bims-obesme 2024-12-01 papers

bims-obesme

Biomed News

on Obesity metabolism

Issue of 2024–12–01
eleven papers selected by
Xiong Weng, University of Edinburgh

Ablation of FAM210A in brown adipocytes of mice exacerbates high fat diet induced metabolic dysfunction.
Acute exercise promotes WAT browning by remodeling mRNA m6A methylation.
PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity.
Transposable element 5mC methylation state of blood cells predicts age and disease.
Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.
Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.
Circular RNAs as multifaceted molecular regulators of vital activity and potential biomarkers of aging.
Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility.
Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue.
Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery.
Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival.

Diabetes. 2024 Nov 27. pii: db240294. [Epub ahead of print]

Ablation of FAM210A in brown adipocytes of mice exacerbates high fat diet induced metabolic dysfunction.

Jiamin Qiu, Mennatallah A Khedr, Meijin Pan, Christina R Ferreira, Jingjuan Chen, Madigan M Snyder, Kolapo M Ajuwon, Feng Yue, Shihuan Kuang.

Thermogenesis of brown adipose tissues (BAT) provides metabolic benefits against pathological conditions such as Type 2 diabetes, obesity, cardiovascular diseases, and cancer. The thermogenic function of BAT relies on mitochondria, but whether mitochondrial remodeling is required for the beneficial effects of BAT remains unclear. We have recently identified FAM210A as a BAT-enriched mitochondrial protein essential for cold-induced thermogenesis through the modulation of OPA1-dependent cristae remodeling. Here we report a key role of FAM210A in the systemic response to high-fat diet (HFD). We discovered that HFD suppressed FAM210A expression, associated with excessive OPA1 cleavage in BAT. Ucp1-Cre-driven BAT-specific Fam210a knockout (Fam210aUKO) similarly elevates OPA1 cleavage, accompanied by whitening of BAT. When subjected to HFD, the Fam210aUKO mice gained similar fat mass as sibling control mice, but developed glucose intolerance, insulin resistance, and liver steatosis. The metabolic dysfunction was associated with an overall increased lipid content in both liver and BAT. Additionally, Fam210aUKO leads to inflammation in white adipose tissues. These data demonstrate that FAM210A in BAT is necessary for counteracting HFD-induced metabolic dysfunction but not obesity.

DOI: https://doi.org/10.2337/db24-0294
Life Sci. 2024 Nov 22. pii: S0024-3205(24)00859-2. [Epub ahead of print] 123269

Acute exercise promotes WAT browning by remodeling mRNA m6A methylation.

Wei Chen, Youhua Liu, Jiaqi Liu, Yushi Chen, Xinxia Wang.

   AIMS: Regular exercise promotes the beiging and metabolic adaptations of white adipose tissue (WAT) through the cumulative transcriptional responses that occur after each exercise session. However, the effects of a single bout of acute exercise and the role of N6-methyladenosine (m6A) in these adaptations remain unclear. We aim to investigate this further.
MATERIALS AND METHODS: We constructed mouse models for chronic (8 weeks of running) and acute (single 1-hour run) exercise to study the effects on white adipose tissue (WAT) metabolism and beiging through metabolic phenotyping and transcriptome sequencing. Additionally, we explored the impact of acute exercise on WAT m6A modification and target genes, combining m6A regulators with cell models to elucidate the role of m6A in WAT exercise adaptation.
KEY FINDINGS: Here, we reveal that upregulated m6A modification after acute exercise induces the formation of glycolytic beige fat (g-beige fat) in WAT. Mechanistically, the metabolite β-hydroxybutyrate (BHBA) secreted after acute exercise upregulates m6A modification in WAT. This enhances m6A-dependent translation of the histone acetyltransferase CREBBP, promoting the transcription of key beiging genes by increasing chromatin accessibility. Pharmacologically elevating circulating BHBA mimics the metabolic response induced by acute exercise, upregulating m6A modification and its downstream signals. Additionally, BHBA exhibits long-term effects, improving metabolic homeostasis in obesity by promoting thermogenesis in WAT.
SIGNIFICANCE: Our results reveal the role of metabolites in WAT metabolic adaptation through m6A-mediated chromatin accessibility after acute exercise, providing a novel therapeutic target for regulating WAT metabolism from a nutritional epigenetics perspective.

Keywords:  Adipose tissue; Beiging; Exercise; m(6)A; β-hydroxybutyrate

DOI:  https://doi.org/10.1016/j.lfs.2024.123269
Cell Rep. 2024 Nov 07. pii: S2211-1247(24)01296-8. [Epub ahead of print] 114945

PPARγ-dependent remodeling of translational machinery in adipose progenitors is impaired in obesity.

Mirian Krystel De Siqueira, Gaoyan Li, Yutian Zhao, Siqi Wang, In Sook Ahn, Mikayla Tamboline, Andrew D Hildreth, Jakeline Larios, Alejandro Schcolnik-Cabrera, Zaynab Nouhi, Zhengyi Zhang, Marcus J Tol, Vijaya Pandey, Shili Xu, Timothy E O'Sullivan, Julia J Mack, Peter Tontonoz, Tamer Sallam, James A Wohlschlegel, Laura Hulea, Xinshu Xiao, Xia Yang, Claudio J Villanueva.

  Adipose tissue regulates energy homeostasis and metabolic function, but its adaptability is impaired in obesity. In this study, we investigate the impact of acute PPARγ agonist treatment in obese mice and find significant transcriptional remodeling of cells in the stromal vascular fraction (SVF). Using single-cell RNA sequencing, we profile the SVF of inguinal and epididymal adipose tissue of obese mice following rosiglitazone treatment and find an induction of ribosomal factors in both progenitor and preadipocyte populations, while expression of ribosomal factors is reduced with obesity. Notably, the expression of a subset of ribosomal factors is directly regulated by PPARγ. Polysome profiling of the epididymal SVF shows that rosiglitazone promotes translational selectivity of mRNAs that encode pathways involved in adipogenesis and lipid metabolism. Inhibition of translation using a eukaryotic translation initiation factor 4A (eIF4A) inhibitor is sufficient in blocking adipogenesis. Our findings shed light on how PPARγ agonists promote adipose tissue plasticity in obesity.

Keywords:  CP: Metabolism; adipocytes; adipose progenitors; adipose stem cells; diabetes; glucose; obesity; ribosomes; rosiglitazone; translation

DOI:  https://doi.org/10.1016/j.celrep.2024.114945
Nat Aging. 2024 Nov 27.

Transposable element 5mC methylation state of blood cells predicts age and disease.

Francesco Morandini, Jinlong Y Lu, Cheyenne Rechsteiner, Aladdin H Shadyab, Ramon Casanova, Beverly M Snively, Andrei Seluanov, Vera Gorbunova.

Transposable elements (TEs) are DNA sequences that expand selfishly in the genome, possibly causing severe cellular damage. While normally silenced, TEs have been shown to activate during aging. DNA 5-methylcytosine (5mC) is one of the main epigenetic modifications by which TEs are silenced and has been used to train highly accurate age predictors. Yet, one common criticism of such predictors is that they lack interpretability. In this study, we investigate the changes in TE 5mC methylation that occur during aging in human blood using published methylation array data. We find that evolutionarily young long interspersed nuclear elements 1 (L1s), the only known TEs capable of autonomous transposition in humans, undergo the fastest loss of 5mC methylation, suggesting an active mechanism of de-repression. The same young L1s also showed preferential gain in chromatin accessibility but not expression. The long terminal repeat retrotransposons THE1A and THE1C also showed very rapid 5mC loss. We then show that accurate age predictors can be trained on both 5mC methylation of individual TE copies and average methylation of TE families genome wide. Lastly, we show that while old L1s gradually lose 5mC during the entire lifespan, demethylation of young L1s only happens late in life and is associated with cancer.

DOI: https://doi.org/10.1038/s43587-024-00757-2
Nat Commun. 2024 Nov 28. 15(1): 10102

Plasma membrane remodeling determines adipocyte expansion and mechanical adaptability.

María C M Aboy-Pardal, Marta C Guadamillas, Carlos R Guerrero, Mauro Català-Montoro, Mónica Toledano-Donado, Sara Terrés-Domínguez, Dácil M Pavón, Víctor Jiménez-Jiménez, Daniel Jimenez-Carretero, Moreno Zamai, Cintia Folgueira, Ana Cerezo, Fidel-Nicolás Lolo, Rubén Nogueiras, Guadalupe Sabio, Miguel Sánchez-Álvarez, Asier Echarri, Ricardo Garcia, Miguel A Del Pozo.

Adipocytes expand massively to accommodate excess energy stores and protect the organism from lipotoxicity. Adipose tissue expandability is at the center of disorders such as obesity and lipodystrophy; however, little is known about the relevance of adipocyte biomechanics on the etiology of these conditions. Here, we show in male mice in vivo that the adipocyte plasma membrane undergoes caveolar domain reorganization upon lipid droplet expansion. As the lipid droplet grows, caveolae disassemble to release their membrane reservoir and increase cell surface area, and transfer specific caveolar components to the LD surface. Adipose tissue null for caveolae is stiffer, shows compromised deformability, and is prone to rupture under mechanical compression. Mechanistically, phosphoacceptor Cav1 Tyr14 is required for caveolae disassembly: adipocytes bearing a Tyr14Phe mutation at this residue are stiffer and smaller, leading to decreased adiposity in vivo; exhibit deficient transfer of Cav1 and EHD2 to the LD surface, and show distinct Cav1 molecular dynamics and tension adaptation. These results indicate that Cav1 phosphoregulation modulates caveolar dynamics as a relevant component of the homeostatic mechanoadaptation of the differentiated adipocyte.

DOI: https://doi.org/10.1038/s41467-024-54224-y
Immunity. 2024 Nov 26. pii: S1074-7613(24)00521-1. [Epub ahead of print]

Interleukin-2-secreting T helper cells promote extra-follicular B cell maturation via intrinsic regulation of a B cell mTOR-AKT-Blimp-1 axis.

Caterina E Faliti, Maria Mesina, Jinyong Choi, Simon Bélanger, Monique A Marshall, Christopher M Tipton, Sakeenah Hicks, Prashanti Chappa, Maria A Cardenas, Mohamed Abdel-Hakeem, Theresa C Thinnes, Christopher Cottrell, Christopher D Scharer, William R Schief, David Nemazee, Matthew C Woodruff, John M Lindner, Ignacio Sanz, Shane Crotty.

  During antigen-driven responses, B cells can differentiate at extra-follicular (EF) sites or initiate germinal centers (GCs) in processes that involve interactions with T cells. Here, we examined the roles of interleukin (IL)-2 secreted by T helper (Th) cells during cognate interactions with activated B cells. IL-2 boosted the expansion of EF plasma cells and the secretion of low-mutated immunoglobulin G (IgG). Conversely, genetically disrupting IL-2 expression by CD4+ T cells, or IL-2 receptor (CD25) expression by B cells, promoted B cell entry into the GC and high-affinity antibody secretion. Mechanistically, IL-2 induced early mTOR activity, expression of the transcriptional regulator IRF4, and metabolic changes in B cells required to form Blimp-1-expressing plasma cells. Thus, T cell help via IL-2 regulates an mTOR-AKT-Blimp-1 axis in activated B cells, providing insight into the mechanisms that determine EF versus GC fates and positioning IL-2 as an early switch controlling plasma cell versus GC B cell commitment.

Keywords:  CD4 T cells; IL-2 cytokine; T follicular helper cells; Tfh cells; antibodies; mTOR; metabolism; plasma cells; vaccine

DOI:  https://doi.org/10.1016/j.immuni.2024.11.006
Epigenomics. 2024 Nov 26. 1-11

Circular RNAs as multifaceted molecular regulators of vital activity and potential biomarkers of aging.

Anna-Maria D Zharova, Alexey D Perenkov, Maria V Vedunova.

  Aging presents a significant challenge to health and social care systems due to the increasing proportion of the elderly population. The identification of reliable biomarkers to assess the progression of aging remains an unresolved question. Circular RNAs (circRNAs) are single-stranded covalently closed RNAs. They have been found to regulate various biological processes. CircRNAs are present in human biological fluids, are relatively stable, and accumulate with age, making them promising as biomarkers of aging. Current information on the expression of circRNAs in aging was analyzed using scientific databases. In this review, we have identified key stages in the study of circRNAs during aging and summarized the current understanding of their biogenesis. By focusing on the role of circRNAs in processes that contribute to aging - such as genomic stability, metabolism, cell death, and signaling pathways - we hypothesize that circRNAs may drive the aging process through their age-related accumulation and resultant deregulation. Examples of age-related differential expression of circRNAs in various species, including humans, are provided. This review highlights the importance of finding novel epigenetic biomarkers of aging, beyond the already identified molecules (circFOXO3, circRNA100783, circPVT1), and highlights circRNAs as a potential therapeutic target for the treatment of age-associated diseases.

Keywords:  aging; biomarkers; circRNA; elderly population; lifespan; ncRNA; splicing

DOI:  https://doi.org/10.1080/17501911.2024.2430165
Dev Cell. 2024 Nov 15. pii: S1534-5807(24)00661-0. [Epub ahead of print]

Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility.

Lu Deng, Xi C He, Shiyuan Chen, Ning Zhang, Fengyan Deng, Allison Scott, Yanfeng He, Dai Tsuchiya, Sarah E Smith, Michael Epp, Seth Malloy, Fang Liu, Mark Hembree, Qinghui Mu, Jeffrey S Haug, Ermanno Malagola, Huzaifa Hassan, Kaitlyn Petentler, Rhonda Egidy, Lucinda Maddera, Jonathon Russell, Yan Wang, Hua Li, Chongbei Zhao, Anoja Perera, Timothy C Wang, Calvin J Kuo, Linheng Li.

  The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5+ intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19+ cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.

Keywords:  Fzd5; Wnt pathway; chromatin accessibility; intestinal stem cell; plasticity; single-cell transcriptome and epigenome

DOI:  https://doi.org/10.1016/j.devcel.2024.10.021
Mol Cell Biochem. 2024 Nov 30.

Human umbilical cord mesenchymal stem cells improve bone marrow hematopoiesis through regulation of bone marrow adipose tissue.

Jingyi Feng, Miao Zhang, Huanying Ren, Yan Ren, Zhuanghui Hao, Sicheng Bian, Jiangxia Cui, Shuo Li, Jing Xu, Muteb Muyey Daniel, Fanggang Ren, Zhifang Xu, Yanhong Tan, Xiuhua Chen, Yaofang Zhang, Jianmei Chang, Hongwei Wang.

  Bone marrow adipose tissue (BMAT) exhibits a multitude of biological functionalities and influences hematopoiesis. The adiposity status of the bone marrow may play a role in the decline of hematopoietic function. Mesenchymal stem cells (MSCs) constitute crucial regulators within the bone marrow microenvironment; however, their precise role in modulating BMAT and the subsequent implications for hematopoiesis remain poorly understood. We conducted in vivo studies to observe the effects of human umbilical cord mesenchymal stem cells (hucMSCs) on BMAT accumulation and restoration of hematopoietic function in mice with drug-induced hematopoietic impairment. Concurrently, in vitro co-culture experiments were used to investigate the impact of hucMSCs on preadipocytes and mature adipocytes, and the potential subsequent consequences for hematopoietic cells. Moreover, we explored the potential mechanisms underlying these interactions. Our findings reveal that hucMSCs concomitantly mitigate BMAT accumulation and facilitate the recovery of hematopoietic function in mouse models with drug-induced hematopoietic impairment. In vitro, hucMSCs potentially impede adipogenic differentiation of 3T3-L1 preadipocytes through interference with the JAK2/STAT3 signaling pathway and affect the functionality of mature adipocytes, thus mitigating the detrimental effects of adipocytes on hematopoietic stem cells (HSCs). Furthermore, we demonstrate that hucMSCs may protect hematopoietic cells from adipocyte-induced damage by protecting antioxidative mechanisms. These results suggest that hucMSCs exhibit an inhibitory effect on the excessive expansion of adipose tissue and modulate adipose tissue function, which may potentially contribute to the regulation of the bone marrow microenvironment and favorably influence hematopoietic function improvement.

Keywords:  Adipose; Bone marrow; Chemotherapy; Hematopoiesis; Mesenchymal stem cells (MSCs)

DOI:  https://doi.org/10.1007/s11010-024-05156-0
Cell Stem Cell. 2024 Nov 22. pii: S1934-5909(24)00377-1. [Epub ahead of print]

Generation of iPSC-derived human venous endothelial cells for the modeling of vascular malformations and drug discovery.

Zihang Pan, Qiyang Yao, Weijing Kong, Xiaojing Ma, Liangliang Tian, Yun Zhao, Shuntian Zhu, Sheng Chen, Mengze Sun, Jiao Liu, Simin Jiang, Jianxun Ma, Qijia Liu, Xiaohong Peng, Xiaoxia Li, Zixuan Hong, Yi Hong, Xue Wang, Jiarui Liu, Jingjing Zhang, Wei Zhang, Bingbing Sun, Sara Pahlavan, Youchen Xia, Weimin Shen, Yuyong Liu, Wenjian Jiang, Zhengwei Xie, Wei Kong, Xi Wang, Kai Wang.

  Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impedes drug discovery. Here, we devise a robust protocol for the generation of human induced VECs (iVECs) through manipulation of cell-cycle dynamics via the retinoic signaling pathway. We introduce an L914F mutation into the TIE2 gene locus of induced pluripotent stem cells (iPSCs) and show that the mutated iVECs form dilated blood vessels after transplantation into mice, thereby recapitulating the phenotypic characteristics observed in VMs. Moreover, utilizing a deep neural network and a high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq) approach, we perform drug screening and demonstrate that bosutinib effectively rescues the disease phenotype in vitro and in vivo. In summary, by leveraging genome editing and stem cell technology, we generate VM models that enable the development of additional therapeutics.

Keywords:  arteriovenous specification; disease model; iPSCs; vascular anomalies; vascular development; venous endothelial cells; venous malformations

DOI:  https://doi.org/10.1016/j.stem.2024.10.015
J Clin Invest. 2024 Nov 26. pii: e177375. [Epub ahead of print]

Beclin 1 prevents ISG15-mediated cytokine storms to secure fetal hematopoiesis and survival.

Wen Wei, Xueqin Gao, Jiawei Qian, Lei Li, Chen Zhao, Li Xu, Yanfei Zhu, Zhenzhen Liu, Nengrong Liu, Xueqing Wang, Zhicong Jin, Bowen Liu, Lan Xu, Jin Dong, Suping Zhang, Jiarong Wang, Yumu Zhang, Yao Yu, Zhanjun Yan, Yanjun Yang, Jie Lu, Yixuan Fang, Na Yuan, Jianrong Wang.

  Proper control of inflammatory responses is essential for embryonic development, but the underlying mechanism is poorly understood. Here, we show that under physiological conditions, inactivation of ISG15, an inflammation amplifier, is associated with the interaction of Beclin 1 (Becn1), via its ECD domain, with STAT3 in the major fetal hematopoietic organ of mice. Conditional loss of Becn1 caused sequential dysfunction and exhaustion of fetal liver hematopoietic stem cells, leading to lethal inflammatory cell-biased hematopoiesis in the fetus. Molecularly, the absence of Becn1 resulted in the release of STAT3 from Becn1 tethering and subsequent phosphorylation and translocation to the nucleus, which in turn directly activated the transcription of ISG15 in fetal liver hematopoietic cells, coupled with increased ISGylation and production of inflammatory cytokines, whereas inactivating STAT3 reduced ISG15 transcription and inflammation but improved hematopoiesis potential, and further silencing ISG15 mitigated the above collapse in the Becn1 null hematopoietic lineage. The Becn1-STAT3-ISG15 axis remains functional in autophagy-disrupted fetal hematopoietic organs. These results suggest that Becn1, in an autophagy-independent manner, secures hematopoiesis and survival of the fetus by directly inhibiting STAT3-ISG15 activation to prevent cytokine storms. Our findings highlight a previously undocumented role of Becn1 in governing ISG15 to safeguard the fetus.

Keywords:  Autophagy; Cellular immune response; Hematology; Hematopoietic stem cells; Immunology

DOI:  https://doi.org/10.1172/JCI177375