bims-obesme 2025-05-11 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2025–05–11
thirteen papers selected by
Xiong Weng, University of Edinburgh

Role of Branched-Chain Amino Acid Catabolism in the Regulation of Adipocyte Metabolism.
Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.
Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.
Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.
Transcriptomic and Epigenomic Signatures of Liver Metabolism and Insulin Sensitivity in Aging Mice.
m6A alters ribosome dynamics to initiate mRNA degradation.
DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies.
Balancing metabolism and regeneration in liver diseases through HNF4α targeting.
Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.
Identification of a specific set of genes predicting obesity before phenotype appearance.
Phase separation in mitochondrial fate and mitochondrial diseases.
Co-chaperone P23 Inhibits Ferroptosis in Sepsis-Associated Acute Kidney Injury by Regulating GPX4 Stability.
LEC2 induces somatic cell reprogramming through epigenetic activation of plant cell totipotency regulators.

Endocrinology. 2025 May 08. pii: bqaf089. [Epub ahead of print]

Role of Branched-Chain Amino Acid Catabolism in the Regulation of Adipocyte Metabolism.

Haizhou Jiang, Feifan Guo, Fei Xiao.

  Adipocyte metabolism critically regulates systemic energy homeostasis, and its dysfunction contributes to obesity pathogenesis. Notably, elevated circulating branched-chain amino acid (BCAA) levels and impaired adipose tissue BCAA catabolism have been observed in both animal models and humans with obesity; however, the mechanisms underlying BCAA metabolism's regulation of adipocyte function remain incompletely understood. This review synthesizes recent advances in the roles of BCAA catabolic enzymes, their metabolites, and BCAAs themselves in modulating adipocyte metabolism, encompassing adipogenesis, lipid metabolism, and thermogenesis. Emerging evidence reveals that BCAA catabolism influences adipocyte metabolism through multiple pathways: by utilizing BCAAs as an energy substrate, and modulating signaling cascades via metabolites and unidentified mechanisms. Importantly, adipocyte BCAA catabolism directly impacts systemic BCAA clearance and plasma BCAA concentrations. Dietary interventions involving BCAA supplementation, restriction, or deprivation demonstrate diverse metabolic effects on adipocytes, mediated through key nutrient-sensing pathways including mammalian target of rapamycin complex 1 (mTORC1) and general control nonderepressible kinase 2 (GCN2)/activating transcription factor 4 (ATF4) signaling. We further discuss translational implications, evaluating therapeutic strategies targeting BCAA catabolism or dietary BCAA manipulation for obesity management. This review advances our understanding of amino acid metabolism's contribution to adipocyte function and obesity development.

Keywords:  adipogenesis; adipose tissue; branched-chain amino acids; lipid metabolism; thermogenesis

DOI:  https://doi.org/10.1210/endocr/bqaf089
Cell Rep Med. 2025 May 02. pii: S2666-3791(25)00189-2. [Epub ahead of print] 102116

Muscle metabolic resilience and enhanced exercise adaptation by Esr1-induced remodeling of mitochondrial cristae-nucleoid architecture in males.

Zhenqi Zhou, Timothy M Moore, Alexander R Strumwasser, Vicent Ribas, Hirotaka Iwasaki, Noelle Morrow, Alice Ma, Peter H Tran, Jonathan Wanagat, Thomas Q de Aguiar Vallim, Bethan Clifford, Zhengyi Zhang, Tamer Sallam, Brian W Parks, Karen Reue, Orian Shirihai, Rebeca Acin-Perez, Marco Morselli, Matteo Pellegrini, Sushil K Mahata, Frode Norheim, Mingqi Zhou, Marcus M Seldin, Aldons J Lusis, Cathy C Lee, Mark O Goodarzi, Jerome I Rotter, Joshua R Hansen, Ben Drucker, Tyler J Sagendorf, Joshua N Adkins, James A Sanford, Francesco J DeMayo, Sylvia C Hewitt, Kenneth S Korach, Andrea L Hevener.

  Reduced estrogen action is associated with obesity and insulin resistance. However, the cell and tissue-specific actions of estradiol in maintaining metabolic health remain inadequately understood, especially in men. We observed that skeletal muscle ESR1/Esr1 (encodes estrogen receptor α [ERα]) is positively correlated with insulin sensitivity and metabolic health in humans and mice. Because skeletal muscle is a primary tissue involved in oxidative metabolism and insulin sensitivity, we generated muscle-selective Esr1 loss- and gain-of-expression mouse models. We determined that Esr1 links mitochondrial DNA replication and cristae-nucleoid architecture with metabolic function and insulin action in the skeletal muscle of male mice. Overexpression of human ERα in muscle protected male mice from diet-induced disruption of metabolic health and enhanced mitochondrial adaptation to exercise training intervention. Our findings indicate that muscle expression of Esr1 is critical for the maintenance of mitochondrial function and metabolic health in males and that tissue-selective activation of ERα can be leveraged to combat metabolic-related diseases in both sexes.

Keywords:  estrogen action; exercise adaptation; insulin sensitivity; mitochondrial cristae architecture; mitochondrial function; mtDNA replication; oxidative metabolism

DOI:  https://doi.org/10.1016/j.xcrm.2025.102116
Dev Cell. 2025 Apr 27. pii: S1534-5807(25)00210-2. [Epub ahead of print]

Paraoxonase-like APMAP maintains endoplasmic-reticulum-associated lipid and lipoprotein homeostasis.

Blessy Paul, Holly Merta, Rupali Ugrankar-Banerjee, Monica R Hensley, Son Tran, Goncalo Dias do Vale, Lauren Zacherias, Charles K Hewett, Jeffrey G McDonald, Joan Font-Burgada, Thomas P Mathews, Steven A Farber, W Mike Henne.

  Oxidative stress perturbs lipid homeostasis and contributes to metabolic diseases. Though ignored when compared with mitochondrial oxidation, the endoplasmic reticulum (ER) generates reactive oxygen species requiring antioxidant quality control. Using multi-organismal profiling featuring Drosophila, zebrafish, and mammalian hepatocytes, here we characterize the paraoxonase-like C20orf3/adipocyte plasma-membrane-associated protein (APMAP) as an ER-localized antioxidant that suppresses ER lipid oxidation to safeguard ER function. APMAP-depleted cells exhibit defective ER morphology, ER stress, and lipid peroxidation dependent on ER-oxidoreductase 1α (ERO1A), as well as sensitivity to ferroptosis and defects in ApoB-lipoprotein homeostasis. Similarly, organismal APMAP depletion in Drosophila and zebrafish perturbs ApoB-lipoprotein homeostasis. Strikingly, APMAP loss is rescued with chemical antioxidant N-acetyl-cysteine (NAC). Lipidomics identifies that APMAP loss elevates phospholipid peroxidation and boosts ceramides-signatures of lipid stress. Collectively, we propose that APMAP is an ER-localized antioxidant that promotes lipid and lipoprotein homeostasis in the ER network.

Keywords:  ER; PON; ceramide; endoplasmic reticulum; lipoprotein; paraoxonase; redox homeostasis

DOI:  https://doi.org/10.1016/j.devcel.2025.04.008
Cell Rep. 2025 May 07. pii: S2211-1247(25)00453-X. [Epub ahead of print]44(5): 115682

Mitochondrial GCN5L1 coordinates with YME1L and MICOS to remodel mitochondrial cristae in white adipocytes and modulate obesity.

Juan Xu, Qiqi Zhang, Xinyu Yang, Qiqi Tang, Yitong Han, Jiahui Meng, Jiaqi Zhang, Xin Lu, Danni Wang, Jing Liu, Bo Shan, Xue Bai, Kai Zhang, Longhao Sun, Lingdi Wang, Lu Zhu.

  The relationship between mitochondrial architecture and energy homeostasis in adipose tissues is not well understood. In this study, we utilized GCN5L1-knockout mice in white (AKO) and brown (BKO) adipose tissues to examine mitochondrial homeostasis in adipose tissues. GCN5L1, a regulator of mitochondrial metabolism and dynamics, influences resistance to high-fat-diet-induced obesity in AKO but not BKO mice. This resistance is mediated by an increase in mitochondrial cristae that stabilizes oxidative phosphorylation (OXPHOS) complexes and enhances energy expenditure. Our protein-interactome analysis reveals that GCN5L1 is associated with the mitochondrial crista complex MICOS (MIC13) and the protease YME1L, facilitating the degradation of MICOS and disassembly of cristae during obesity. This interaction results in decreased OXPHOS levels and subsequent adipocyte expansion. Accumulation of GCN5L1 in the mitochondrial intermembrane space is triggered by a high-fat diet. Our findings highlight a regulatory pathway involving YME1L/GCN5L1/MIC13 that remodels mitochondrial cristae in WAT in response to overnutrition-induced obesity.

Keywords:  CP: Cell biology; CP: Metabolism; MICOS; OXPHOS; YME1L; beige; mitochondria; mitochondrial crista remodeling; white adipose tissue

DOI:  https://doi.org/10.1016/j.celrep.2025.115682
Mech Ageing Dev. 2025 May 03. pii: S0047-6374(25)00044-2. [Epub ahead of print] 112068

Transcriptomic and Epigenomic Signatures of Liver Metabolism and Insulin Sensitivity in Aging Mice.

John T González, Olivia H Scharfman, Wanling Zhu, Jessica Kasamoto, Victoria Gould, Rachel J Perry, Albert T Higgins-Chen.

  Age-related declines in insulin sensitivity and glucose metabolism contribute to metabolic disease. Despite the liver's central role in glucose homeostasis, a comprehensive phenotypic characterization and concurrent molecular analysis of insulin resistance and metabolic dysfunction in the aging liver is lacking. We characterized hepatic insulin resistance and mitochondrial metabolic defects through metabolic cage, hyperinsulinemic-euglycemic clamp, and tracer studies paired with transcriptomic and DNA methylation analyses in young and aged male mice. Aged mice exhibited benchmark measures of whole body and liver insulin resistance. Aged mice showed lower pyruvate dehydrogenase flux, decreased fatty acid oxidation and citrate synthase fluxes, and increased pyruvate carboxylase flux under insulin-stimulated conditions. Molecular analysis revealed age-related changes in metabolic genes Pck1, Socs3, Tbc1d4, and Enpp1. Unsupervised network analysis identified an intercorrelated phenotype module (ME-Glucose), RNA module, and DNA methylation module. The DNA methylation module was enriched for lipid metabolism pathways and TCF-1 binding, while the RNA module was enriched for MZF-1 binding and regulation by miR-155-5p. Protein-protein interaction network analysis revealed interactions between module genes and canonical metabolic pathways, highlighting genes including Ets1, Ppp1r3b, and Enpp3. This study reveals novel genes underlying age-related hepatic insulin resistance as potential targets for metabolic interventions to promote healthy aging.

Keywords:  DNA methylation; Insulin resistance; Metabolic flux analysis; Mitochondrial dysfunction; Tricarboxylic acid (TCA) cycle

DOI:  https://doi.org/10.1016/j.mad.2025.112068
Cell. 2025 May 05. pii: S0092-8674(25)00455-6. [Epub ahead of print]

m6A alters ribosome dynamics to initiate mRNA degradation.

Shino Murakami, Anthony O Olarerin-George, Jianheng Fox Liu, Sara Zaccara, Ben Hawley, Samie R Jaffrey.

  Degradation of mRNA containing N6-methyladenosine (m6A) is essential for cell growth, differentiation, and stress responses. Here, we show that m6A markedly alters ribosome dynamics and that these alterations mediate the degradation effect of m6A on mRNA. We find that m6A is a potent inducer of ribosome stalling, and these stalls lead to ribosome collisions that form a unique conformation unlike those seen in other contexts. We find that the degree of ribosome stalling correlates with m6A-mediated mRNA degradation, and increasing the persistence of collided ribosomes correlates with enhanced m6A-mediated mRNA degradation. Ribosome stalling and collision at m6A is followed by recruitment of YTHDF m6A reader proteins to promote mRNA degradation. We show that mechanisms that reduce ribosome stalling and collisions, such as translation suppression during stress, stabilize m6A-mRNAs and increase their abundance, enabling stress responses. Overall, our study reveals the ribosome as the initial m6A sensor for beginning m6A-mRNA degradation.

Keywords:  N(6)-methyladenosine; TimeLapse-seq; adaptive response; amino acid depletion; m(6)A; mRNA decay; mRNA degradation; mRNA stability; ribosome collision; ribosome stall

DOI:  https://doi.org/10.1016/j.cell.2025.04.020
Clin Epigenetics. 2025 May 03. 17(1): 72

DNA methylation in primary myelofibrosis is partly associated with driver mutations and distinct from other myeloid malignancies.

Esra Dursun Torlak, Vithurithra Tharmapalan, Kim Kricheldorf, Joelle Schifflers, Madeline Caduc, Martin Zenke, Steffen Koschmieder, Wolfgang Wagner.

   BACKGROUND: Primary myelofibrosis (PMF) is a clonal blood disorder characterized by mutually exclusive driver mutations in JAK2, CALR, or MPL genes. So far, it is largely unclear if the driver mutations have a specific impact on DNA methylation (DNAm) profiles and how epigenetic alterations in PMF are related to other myeloid malignancies.
RESULTS: When we compared DNAm profiles from PMF patients we found very similar epigenetic modifications in JAK2 and CALR mutated cases, whereas MPL mutations displayed less pronounced and distinct patterns. Furthermore, induced pluripotent stem cell (iPSC) models with JAK2 mutations indicated only a moderate association with PMF-related epigenetic changes, suggesting that these alterations may not be directly driven by the mutations themselves. Additionally, PMF-associated epigenetic changes showed minimal correlation with allele burden and seemed to be largely influenced by shifts in the cellular composition. PMF DNAm profiles compared with those from other myeloid malignancies-such as acute myeloid leukemia, juvenile myelomonocytic leukemia, and myelodysplastic syndrome-showed numerous overlapping changes, making it difficult to distinguish PMF based on individual CpGs. However, a PMF score created by combining five CpGs was able to discern PMF from other diseases.
CONCLUSION: These findings demonstrate that PMF driver mutations do not directly evoke epigenetic changes. While PMF shares epigenetic alterations with other myeloid malignancies, DNA methylation patterns can distinguish between PMF and related diseases.

Keywords:  AML; CpG; DNA methylation; Epigenetic; JMML; MDS; MPN; Myeloid malignancies; Primary myelofibrosis

DOI:  https://doi.org/10.1186/s13148-025-01877-1
Trends Endocrinol Metab. 2025 May 05. pii: S1043-2760(25)00078-5. [Epub ahead of print]

Balancing metabolism and regeneration in liver diseases through HNF4α targeting.

Céline Van Dender, Jolien Vandewalle, Claude Libert.

  Transcription factor hepatocyte nuclear factor 4 alpha (HNF4α) is considered the master regulator of hepatocyte differentiation. During homeostasis, HNF4α maintains liver identity by supporting metabolism while inhibiting proliferation. It is downregulated in response to both acute and chronic insults; however, although this supports hepatic regeneration in mild acute settings, severe or chronic downregulation may further compromise liver function and lead to a lethal outcome. Here, we provide an overview of liver diseases associated with downregulation, altered expression, or dysfunction of HNF4α and suggest the potential underlying mechanisms. We further propose that therapy with Hnf4a mRNA or HNF4α agonists to reactivate HNF4α may be beneficial in pathophysiological contexts characterized by loss of liver function.

Keywords:  HNF4α; cell identity; hepatocyte; metabolism; regeneration; transcription

DOI:  https://doi.org/10.1016/j.tem.2025.04.003
Aging Cell. 2025 May 02. e70085

Mitochondrial Respiratory Dysfunction Is Not Correlated With Mitochondrial Genotype in Premature Aging Mice.

Hiroaki Tamashiro, Kaori Ishikawa, Koichi Sadotomo, Emi Ogasawara, Kazuto Nakada.

  mtDNA mutator mice (Polgmut/mut mice) have reinforced the mitochondrial theory of aging. These mice accumulate multiple mutations in mtDNA with age due to a homozygous proofreading-deficient mutation in mtDNA polymerase gamma (Polg), resulting in mitochondrial respiratory dysfunction and premature aging phenotypes. However, whether the accumulation of multiple mutations in Polgmut/mut mice induces mitochondrial respiratory dysfunction remains unclear. Here, we determined the accurate mtDNA genotype, including the frequency of total mutations and the number of non-synonymous substitutions and pathogenic mutations, using next-generation sequencing in the progeny of all three genotypes obtained from the mating of heterozygous mtDNA mutator mice (Polg+/mut mice) and examined their correlation with mitochondrial respiratory activity. Although Polg+/mut mice showed equivalent mtDNA genotype to Polg+/+ (wild-type) mice, the mitochondrial respiratory activity in the Polg+/mut mice was mildly reduced. To further investigate the causal relationship between mtDNA genotype and mitochondrial respiratory activity, we experimentally varied the mtDNA genotype in Polg mice. However, mitochondrial respiratory activity was mildly reduced in Polg+/mut mice and severely reduced in Polgmut/mut mice, regardless of the mtDNA genotype. Moreover, by varying the mtDNA genotype, some Polg+/+ mice showed mtDNA genotype equivalent to those of Polgmut/mut mice, but mitochondrial respiratory activity in Polg+/+ mice was normal. These results indicate that the mitochondrial respiratory dysfunction observed in mice with proofreading-deficient mutation in Polg is correlated with the nuclear genotype of Polg rather than the mtDNA genotype. Thus, the mitochondrial theory of aging in Polgmut/mut mice needs further re-examination.

Keywords:  aging; mitochondria; mitochondrial DNA

DOI:  https://doi.org/10.1111/acel.70085
iScience. 2025 May 16. 28(5): 112377

Identification of a specific set of genes predicting obesity before phenotype appearance.

Céline Jousse, Laurent Parry, Gwendal Cueff, Marion Brandolini-Bunlon, Jérémy Tournayre, Alain Bruhat, Anne-Catherine Maurin, Cyrielle Vituret, Julien Averous, Yuki Muranishi, Pierre Fafournoux.

  Obesity poses significant health and socioeconomic challenges, necessitating early detection of predisposition for effective personalized prevention. To identify candidate predictive markers, our study used two mouse models: one exhibiting interindividual variability in obesity predisposition and another inducing metabolic phenotypes through maternal nutritional stresses. In both cases, predisposition was assessed by challenging mice with a high-fat diet. Using multivariate analyses of transcriptomic data from white adipose tissue, we identified a set of genes whose expression correlates with an elevated susceptibility to obesity. Importantly, the expression of these genes was impacted prior to the appearance of any symptoms. A prediction model, incorporating both mouse and publicly available human datasets, confirmed the discriminative capacities of our set of genes across species, sexes, and adipose tissue deposits. These genes are promising candidates to serve as diagnostic tools for identifying individuals at risk of obesity.

Keywords:  Genetics; Physiology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2025.112377
Proc Natl Acad Sci U S A. 2025 May 27. 122(21): e2422255122

Phase separation in mitochondrial fate and mitochondrial diseases.

Qingyi Chen, Sanqi An, Chuanlong Wang, Yanshuang Zhou, Xingguo Liu, Wenkai Ren.

  Mitochondria are central metabolic organelles that control cell fate and the development of mitochondrial diseases. Traditionally, phase separation directly regulates cell functions by driving RNA, proteins, or other molecules to concentrate into lipid droplets. Recent studies show that phase separation regulates cell functions and diseases through the regulation of subcellular organelles, particularly mitochondria. In fact, phase separation is involved in various mitochondrial activities including nucleoid assembly, autophagy, and mitochondria-related inflammation. Here, we outline the key mechanisms through which phase separation influences mitochondrial activities and the development of mitochondrial diseases. Insights into how phase separation regulates mitochondrial activities and diseases will help us develop interventions for related diseases.

Keywords:  mitochondrial disease; mitochondrial dynamics; mitophagy; nucleoid assembly; phase separation

DOI:  https://doi.org/10.1073/pnas.2422255122
Shock. 2025 May 06.

Co-chaperone P23 Inhibits Ferroptosis in Sepsis-Associated Acute Kidney Injury by Regulating GPX4 Stability.

Minjie Luo, Qing Xu, Ying Sun, Nina He, Zhongchi Wen, Ziqin Wang, Jie Zhao, Ying Liu.

   ABSTRACT: Ferroptosis, an iron-dependent form of regulated cell death, has been implicated in severe kidney diseases, particularly those characterized by the depletion of GPX4. Despite its clinical significance, the molecular mechanisms driving GPX4 reduction in SA-AKI remain poorly understood. In this study, we uncover a novel regulatory axis involving the RNA-binding protein P23 and GPX4 mRNA stability in SA-AKI pathogenesis. Using integrated in vivo and in vitro models, we demonstrate that P23 expression is significantly upregulated during SA-AKI and functions as a critical suppressor of ferroptosis. Mechanistically, pharmacological inhibition of P23 with celastrol exacerbated renal dysfunction and amplified ferroptotic damage, as evidenced by elevated lipid peroxidation, iron overload, and GPX4 downregulation. Conversely, P23 overexpression robustly attenuated ferroptosis by stabilizing GPX4 mRNA, thereby preserving GPX4 protein levels and redox homeostasis. Crucially, RIP and Co-IP assays revealed that P23 directly binds to GPX4 mRNA and protein, forming a protective complex that impedes mRNA degradation and ferroptotic cascades. These findings establish P23 as a multifunctional regulator of ferroptosis and highlight its RNA-binding activity as a therapeutically targetable mechanism for mitigating SA-AKI. Our work provides a foundation for developing P23-centric interventions to combat ferroptosis-driven kidney injury in sepsis.

Keywords:  Ferroptosis; GPX4; P23; SA-AKI

DOI:  https://doi.org/10.1097/SHK.0000000000002623
Nat Commun. 2025 May 06. 16(1): 4185

LEC2 induces somatic cell reprogramming through epigenetic activation of plant cell totipotency regulators.

Jing Peng, Qi Zhang, Li Ping Tang, Biao Jie Xu, Thomas Laux, Xian Sheng Zhang, Ying Hua Su.

Many plant species can develop embryos from somatic cells without fertilization. During this process, known as somatic embryogenesis, changes in the DNA methylation patterns are characteristic of reprogramming somatic cells into an embryogenic state. However, the underlying mechanisms connecting DNA methylation and activating totipotency-regulating genes have remained largely unknown. Here, we show that during somatic embryogenesis induced by overexpressing the totipotency-regulating transcription factor LEAFY COTYLEDON2 (LEC2) in Arabidopsis, CHH hypermethylation is deposited by the LEC2-activated RNA-directed DNA methylation (RdDM) pathway. A reader complex composed of SU(VAR)3-9 HOMOLOGS (SUVH) and its chaperone SUVH-INTERACTING DNAJ DOMAIN-CONTAINING PROTEIN (SDJ) binds to the CHH hypermethylated regions and recruits AT-HOOK MOTIF CONTAINING NUCLEAR LOCALIZED (AHL) chromatin modification proteins to increase chromatin accessibility, resulting in the transcriptional activation of totipotency-regulating genes. Our work reveals a molecular framework of how epigenetic modifications mediate somatic cell reprogramming, offering a pathway toward enhancing somatic embryogenesis in agricultural regeneration biology.

DOI: https://doi.org/10.1038/s41467-025-59335-8