà-Gil, Antonio Zorzano, Óscar Yanes, Alejo Efeyan, Ruben Nogueiras, Jordi Gracia-Sancho, Joan Vendrell, Victòria Ceperuelo-Mallafré, Sonia Fernández-Veledo.
      Succinate, a mitochondrial metabolite, also functions as an extracellular signal through its receptor succinate receptor 1 (SUCNR1), coordinating responses to nutrient availability. The physiological role of SUCNR1 within hepatocytes, however, is unclear. We show that hepatic succinate levels and Sucnr1 expression are dynamically regulated by nutritional status. Mice lacking Sucnr1 in hepatocytes [Hep-Sucnr1 knockout (KO)] exhibit a fasting-like phenotype characterized by enhanced gluconeogenesis, elevated amino acids, and impaired metabolic flexibility. Mechanistically, loss of Sucnr1 compromises glucose-derived oxidative flux through the tricarboxylic acid cycle, increases reliance on glutamine-dependent anaplerosis, and induces mitochondrial stress adaptations. Upon refeeding, Hep-Sucnr1 KO mice show blunted mammalian target of rapamycin activation, incomplete glycogen restoration, and an altered hepatic proteomic response. Sucnr1 expression increases during liver maturation, is enriched in pericentral hepatocytes, and its loss is associated with functional reprogramming of pericentral metabolic functions without disruption of zonation. Together, our findings establish SUCNR1 as a critical regulator of hepatic metabolic adaptation, linking succinate signaling to mitochondrial flexibility and nutrient-dependent metabolic responses.
    DOI:  https://doi.org/10.1126/sciadv.aec8873
  2. Cell. 2026 Jun 11. pii: S0092-8674(26)00587-8. [Epub ahead of print]189(12): 3501-3505
    Charting human cellular senescence in aging and disease.
    NIH SenNet consortium
      Cellular senescence comprises diverse cell states emerging across human tissues during aging and disease. Integrating single-cell and spatial multi-omics with AI-driven analyses enables systematic mapping of senescent cell heterogeneity ("senotypes"), revealing tissue-specific programs and microenvironmental interactions. These advances provide frameworks for biomarker discovery and development of targeted senotherapeutic strategies.
    DOI:  https://doi.org/10.1016/j.cell.2026.05.028
  3. Nat Cell Biol. 2026 Jun 10.
    Mitochondria-ER contacts function as an iron supply hub.
    Hijiri Oshio, Isshin Shiiba, Naoki Ito, Naozumi Okada, Fuya Yamaguchi, Yuto Ishikawa, Shun Nagashima, Yuuta Fujikawa, Keitaro Umezawa, Yuri Miura, Misaki Shimizu, Yoshiro Saito, Tomoyuki Yamaguchi, Ryoko Inatome, Shigeru Yanagi.
      Mitochondrial iron dynamics are essential for cellular respiration and metabolic homeostasis, yet the molecular mechanisms governing iron supply to mitochondria remain poorly understood. Here we identify a pathway in which haem serves as an iron source for mitochondria, maintaining mitochondrial iron homeostasis and mitochondrial supercomplex integrity, regulated at mitochondria-endoplasmic reticulum contact sites (MERCs). We demonstrate that haem oxygenase 2 (HMOX2), an ER-resident enzyme, is also localized to MERCs and facilitates the supply of haem-derived iron to mitochondria. This process is orchestrated by the mitochondrial ubiquitin ligase MITOL (also known as MARCH5/MARCHF5), which ubiquitinates HMOX2 at K68 with K63-linked polyubiquitin chains, enhancing its haem-degrading activity. Notably, loss of HMOX2 or disruption of MITOL-mediated ubiquitination impairs mitochondrial iron homeostasis and mitochondrial respiration. These findings establish a paradigm in which MERCs function as an iron supply hub, integrating haem metabolism with mitochondrial iron utilization.
    DOI:  https://doi.org/10.1038/s41556-026-01974-0
  4. Sci Adv. 2026 Jun 12. 12(24): eadz1953
    A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
    Chrysovalantou E Xirouchaki, Esther García-Domínguez, Eamon Coughlan, Meagan J McGrath, Saveen Giri, Shuwei Liang, Florian Wiede, Anne Bigot, Junichi Sadoshima, Maria C Gomez-Cabrera, Andrew Philp, Marcus Moberg, William Apró, William Roman, Christina A Mitchell, Tony Tiganis.
      A decline in nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.adz1953
  5. Mol Cell. 2026 Jun 11. pii: S1097-2765(26)00323-0. [Epub ahead of print]
    SenCat: Cataloging human cell senescence through multi-omic profiling of multiple senescent primary cell types.
    Carlos Anerillas, Gisela Altés, Katarina Gresova, Dimitrios Tsitsipatis, Krystyna Mazan-Mamczarz, Reema Banarjee, Ana S G Cunningham, Martin Salamini-Montemurri, Jen-Hao Yang, Rachel Munk, Martina Rossi, Yulan Piao, Bradley Olinger, Quinn Strassheim, Jennifer L Martindale, Jinshui Fan, Chang-Yi Cui, Supriyo De, Delaney V Rutherford, Ying Hao, Ziyi Li, Jessica Roberts, Yue Andy Qi, Kotb Abdelmohsen, Rafael de Cabo, Allison B Herman, Manolis Maragkakis, Nathan Basisty, Myriam Gorospe.
      There is an urgent need to comprehensively catalog senescence markers across cell types in an organism in order to characterize senescent-cell heterogeneity. Here, we profiled the transcriptomes and proteomes in 14 different primary human cell types undergoing over 30 senescence paradigms to create a senescence catalog we termed "SenCat." We found that while senescent cells from all primary cell types did not share a single unique marker, they did activate shared specific metabolic and damage-response pathways implicated in tissue repair. Moreover, machine-learning-refined SenCat signatures enabled senescence scoring and identification across multiple human and mouse datasets, both at bulk and single-cell levels. In sum, SenCat represents a much-needed resource to identify senescence across multiple cell types and tissues in the body.
    Keywords:  aging; machine learning; mass spectrometry; proteomics; senolytics; senotype; single-nuclei RNA-sequencing; transcriptomics
    DOI:  https://doi.org/10.1016/j.molcel.2026.05.017
  6. Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00121-2. [Epub ahead of print]403 145-176
    Role of autophagy in adipose tissue: Implications for metabolic health.
    Núria Borràs-Ferré, Antonio Zorzano, Montserrat Romero.
      Autophagy is increasingly considered a key regulator of adipose tissue biology, with growing evidence linking this cellular degradation pathway to crucial aspects of metabolic health. In recent years, research has revealed that autophagy influences adipocyte differentiation, lipid handling, mitochondrial quality control, and inflammatory responses within adipose depots. These functions are essential for maintaining the plasticity and functionality of both white and brown adipose depots. As our understanding of how autophagy shapes fat tissue dynamics grows, this process is emerging as a promising target for treating obesity and related metabolic disorders. Future clinical applications may involve precision therapeutics that combine pharmacological, dietary, and genetic tools to modulate autophagy in an adipose tissue-specific and personalized manner. In this review, we summarize current knowledge of the role of autophagy in adipose tissue physiology and its impact on systemic metabolism. We also discuss how autophagy dysregulation contributes to metabolic diseases such as obesity and insulin resistance, and therefore its potential use as a therapeutic target in clinical practice.
    Keywords:  Adipose tissue; Autophagy; Endosomes; Metabolism
    DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.015
  7. Cell Death Dis. 2026 Jun 08.
    SUMOylation-driven nuclear translocation of HSF2BP alleviates MASLD via COX6A1-dependent mitochondrial reprogramming.
    Mengzhou Wang, Xiaoning Wu, Tao Wang, Wuming Liu, Yuanyuan Zhang, Lin Zhang, Junzhou Zhao, Guozhi Yin, Wei Yang, Zheng Wu, Yi Lyu, Rongqian Wu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) remains a major global health burden with limited therapeutic options. Heat shock factor 2 binding protein (HSF2BP), originally characterized as a germ cell-specific regulator of meiosis, is significantly upregulated in both MASLD patient livers and high-fat diet (HFD)-fed mice. Here, we identify HSF2BP as a key metabolic regulator in hepatocytes that alleviates hepatic lipid accumulation by enhancing mitochondrial function. Hepatocyte-specific overexpression of HSF2BP improves glucose tolerance, reduces lipid deposition, and increases mitochondrial respiration, whereas its knockout exacerbates steatosis. Mechanistically, we show that HSF2BP undergoes SUMOylation through interaction with UBC9, promoting its nuclear translocation and triggering an upregulation of COX6A1, a core subunit of mitochondrial complex IV. This process is impaired in MASLD due to global suppression of hepatic SUMOylation. Pharmacological inhibition of SUMOylation using TAK-981 abolishes the protective effect of HSF2BP against hepatic steatosis, whereas enhancing SUMOylation through UBC9 overexpression or treatment with the SUMO activator N106 markedly ameliorates lipid accumulation in the liver. Collectively, our findings uncover a SUMOylation-dependent mechanism by which HSF2BP regulates mitochondrial integrity and lipid homeostasis, providing a promising therapeutic axis for MASLD.
    DOI:  https://doi.org/10.1038/s41419-026-08935-3
  8. Nat Aging. 2026 Jun 09.
    Single-nucleus interrogation of primate small intestinal aging reveals NCoR1 decline as a conserved feature that is reversed by metformin.
    Jingyi Li, Xiaoyong Lu, Tianhong Tong, Xin Zhou, Baohu Zhang, Xiaoyan Sun, Bing Zhao, Gang Xu, Jinjiang Yang, Yanling Fan, Jianli Hu, Haoteng Yan, Zhejun Ji, Mingheng Li, Shanshan Che, Yuanhan Yang, Yingjie Ding, Qiaoran Wang, Shuhui Sun, Shuai Ma, Si Wang, Juan Carlos Izpisua Belmonte, Jing Qu, Weiqi Zhang, Guang-Hui Liu.
      How the small intestine ages at the cellular and molecular level has been unclear. Here we profile single nuclei from young and aged primate small intestine and find that aging brings barrier dysfunction, chronic inflammation and a shift in stem cell differentiation away from absorptive cells toward secretory cells. Through integrative multimodal analysis, we identify the transcriptional corepressor NCoR1 as a key player whose decline is conserved in the aging human gut. In human intestinal epithelial cells and organoids, knocking down NCOR1 recapitulates aging phenotypes including senescence, disrupted junctions and lineage imbalance, whereas overexpressing NCoR1 alleviates them. Metformin-a geroprotective drug-restores NCoR1 levels and delays intestinal aging in nonhuman primates. Our work points to NCoR1 as a central regulator of small intestinal aging and suggests a pharmacologically actionable strategy to counter age-related intestinal decline.
    DOI:  https://doi.org/10.1038/s43587-026-01131-0
  9. Diabetologia. 2026 Jun 08.
    Genetics of MASLD: a diabetes perspective.
    Josh Bilson, Hanieh Yaghootkar.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in people with type 2 diabetes and represents a major contributor to liver-related and extrahepatic morbidity and mortality. Despite this strong epidemiological overlap, the clinical course of MASLD in diabetes is highly heterogeneous and not fully explained by conventional metabolic risk factors. Human genetic studies have provided important insights into this variability by revealing that hepatic steatosis and its downstream consequences can arise through biologically distinct pathways. Genome-wide association studies have identified multiple genetic loci influencing liver fat accumulation, disease severity and progression. These loci implicate diverse mechanisms, including liver-intrinsic defects in lipid handling, enhanced hepatic lipogenesis, and systemic metabolic dysfunction related to insulin resistance and adipose tissue biology. Genetic evidence indicates that similar degrees of hepatic steatosis may therefore reflect different underlying biological processes, with differing implications for glycaemic management, cardiovascular risk and liver disease progression. In this review, we examine the genetic architecture of hepatic steatosis and MASLD in the context of diabetes. We discuss evidence from family studies, genome-wide association analyses, imaging genetics and Mendelian randomisation, with an emphasis on cautious causal interpretation. We also explore gene-diabetes and gene-environment interactions that modify disease expression and may contribute to variability in clinical outcomes and treatment response. Finally, we consider the translational implications of MASLD genetics, including risk stratification, therapeutic target discovery and emerging genotype-informed approaches to clinical management. We highlight key research gaps, particularly the need for ancestry-diverse studies, improved phenotyping in diabetes populations, and integration of genetic analyses into prospective clinical trials. Together, current genetic evidence supports a mechanism-based framework for understanding MASLD heterogeneity in diabetes and provides a foundation for more precise approaches to risk assessment and management.
    Keywords:  Genetics; Liver fat; MASLD; Metabolic dysfunction-associated steatotic liver disease; Review; Type 2 diabetes
    DOI:  https://doi.org/10.1007/s00125-026-06759-6
  10. Nat Commun. 2026 Jun 12.
    Nitrate-Sialin2 axis couples ER-mitochondrial calcium signaling with fatty acid metabolism to drive white adipose browning.
    Ou Jiang, Zichen Cao, Sihan Kong, Qibing Wu, Tianyi Zhang, Xinyue Chen, Bo Zhou, Yao Feng, Songyue Wu, Jinsong Wang, Mo Chen, Xiaoyu Li, Songlin Wang.
      White adipose browning is a promising route to restore energy balance; however, how inorganic anion signals engage intracellular organelle networks to drive this process remains unclear. Here, we identify Sialin2 as a nitrate sensor that converts dietary nitrate into a spatially confined thermogenic program by coupling ER-mitochondria Ca2+ transfer with lipid routing into mitochondrial oxidation. Sialin2 localizes to mitochondria and the endoplasmic reticulum (ER), where it strengthens ER-mitochondria contacts and engages the inositol 1,4,5-trisphosphate receptor type 1 (IP3R1)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter 1 (MCU1) conduit to enhance inducible mitochondrial Ca2+ uptake. In parallel, Sialin2 associates with lysosomal acid lipase (LIPA), acyl-CoA synthetase long-chain family member 3 (ACSL3), and carnitine palmitoyltransferase 1 A (CPT1A) to channel lipid-droplet-derived fatty acids into β-oxidation, thereby fueling the tricarboxylic acid cycle and uncoupling protein 1 (UCP1)-dependent respiration. Loss of Slc17a5 abolishes nitrate-evoked browning and metabolic benefits, whereas nitrate supplementation improves adipose thermogenesis and systemic metabolic indices in male mice with diet-induced obesity without adrenergic stimulation. Together, these findings identify an organelle-specific nitrate-sensing mechanism that couples inorganic anion signalling to substrate routing in adipocytes and establish a non-hormonal pathway for restoring metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s41467-026-74256-w
  11. Nat Aging. 2026 Jun 09.
    A damage accumulation model identifies distinct aging regimes across species.
    Naveh Raz, Yifan Yang, Glen Pridham, Ben Shenhar, Shachaf Frenkel, Tomer Levy, Tsvi Tlusty, Avi Mayo, Uri Alon.
      Different species age in similar ways but their lifespans differ by orders of magnitude. It is not clear how these similarities and differences arise from the accumulation of damage that underlies aging. Does long lifespan arise from reduced damage production, increased removal or enhanced robustness to damage? Here we apply the saturating removal model-a stochastic model of damage accumulation and removal-and fit it to survival data from well-studied species. Several parameters have near-universal values including ratios of removal rate, noise amplitude and death threshold. The model parameter that best predicts lifespan is the damage production rate, which spans seven orders of magnitude. We identify two distinct aging regimes: ballistic aging where damage production outpaces removal, characterizing yeast, nematodes, flies and mice, and quasi-steady-state aging, where damage tracks a moving set point of balanced production and removal, characterizing humans, dogs, guinea pigs and cats. These results provide a mechanistic model-based basis of comparative aging that awaits experimental validation.
    DOI:  https://doi.org/10.1038/s43587-026-01138-7
  12. Stem Cell Reports. 2026 Jun 11. pii: S2213-6711(26)00169-4. [Epub ahead of print] 102958
    Scalable hypothalamic neuron differentiation from human pluripotent stem cells suitable for modeling metabolic disorders.
    Vukasin M Jovanovic, Narisu Narisu, Lori L Bonnycastle, David Castellano, Seungmi Ryu, Ravi Tharakan, Kendall T Mesch, Qiang Chen, Fahrünisa Meryem Betül Erol, Hannah J Glover, Tingfen Yan, Neelam Sinha, Chaitali Sen, Shu Yang, Dvir Blivis, Daniel F Bennett, Giovanni Rosales-Soto, Jason Inman, Pinar Ormanoglu, Christopher A LeClair, Natalie D Shaw, Menghang Xia, Martin Schneider, Erick O Hernandez-Ochoa, Michael R Erdos, Anton Simeonov, Shuibing Chen, Francis S Collins, Claudia A Doege, Carlos A Tristan.
      The hypothalamus, composed of multiple nuclei, is essential for maintaining the body's homeostasis. Within the mediobasal hypothalamus, the arcuate nucleus (ARC) contains key neuronal populations, including appetite-suppressing pro-opiomelanocortin (POMC) neurons that regulate energy and glucose balance. Here, we present a chemically defined, scalable method for differentiating human pluripotent stem cells (hPSCs) into hypothalamic neurons enriched for POMC cells, compatible with robotic cell culture platforms for high-throughput use. Neuronal identity was validated by MERFISH single-cell transcriptomics, RNA-Seq, ATAC-Seq, and comparison to human hypothalamus. The method is robust across multiple hPSC lines, showing consistent induction of ventral diencephalon and hypothalamic markers. Derived neurons display metabolic disease-relevant features, including body mass index (BMI)-associated gene enrichment, and ATAC-Seq identifies potential candidate regulatory regions linked to hypothalamic development and metabolic traits. Functional assays reveal neuronal responses to insulin and the GLP-1 receptor agonist Exendin-4, and transcriptional responses to altered glucose conditions. This platform delivers a physiologically relevant model of human hypothalamic neurons that enables deeper mechanistic and therapeutic studies of metabolic disease.
    Keywords:  GLP1R agonist; GnRH neurons; POMC neurons; automated biomanufacturing; human hypothalamus; iPSC; insulin; metabolic disease modeling; obesity; pluripotent stem cells; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102958
  13. Nat Commun. 2026 Jun 09.
    Cell-to-cell variability and gain of methylation at polycomb CpG islands as a hallmark of aging.
    Hagit Masika, Shmuel Ruppo, Stephen J Clark, Marc Jan Bonder, Ferdinand von Meyenn, Merav Hecht, Shari Orlanski, Efrat Katsman, Oriya Vardi-Yaakov, Abraham Zlotogorski, Tahel Fachler-Sharp, Sharona Elgavish, Yuval Dor, Wolf Reik, Tommy Kaplan, Howard Cedar.
      Aging is a complex multifactorial process that affects cellular function and tissue homeostasis over time. Despite substantial research, the molecular mechanisms driving cellular aging remain poorly understood. Many studies focused on changes in DNA methylation as an indicator of aging. In particular, methylation at polycomb CpG islands was shown to be predictive of phenotypic changes associated with aging. Since many age-related pathological processes are thought to originate from single cells, we asked whether polycomb CpG island methylation occurs preferentially in a subset of cells within a population. Using single-cell whole-genome methylation data across ages and tissues, we identify polycomb CpG methylation as a hallmark of cellular aging. This revealed that aging occurs at varying rates, with faster proliferating cells showing accelerated gain of methylation. Differential gene expression analysis identified changes in immune response, translation, tumorigenesis and neurodegeneration. These results challenge traditional models of homogeneous cellular aging and suggest that aging is a highly individualized process at the single-cell level, that may be driven by programmed changes in polycomb CpG island DNA methylation.
    DOI:  https://doi.org/10.1038/s41467-026-74118-5
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