bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–06–08
thirteen papers selected by
Xiong Weng, University of Edinburgh
  1. MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT.
  2. Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity.
  3. Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
  4. Analysis of Epigenome-Wide Association Studies.
  5. Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
  6. Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.
  7. Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions.
  8. Is taurine an aging biomarker?
  9. Editing epigenetic age.
  10. HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes.
  11. Testing the carbohydrate-insulin model: Some aspects are consistent, but overall the data do not support the model.
  12. Gut microbial conversion of dietary elderberry extract to hydrocinnamic acid improves obesity-associated metabolic disorders.
  13. ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
  1. Nat Commun. 2025 May 31. 16(1): 5063
    MACanalyzeR scRNAseq analysis tool reveals PPARγHIGH/GDF15HIGH lipid-associated macrophages facilitate thermogenic expansion in BAT.
    Andrea Ninni, Fabio Zaccaria, Luca Verteramo, Francesca Sciarretta, Loreana Sanches Silveira, José Cesar Rosa-Neto, Simone Carotti, Lorenzo Nevi, Paolo Grumati, Satish Patel, Giulia Carrera, Alessandro Sgambato, Donatella Lucchetti, Filomena Colella, Ilenia Severi, Martina Senzacqua, Antonio Giordano, Sergio Bernardini, Claudia Di Biagio, Flavia Tortolici, Giuseppe Rizzo, Clement Cochain, Valerio Chiurchiù, Stoyan Ivanov, Beiyan Zhou, Jesse W Williams, David B Savage, Katia Aquilano, Daniele Lettieri-Barbato.
      Macrophages are key regulators of adipose tissue plasticity. Obesity impairs brown adipose tissue (BAT) function in humans, yet macrophage-mediated mechanisms remain elusive. Here, we introduce MACanalyzeR, a single-cell RNA sequencing (scRNAseq) tool designed for comprehensive monocyte/macrophage metabolic profiling. Applying MACanalyzeR to BAT from obese male murine models (db/db and HFD-fed mice), we identify lipid-associated macrophages (LAMs) with foamy characteristics. Unlike db/db BAT LAMs, those in HFD BAT correlate with thermogenic gene expression and PPAR signaling activation. A distinct PpargHIGH LAM subcluster progressively accumulates in thermogenically active BAT. Macrophage-specific Pparg depletion disrupts BAT thermogenesis, inducing a white-like phenotype and metabolic dysfunctions. Mechanistically, PpargHIGH LAMs secrete GDF15, a key regulator of BAT identity and lipid metabolism under high-energy demand. Our study establishes MACanalyzeR as a powerful tool for immunometabolic interrogation and identifies PpargHIGH LAMs as critical mediators of BAT homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-60295-2
  2. J Clin Invest. 2025 May 30. pii: e190765. [Epub ahead of print]
    Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity.
    Brian I Park, Andrew R Reeves, Ying Zhu, Robin A Wilson, Sophia C Fernandes, Kimberly K Buhman, Kelli A Lytle, Michael D Jensen, Andrew S Greenberg.
      Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.
    Keywords:  Adipose tissue; Endocrinology; Insulin; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI190765
  3. Nat Metab. 2025 Jun 03.
    Cysteine depletion triggers adipose tissue thermogenesis and weight loss.
    Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Prabhakar Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Bandy Chen, Maxim N Artyomov, Fahmeed Hyder, Tamas L Horvath, Marc Schneeberger, Yuki Sugiura, Vishwa Deep Dixit.
      Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
    DOI:  https://doi.org/10.1038/s42255-025-01297-8
  4. Methods Mol Biol. 2025 ;2885 717-725
    Analysis of Epigenome-Wide Association Studies.
    Piyush Gampawar, Edith Hofer, Nerea Alonso.
      Epigenome-wide association studies (EWAS) investigate epigenetic modifications across the genome in relation to phenotypes of interest. The most commonly studied epigenetic modification in EWAS is DNA methylation, particularly at cytosine-phosphate-guanine (CpG) sites. Despite its potential, few EWAS have been conducted in bone diseases, and replication studies remain limited. Similar to genome-wide association studies, EWAS require rigorous steps for quality control of both samples and probes to ensure reliable results. Association analyses can focus on individual differentially methylated probes or adopt a regional approach to identify differentially methylated regions, providing insights into epigenetic contributions to disease.
    Keywords:  Bioinformatics; DNA methylation; EWAS; Quality control
    DOI:  https://doi.org/10.1007/978-1-0716-4306-8_35
  5. Nat Commun. 2025 Jun 04. 16(1): 5206
    Brown adipose tissue secretes OLFM4 to coordinate sensory and sympathetic innervation via Schwann cells.
    Mingqiang Lai, Wu Zhou, Wenchong Zou, Lianlian Qiu, Zhaoyu Liang, Wanyi Chen, Yiqing Wang, Bin Guo, Chaoran Zhao, Sheng Zhang, Pinglin Lai, Le Hu, Xiaolin Liu, Yu Jiang, Yinghua Chen, Min-Jun Huang, Xiaochun Bai, Zhipeng Zou.
      Non-shivering thermogenesis of brown adipose tissue (BAT) is tightly controlled by neural innervation. However, the underlying mechanism remains unclear. Here, we reveal that BAT regulates its own thermoadaptive innervation by crosstalk with Schwann cells (SCs). Loss of Olfm4 (encoding Olfactomedin-4), a risk gene in human obesity, causes BAT dysfunction and reduces whole-body thermogenesis, predisposing to obesity in mice. Mechanistically, BAT-derived OLFM4 traps Noggin, an endogenous inhibitor of BMPs, liberating BMP7-BMPR1B signaling to promote SC differentiation. Conversely, Olfm4 loss reduced BMP7 signaling in mature SCs, leading to MEK/ERK-dependent dedifferentiation and dysfunction, ultimately impairing both sensory and sympathetic innervation. Thermoneutrality exposure reduces Olfm4 expression in BAT, resulting in a similar phenotype. MEK/ERK inhibition, ERK1 depletion, or cold exposure reverses this SC dedifferentiation, enhancing resistance to obesity. These findings suggest that this neurotrophic BAT-SC crosstalk controls thermoadaptive BAT innervation. Reactivating OLFM4 signaling may be a promising therapeutic strategy for obesity and related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60474-1
  6. Nat Commun. 2025 May 31. 16(1): 5059
    Charting unknown metabolic reactions by mass spectrometry-resolved stable-isotope tracing metabolomics.
    Yang Gao, Mingdu Luo, Hongmiao Wang, Zhiwei Zhou, Yandong Yin, Ruohong Wang, Beizi Xing, Xiaohua Yang, Yuping Cai, Zheng-Jiang Zhu.
      Metabolic reactions play important roles in organisms such as providing energy, transmitting signals, and synthesizing biomacromolecules. Charting unknown metabolic reactions in cells is hindered by limited technologies, restricting the holistic understanding of cellular metabolism. Using mass spectrometry-resolved stable-isotope tracing metabolomics, we develop an isotopologue similarity networking strategy, namely IsoNet, to effectively deduce previously unknown metabolic reactions. The strategy uncovers ~300 previously unknown metabolic reactions in living cells and mice. Specifically, we elaborately chart the metabolic reaction network related to glutathione, unveiling three previously unreported reactions nestled within glutathione metabolism. Among these, a transsulfuration reaction, synthesizing γ-glutamyl-seryl-glycine directly from glutathione, underscores the role of glutathione as a sulfur donor. Functional metabolomics studies systematically characterize biochemical effects of previously unknown reactions in glutathione metabolism, showcasing their diverse functions in regulating cellular metabolism. Overall, these newly uncovered metabolic reactions fill gaps in the metabolic network maps, facilitating exploration of uncharted territories in cellular biochemistry.
    DOI:  https://doi.org/10.1038/s41467-025-60258-7
  7. Nat Commun. 2025 Jun 05. 16(1): 5223
    Investigating the sources of variable impact of pathogenic variants in monogenic metabolic conditions.
    Angela Wei, Richard Border, Boyang Fu, Sinéad Cullina, Nadav Brandes, Seon-Kyeong Jang, Sriram Sankararaman, Eimear E Kenny, Miriam S Udler, Vasilis Ntranos, Noah Zaitlen, Valerie A Arboleda.
      Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMe Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.
    DOI:  https://doi.org/10.1038/s41467-025-60339-7
  8. Science. 2025 Jun 05. 388(6751): eadl2116
    Is taurine an aging biomarker?
    Maria Emilia Fernandez, Michel Bernier, Nathan L Price, Simonetta Camandola, Miguel A Aon, Kelli Vaughan, Julie A Mattison, Joshua D Preston, Dean P Jones, Toshiko Tanaka, Qu Tian, Marta González-Freire, Luigi Ferrucci, Rafael de Cabo.
      Low circulating taurine concentrations have been proposed as a driver of the aging process. We found that circulating taurine concentrations increased or remained unchanged with age in three geographically distinct human cohorts as well as in nonhuman primates and mice when measured longitudinally (repeatedly in the same population) or cross-sectionally (sampling distinct populations at various ages). Moreover, considerable variability was observed in associations between taurine and age-related changes in health outcomes pertaining to gross motor function and energy homeostasis. Our results suggest that changes in circulating taurine are not a universal feature of aging and that its pleiotropic effects may be dependent on the temporal and physiological context of each individual.
    DOI:  https://doi.org/10.1126/science.adl2116
  9. Nat Aging. 2025 Jun 02.
    Editing epigenetic age.
    Bastiaan T Heijmans.
      
    DOI:  https://doi.org/10.1038/s43587-025-00893-3
  10. Elife. 2025 Jun 03. pii: RP103663. [Epub ahead of print]13
    HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes.
    Hongchen Li, Xinchao Zhang, Xiaoben Liang, Shuyan Li, Ziyi Cui, Xinyu Zhao, Kai Wang, Bingbing Zha, Haijie Ma, Ming Xu, Lei Lv, Yanping Xu.
      The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and TET2 knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the FBP1 promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
    Keywords:  FBP1; HNF4α; TET2; cell biology; diabetes; gluconeogenesis; mouse
    DOI:  https://doi.org/10.7554/eLife.103663
  11. Cell Metab. 2025 Jun 03. pii: S1550-4131(25)00221-9. [Epub ahead of print]37(6): 1241-1242
    Testing the carbohydrate-insulin model: Some aspects are consistent, but overall the data do not support the model.
    John R Speakman, Ying Liu.
      
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.011
  12. bioRxiv. 2025 May 18. pii: 2025.05.18.654739. [Epub ahead of print]
    Gut microbial conversion of dietary elderberry extract to hydrocinnamic acid improves obesity-associated metabolic disorders.
    Sara Alqudah, Beckey DeLucia, Lucas J Osborn, Rachel L Markley, Viharika Bobba, Sarah M Preston, Tharika Thambidurai, Layan Hamidi Nia, Clifton G Fulmer, Naseer Sangwan, Ina Nemet, Jan Claesen.
      Obesity-associated metabolic disorders such as type 2 diabetes mellitus and metabolic dysfunction associated fatty liver disease are major global health concerns, yet current pharmacological treatments often present with major side-effects. Dietary interventions including polyphenol-rich foods offer a promising complementary option for obesity amelioration, but their efficacy is dependent on specific gut microbial metabolism and the underlying molecular mechanisms mostly remain elusive. Here, we demonstrated that dietary elderberry (Eld) extract abrogates the effects of an obesogenic diet in a gut microbiota-dependent manner, by preventing insulin resistance and reducing hepatic steatosis in mice. We developed a targeted, quantitative liquid chromatography-tandem mass spectrometry method for detection of gut bacterial polyphenol catabolites and identified hydrocinnamic acid as a key microbial metabolite, enriched in the portal vein plasma of Eld supplemented animals. Next, we showed that hydrocinnamic acid potently activates hepatic AMP-activated protein kinase α, explaining its role in improved liver lipid homeostasis. Furthermore, we uncovered the metabolic pathway cumulating in hydrocinnamic acid production in the common gut commensal Clostridium sporogenes . Our characterization of hydrocinnamic acid as a diet-derived, and microbiota-dependent metabolite with insulin-sensitizing and anti-steatotic activities will contribute to microbiome-targeted dietary interventions to prevent and treat obesity-associated metabolic diseases.
    DOI:  https://doi.org/10.1101/2025.05.18.654739
  13. Nat Commun. 2025 Jun 03. 16(1): 5133
    ROMO1 overexpression protects the mitochondrial cysteinome from oxidations in aging.
    Fengli Xu, Haipeng Huang, Kun Peng, Chongshu Jian, Hao Wu, Zhiwen Jing, Shan Qiu, Ying Chen, Keke Liu, Ling Fu, Yanru Wang, Jing Yang, Xiaotao Duan, Chu Wang, Heping Cheng, Xianhua Wang.
      Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca2+ uniport while inhibiting vicious membrane permeability transition. Importantly, ROMO1 overexpression reverses mitochondrial cysteinome oxidations in multiple organs and slows functional decline in aged male mice. These findings unravel a redox regulatory mechanism of the mitochondrial cysteinome and mark ROMO1 as a potential target for combating oxidative stress and improving healthspan.
    DOI:  https://doi.org/10.1038/s41467-025-60503-z
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