bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–09–07
twelve papers selected by
Xiong Weng, University of Edinburgh
  1. Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
  2. FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
  3. Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
  4. Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue.
  5. GPR65 Functions as a Key Factor of Bone Aging and a Novel Therapeutic Target for Osteoporosis.
  6. Septal LYVE1+ macrophages control adipocyte stem cell adipogenic potential.
  7. Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis.
  8. GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
  9. Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs-PKCε-insulin receptor kinaseT1150 pathway.
  10. Tirzepatide drives weight loss in people with obesity due to MC4R deficiency.
  11. DNA methylation influences human centromere positioning and function.
  12. Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
  1. Nat Aging. 2025 Sep 02.
    Nerve-associated macrophages control adipose homeostasis across lifespan and restrain age-related inflammation.
    Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li, Manish Mishra, Rihao Qu, Emily L Goldberg, Sviatoslav Sidorov, Payal Damani-Yokota, Stephen T Yeung, Camille Khairallah, David Gonzalez, Taverlyn M Shepard, Christina Camell, Maxim N Artyomov, Yuval Kluger, Kamal M Khanna, Vishwa Deep Dixit.
      Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38+ age-associated macrophages in visceral adipose tissue with inflammatory phenotype. Notably, CD169+CD11c- ATMs are enriched in a subpopulation of nerve-associated macrophages (NAMs) that declines with age. Depletion of CD169+ NAMs in aged mice increases inflammaging and impairs lipolysis suggesting catecholamine resistance in visceral adipose tissue. Our findings reveal NAMs are a specialized ATM subset that control adipose homeostasis and link inflammation to tissue dysfunction during aging.
    DOI:  https://doi.org/10.1038/s43587-025-00952-9
  2. Obesity (Silver Spring). 2025 Sep 02.
    FGF21 and GDF15 Act Synergistically to Regulate Systemic Metabolic Homeostasis in Mice Lacking OPA1 in Thermogenic Adipocytes.
    Joshua Peterson, Jayashree Jena, Ayushi Sood, Shelly Roitershtein, David Smith, Renata O Pereira.
       OBJECTIVE: Our previous studies showed that mice lacking the mitochondrial fusion protein optic atrophy 1 (OPA1 BKO) in brown adipose tissue (BAT) have high metabolic rates and are resistant to diet-induced obesity (DIO) via effects partially mediated by independent actions of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) secretion from BAT. We examined whether FGF21 and GDF15 act synergistically, contributing to the systemic metabolic adaptations reported in OPA1 BKO mice.
    METHODS: We generated mice simultaneously lacking the Opa1, Fgf21, and Gdf15 genes in thermogenic adipocytes (TKO) and assessed energy homeostasis and glucose metabolism after regular chow or high-fat diet feeding.
    RESULTS: Young TKO mice fed regular chow had impaired glucose tolerance, while insulin sensitivity was unchanged. Notably, combined Fgf21 and Gdf15 deletion in OPA1 BKO significantly blunted the resistance to DIO and insulin resistance observed in OPA1 BKO mice.
    CONCLUSIONS: FGF21 and GDF15 act synergistically to maintain glucose homeostasis and promote resistance to DIO in mice lacking OPA1 in BAT, highlighting the potential of combined therapies using FGF21 and GDF15 for the treatment of metabolic disorders.
    Keywords:  Brown Adipose Tissue; FGF21; GDF15; Mitochondrial Stress; Obesity
    DOI:  https://doi.org/10.1002/oby.70004
  3. Sci Adv. 2025 Aug 29. 11(35): eads7381
    Abnormal mitochondrial structure and function in brown adipose tissue of SLC35A4-MP knockout mice.
    Andréa L Rocha, Christian Schmedt, Guy Perkins, Antonio Pinto, Jolene K Diedrich, Huanqi Shan, Kaja Plucińska, Eduardo Vieira de Souza, Joan M Vaughan, Mark Foster, Srinath C Sampath, Srihari C Sampath, Paul Cohen, Mark H Ellisman, Alan Saghatelian.
      Uncovering the role of upstream open reading frames (uORFs) challenges conventional views of one protein per messenger RNA and reveals the capacity of some uORFs to encode microproteins that contribute to cellular biology and physiology. This study explores the functional role of a recently identified mitochondrial microprotein, SLC35A4-MP, in the brown adipose tissue of mice. Our findings reveal dynamic regulation of SLC35A4-MP expression during primary brown adipocyte differentiation in vitro and during cold exposure or high-fat diet (HFD)-induced obesity in mice. Using a knockout mouse model, we show that loss of SLC35A4-MP disrupts mitochondrial lipid composition, decreasing cardiolipins and phosphatidylethanolamine in brown adipose tissue from HFD-fed mice. SLC35A4-MP deficiency also impairs mitochondrial activity, alters mitochondrial number and morphology, and promotes inflammation. Knockout mice accumulate acylcarnitines during cold exposure, indicating defective fatty acid oxidation. These findings reveal SLC35A4-MP as a previously unrecognized microprotein in regulating mitochondrial function and tissue lipid metabolism, adding to the growing list of functional endogenous microproteins.
    DOI:  https://doi.org/10.1126/sciadv.ads7381
  4. Nat Commun. 2025 Sep 04. 16(1): 7033
    Identification of Neuritin 1 as a local metabolic regulator of brown adipose tissue.
    Manuela Sánchez-Feutrie, Montserrat Romero, Sónia R Veiga, Núria Borràs-Ferré, Nick Berrow, Martina Ràfols, Noemí Giménez, Andrea Rodgers-Furones, Alba Sabaté-Pérez, Ángela Rodríguez Pérez, Luis Rodrigo Cataldo, Hans Burghardt, David Sebastián, Natàlia Plana, Vanessa Hernández, Laura Isabel Alcaide, Óscar Reina, Maria J Monte, José Juan G Marin, Manuel Palacín, Remy Burcelin, Per Antonson, Jan-Ake Gustafsson, Antonio Zorzano.
      Brown adipose tissue (BAT) plays a key role in metabolic homeostasis through its thermogenic effects and the secretion of regulatory molecules. Here we report that RAP250 haploinsufficiency stimulates BAT in mice, thus contributing to a decrease in fat accumulation. Local in vivo AAV-mediated RAP250 silencing in BAT reduces body weight and fat mass and enhances glucose oxidation, thereby indicating that RAP250 participates in the regulation of BAT metabolic activity. Analysis of the mechanisms led to the finding that Neuritin 1 is produced and released by brown adipocytes, it plays a key metabolic role, and it participates in the enhanced BAT metabolic activity under RAP250 deficiency. Forced overexpression of Neuritin 1 in UCP1-expressing cells markedly decreases fat mass and body weight gain in mice and induces the expression of thermogenic genes in BAT. Neuritin 1-deficient brown adipocytes also shows a reduced β-adrenergic response. We demonstrate a metabolic role of BAT-derived Neuritin 1 acting through an autocrine/paracrine mechanism. Based on our results, Neuritin-1 emerges as a potential target for the treatment of metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-62255-2
  5. Aging Cell. 2025 Sep 02. e70212
    GPR65 Functions as a Key Factor of Bone Aging and a Novel Therapeutic Target for Osteoporosis.
    Kun Zhang, Yehua Li, Yi Ren, Yifan He, Jiajun Wang, Xiaoxiu Li, Kefei Guo, Yi Yang, Zhemin Shi, Lina Zheng, Wei Hong.
      Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have identified the proton-sensing receptor GPR65, which is specifically expressed in osteoclasts and is significantly down-expressed in osteoclast differentiation, aging, ovariectomy (OVX)-, and tail suspension (TS)-induced osteoporotic bone tissue. In vivo experiments confirmed that knockout of GPR65 exacerbates bone loss and OP induced by TS, OVX, and aging. In vitro experiments demonstrated that silencing GPR65 or application of either endogenous or exogenous antagonist of GPR65 promotes osteoclast differentiation, whereas overexpression of GPR65 or application of either endogenous or exogenous agonist inhibits osteoclast differentiation, and knockout of Gpr65 mitigates this effect. Mechanistic studies revealed that GPR65 inhibits osteoclast differentiation by binding to Gαq, activating GSK3β, and suppressing its phosphorylation, thereby inhibiting the nuclear translocation of NFATc1 that mediates osteoclast differentiation. Furthermore, application of GPR65 agonist alleviated OVX-induced OP in vivo, indicating GPR65 as a novel therapeutic target for bone aging and OP.
    Keywords:  GPCR; GPR65; gαq; osteoclast differentiation; osteoporosis
    DOI:  https://doi.org/10.1111/acel.70212
  6. Science. 2025 Aug 28. 389(6763): eadg1128
    Septal LYVE1+ macrophages control adipocyte stem cell adipogenic potential.
    Xiaotong Yu, Yanan Hu, Hwee Ying Lim, Ziyi Li, Diego Adhemar Jaitin, Katharine Yang, Wan Ting Kong, Jiaqian Xu, David Alejandro Bejarano, Mathilde Bied, Lucie Orliaguet, Gowshika Rengasamy, Zachary Chow, Christopher Zhe Wei Lee, Josephine Lum, Jing Tian, Xiao-Meng Zhang, Honghao Liu, Shu Wen Tan, Jinmiao Chen, Peter See, Yuin-Han Loh, Benoit Malleret, Sonia Baig, M Shabeer M Yassin, Sue-Anne Ee Shiow Toh, Bernard Malissen, Xiujun Fu, Kenji Kabashima, Lai Guan Ng, Camille Blériot, Zhaoyuan Liu, Lingling Sheng, Dan-Ning Zheng, Junwen Qu, Nicolas Venteclef, Bing Su, Ido Amit, Andreas Schlitzer, Veronique Angeli, Florent Ginhoux, Svetoslav Chakarov.
      Tissue macrophages reside in anatomically distinct subtissular niches that shape their identity and function. In white adipose tissue (WAT), we identified three macrophage populations with distinct localization, turnover, and phenotypes. Septal adipose tissue macrophages (sATMs), marked by CD209b and lymphatic vessel endothelial hyaluronan receptor 1, were long-lived and positioned in close proximity to adipocyte stem cells (ASCs) within the WAT septum. Within this shared niche, sATMs instructed the differentiation of ASCs into white adipocytes through transforming growth factor-β1 (TGFβ1). Depletion of sATMs, or the selective loss of TGFβ1 within tissue-resident macrophages, redirected ASC fate toward thermogenic adipocytes, enhancing WAT beiging and protecting against diet-induced obesity. These findings highlight the role of a discrete, anatomically defined macrophage population that governs ASC fate and orchestrates adipose tissue expansion.
    DOI:  https://doi.org/10.1126/science.adg1128
  7. Mol Metab. 2025 Sep 03. pii: S2212-8778(25)00153-X. [Epub ahead of print] 102246
    Adipose tissue macrophage-derived miR-690 modulates adipocyte precursor cell maintenance and adipogenesis.
    Karina Cunha E Rocha, Breanna Tan, Julia Kempf, Cristina Medina, Varsha Beldona, Chengjia Qian, Ying Duan, Qian Xiang, Ahjin Yoo, Xiaomi Du, Amit R Majithia, Wei Ying.
      Obesity is intricately linked to various metabolic diseases; however, some individuals maintain metabolic health despite being classified as obese. A critical factor underlying this paradox is the expansion of white adipose tissue (WAT), which can occur through two mechanisms: hypertrophy (the enlargement of existing fat cells) and hyperplasia (the formation of new fat cells from adipocyte precursor cells, or APCs). Hyperplasia is regarded as a healthier mode of WAT expansion, as it tends to reduce inflammation and protect against insulin resistance. Thus, interventions that promote hyperplasia over hypertrophy could improve metabolic health in obese individuals. In this study, we investigate the role of microRNA-690 (miR-690), an anti-inflammatory and insulin-sensitizing molecule, in maintaining the APC population and facilitating the healthy expansion of epididymal WAT (eWAT). Our findings indicate that in lean mice, macrophages support the APC population by transferring miR-690 to APCs. However, during obesity, the recruitment of pro-inflammatory lipid-associated macrophages (LAMs) to eWAT diminishes miR-690 delivery to APCs, impairing adipogenesis and leading to unhealthy WAT expansion. We demonstrate that strategies aimed at increasing the availability of miR-690 to APCs or mimicking its effects can restore APC functionality. Additionally, mutations in Nadk, the target of miR-690, were shown to mitigate the adverse effects of obesity on APC maintenance in eWAT. These findings suggest that targeting the miR-690-Nadk axis in APCs may provide novel therapeutic strategies to promote healthy adipose tissue expansion and protect against obesity-related metabolic diseases.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102246
  8. Cell. 2025 Aug 29. pii: S0092-8674(25)00977-8. [Epub ahead of print]
    GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
    Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M Kemas, Dana S Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A Stoddart, Nicholas D Holliday, Phillip T Newton, Nicolas J Pillon, Gunnar Schulte, Roger J Summers, Ilga Mutule, Edgars Suna, Jesper V Olsen, Peter Molenaar, Jens Carlsson, Volker M Lauschke, Shane C Wright, Tore Bengtsson.
      
    DOI:  https://doi.org/10.1016/j.cell.2025.08.022
  9. Diabetologia. 2025 Sep 04.
    Cideb knockdown in mice increases mitochondrial fat oxidation and reverses hepatic steatosis and insulin resistance by the plasma membrane sn-1,2-DAGs-PKCε-insulin receptor kinaseT1150 pathway.
    Jie Zheng, Rafael C Gaspar, Ikki Sakuma, Brandon T Hubbard, Dongyan Zhang, Ali Nasiri, Mario Kahn, Mark Perelis, Varman T Samuel, Kitt F Petersen, Gerald I Shulman.
       AIMS/HYPOTHESIS: CIDEB (cell death-inducing DFF45-like effector B) deficiency is associated with a reduced incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) in humans; however, the underlying mechanism responsible for this protective effect remains unclear.
    METHODS: C57BL/6J male mice were fed a high-fat diet (HFD) to recapitulate key aspects of MASLD and hepatic insulin resistance. Cideb knockdown (KD) was achieved using a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO). In vivo rates of hepatic mitochondrial gluconeogenesis and tricarboxylic acid (TCA) cycle flux were assessed by Q-Flux. The Comprehensive Lab Animal Monitoring System (CLAMS) was used to evaluate rates of whole-body energy expenditure. Hepatic and peripheric insulin sensitivity were evaluated using hyperinsulinaemic-euglycaemic clamp studies combined with radio-labelled isotopes.
    RESULTS: We showed that Cideb ASO treatment increased rates of whole-body energy expenditure by ~25% and decreased hepatic triacylglycerol by ~65% in a HFD mouse model of MASLD compared with the wild-type mice. Cideb KD reduced hepatic fat content, which could mostly be attributed to increased rates of hepatic mitochondrial oxidation, in combination with reduced hepatic lipogenesis. Additionally, Cideb KD ameliorated HFD-induced insulin resistance, which could be attributed to decreased plasma membrane sn-1,2-diacylglycerols (DAGs)-protein kinase C (PKC)ε-insulin receptor kinase (IRK)T1150 phosphorylation in liver and skeletal muscle.
    CONCLUSIONS/INTERPRETATION: These findings demonstrate that Cideb KD enhances mitochondrial fat oxidation and reduces hepatic lipogenesis, which in turn mitigates HFD-induced hepatic steatosis and insulin resistance via the plasma membrane sn-1,2-DAGs-PKCε-IRKT1150 pathway, highlighting its potential as a novel therapeutic approach for MASLD and type 2 diabetes.
    Keywords:   Cideb deficiency; Energy expenditure; Hepatic lipid accumulation; Insulin sensitivity; MASLD; MOE ASO; Mitochondrial oxidation
    DOI:  https://doi.org/10.1007/s00125-025-06539-8
  10. Nat Med. 2025 Sep 05.
    Tirzepatide drives weight loss in people with obesity due to MC4R deficiency.
      
    DOI:  https://doi.org/10.1038/s41591-025-03915-0
  11. Nat Genet. 2025 Sep 04.
    DNA methylation influences human centromere positioning and function.
    Catalina Salinas-Luypaert, Danilo Dubocanin, Rosa Jooyoung Lee, Lorena Andrade Ruiz, Riccardo Gamba, Marine Grison, Leonid Velikovsky, Annapaola Angrisani, Andrea Scelfo, Yuan Xu, Marie Dumont, Viviana Barra, Therese Wilhelm, Guillaume Velasco, Marialucrezia Losito, René Wardenaar, Claire Francastel, Floris Foijer, Geert J P L Kops, Karen H Miga, Nicolas Altemose, Daniele Fachinetti.
      Maintaining the epigenetic identity of centromeres is essential to prevent genome instability. Centromeres are epigenetically defined by the histone H3 variant CENP-A. Prior work in human centromeres has shown that CENP-A is associated with regions of hypomethylated DNA located within large arrays of hypermethylated repeats, but the functional importance of these DNA methylation (DNAme) patterns remains poorly understood. To address this, we developed tools to perturb centromeric DNAme, revealing that it causally influences CENP-A positioning. We show that rapid loss of methylation results in increased binding of centromeric proteins and alterations in centromere architecture, leading to aneuploidy and reduced cell viability. We also demonstrate that gradual centromeric DNA demethylation prompts a process of cellular adaptation. Altogether, we find that DNAme causally influences CENP-A localization and centromere function, offering mechanistic insights into pathological alterations of centromeric DNAme.
    DOI:  https://doi.org/10.1038/s41588-025-02324-w
  12. Science. 2025 Sep 04. eadk7978
    Reversible compromise of physiological resilience by accumulation of heteroplasmic mtDNA mutations.
    Huihui Huang, Yi Wang, Zsuzsanna K Zsengeller, Joshua M Gorham, Vamsidhara Vemireddy, Amanda J Clark, Hui Pan, Jonathan M Dreyfuss, Vasantha Jotwani, Michael G Shlipak, Mark J Sarnak, Chirag R Parikh, Heather Thiessen-Philbrook, Ronit Katz, Sushrut S Waikar, Nicole J Lake, Monkol Lek, Wen Shi, Daniela Puiu, Yun Soo Hong, Jonathan G Seidman, Dan E Arking, Samir M Parikh.
      Somatically acquired mitochondrial DNA mutations accumulate with age, but the mechanisms and consequences are poorly understood. Here we show that transient injuries induce a burst of persistent mtDNA mutations that impair resilience to future injuries. mtDNA mutations suppressed energy-intensive nucleotide metabolism. Repletion of adenosine, but not other nucleotides, restored ATP generation, which required a nuclear-encoded purine biosynthetic enzyme, adenylate kinase 4 (AK4). Analysis of 369,912 UK Biobank participants revealed a graded association between mutation burden and chronic kidney disease severity as well as an independent increase in the risk of future acute kidney injury events (p < 10-7). Heteroplasmic mtDNA mutations may therefore reflect the cumulative effect of acute injuries to metabolically active cells, impairing major functions in a fashion amenable to nuclear-controlled purine biosynthesis.
    DOI:  https://doi.org/10.1126/science.adk7978
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