bims-obesme Biomed News
on Obesity metabolism
Issue of 2024–07–07
ten papers selected by
Xiong Weng, University of Edinburgh
  1. Lipid-associated macrophages reshape BAT cell identity in obesity.
  2. Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.
  3. Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca2+ signaling.
  4. Wnt/Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression.
  5. Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.
  6. GTPBP8 plays a role in mitoribosome formation in human mitochondria.
  7. BACH1 inhibits senescence, obesity, and short lifespan by ferroptotic FGF21 secretion.
  8. Why do some individuals with obesity remain metabolically healthy?
  9. Differential signalling requirements for RIPK1-dependent pyroptosis in neutrophils and macrophages.
  10. KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.
  1. Cell Rep. 2024 Jul 03. pii: S2211-1247(24)00776-9. [Epub ahead of print]43(7): 114447
    Lipid-associated macrophages reshape BAT cell identity in obesity.
    Francesca Sciarretta, Andrea Ninni, Fabio Zaccaria, Valerio Chiurchiù, Adeline Bertola, Keaton Karlinsey, Wentong Jia, Veronica Ceci, Claudia Di Biagio, Ziyan Xu, Francesco Gaudioso, Flavia Tortolici, Marta Tiberi, Jiabi Zhang, Simone Carotti, Sihem Boudina, Paolo Grumati, Beiyan Zhou, Jonathan R Brestoff, Stoyan Ivanov, Katia Aquilano, Daniele Lettieri-Barbato.
      Obesity and type 2 diabetes cause a loss in brown adipose tissue (BAT) activity, but the molecular mechanisms that drive BAT cell remodeling remain largely unexplored. Using a multilayered approach, we comprehensively mapped a reorganization in BAT cells. We uncovered a subset of macrophages as lipid-associated macrophages (LAMs), which were massively increased in genetic and dietary model of BAT expansion. LAMs participate in this scenario by capturing extracellular vesicles carrying damaged lipids and mitochondria released from metabolically stressed brown adipocytes. CD36 scavenger receptor drove LAM phenotype, and CD36-deficient LAMs were able to increase brown fat genes in adipocytes. LAMs released transforming growth factor β1 (TGF-β1), which promoted the loss of brown adipocyte identity through aldehyde dehydrogenase 1 family member A1 (Aldh1a1) induction. These findings unfold cell dynamic changes in BAT during obesity and identify LAMs as key responders to tissue metabolic stress and drivers of loss of brown adipocyte identity.
    Keywords:  CP: Metabolism; adipocytes; extracellular mitochondria; immunometabolism; metabolism; mitochondria; single-cell RNA sequencing; thermogenesis; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2024.114447
  2. Cell Rep Med. 2024 Jul 02. pii: S2666-3791(24)00333-1. [Epub ahead of print] 101629
    Weight-loss maintenance is accompanied by interconnected alterations in circulating FGF21-adiponectin-leptin and bioactive sphingolipids.
    Matteo Fiorenza, Antonio Checa, Rasmus M Sandsdal, Simon B K Jensen, Christian R Juhl, Mikkel H Noer, Nicolai P Bogh, Julie R Lundgren, Charlotte Janus, Bente M Stallknecht, Jens Juul Holst, Sten Madsbad, Craig E Wheelock, Signe S Torekov.
      Weight loss is often followed by weight regain. Characterizing endocrine alterations accompanying weight reduction and regain may disentangle the complex biology of weight-loss maintenance. Here, we profile energy-balance-regulating metabokines and sphingolipids in adults with obesity undergoing an initial low-calorie diet-induced weight loss and a subsequent weight-loss maintenance phase with exercise, glucagon-like peptide-1 (GLP-1) analog therapy, both combined, or placebo. We show that circulating growth differentiation factor 15 (GDF15) and C16:0-C18:0 ceramides transiently increase upon initial diet-induced weight loss. Conversely, circulating fibroblast growth factor 21 (FGF21) is downregulated following weight-loss maintenance with combined exercise and GLP-1 analog therapy, coinciding with increased adiponectin, decreased leptin, and overall decrements in ceramide and sphingosine-1-phosphate levels. Subgroup analyses reveal differential alterations in FGF21-adiponectin-leptin-sphingolipids between weight maintainers and regainers. Clinically, cardiometabolic health outcomes associate with selective metabokine-sphingolipid remodeling signatures. Collectively, our findings indicate distinct FGF21, GDF15, and ceramide responses to diverse phases of weight change and suggest that weight-loss maintenance involves alterations within the metabokine-sphingolipid axis.
    Keywords:  FGF21; GDF15; GLP-1 receptor agonist; adiponectin; ceramide; cytokines; exercise; leptin; obesity; sphingolipids
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101629
  3. EMBO J. 2024 Jul 04.
    Gut microbiota metabolite tyramine ameliorates high-fat diet-induced insulin resistance via increased Ca2+ signaling.
    Peng Ma, Yao Zhang, Youjie Yin, Saifei Wang, Shuxin Chen, Xueping Liang, Zhifang Li, Hansong Deng.
      The gut microbiota and their metabolites are closely linked to obesity-related diseases, such as type 2 diabetes, but their causal relationship and underlying mechanisms remain largely elusive. Here, we found that dysbiosis-induced tyramine (TA) suppresses high-fat diet (HFD)-mediated insulin resistance in both Drosophila and mice. In Drosophila, HFD increases cytosolic Ca2+ signaling in enterocytes, which, in turn, suppresses intestinal lipid levels. 16 S rRNA sequencing and metabolomics revealed that HFD leads to increased prevalence of tyrosine decarboxylase (Tdc)-expressing bacteria and resulting tyramine production. Tyramine acts on the tyramine receptor, TyrR1, to promote cytosolic Ca2+ signaling and activation of the CRTC-CREB complex to transcriptionally suppress dietary lipid digestion and lipogenesis in enterocytes, while promoting mitochondrial biogenesis. Furthermore, the tyramine-induced cytosolic Ca2+ signaling is sufficient to suppress HFD-induced obesity and insulin resistance in Drosophila. In mice, tyramine intake also improves glucose tolerance and insulin sensitivity under HFD. These results indicate that dysbiosis-induced tyramine suppresses insulin resistance in both flies and mice under HFD, suggesting a potential therapeutic strategy for related metabolic disorders, such as diabetes.
    Keywords:  Ca2+ Signaling; Diet-induced Obesity; Insulin Resistance; Microbiota
    DOI:  https://doi.org/10.1038/s44318-024-00162-w
  4. Proc Natl Acad Sci U S A. 2024 Jul 09. 121(28): e2322066121
    Wnt/Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression.
    Mengmeng Liu, Rajitha-Udakara-Sampath Hemba-Waduge, Xiao Li, Xiahe Huang, Tzu-Hao Liu, Xianlin Han, Yingchun Wang, Jun-Yuan Ji.
      The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its role in regulating lipid homeostasis remains not fully understood. Here, we report that the activation of canonical Wnt/Wg signaling promotes lipolysis while concurrently inhibiting lipogenesis and fatty acid β-oxidation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila. Using RNA-sequencing and CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays, we identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased de novo lipogenesis and fatty acid β-oxidation, but increased lipolysis. These changes lead to elevated free fatty acids and reduced triglyceride (TG) accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes TG accumulation in both larval and adult adipocytes. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Taken together, these findings suggest that Wnt signaling-induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid β-oxidation.
    Keywords:  Drosophila; Wnt/Wg; lipid droplets; lipolysis; transcriptional repression
    DOI:  https://doi.org/10.1073/pnas.2322066121
  5. Cell Metab. 2024 Jul 02. pii: S1550-4131(24)00226-2. [Epub ahead of print]36(7): 1619-1633.e5
    Proteomic predictors of individualized nutrient-specific insulin secretion in health and disease.
    Jelena Kolic, WenQing Grace Sun, Haoning Howard Cen, Jessica D Ewald, Jason C Rogalski, Shugo Sasaki, Han Sun, Varsha Rajesh, Yi Han Xia, Renata Moravcova, Søs Skovsø, Aliya F Spigelman, Jocelyn E Manning Fox, James Lyon, Leanne Beet, Jianguo Xia, Francis C Lynn, Anna L Gloyn, Leonard J Foster, Patrick E MacDonald, James D Johnson.
      Population-level variation and mechanisms behind insulin secretion in response to carbohydrate, protein, and fat remain uncharacterized. We defined prototypical insulin secretion responses to three macronutrients in islets from 140 cadaveric donors, including those with type 2 diabetes. The majority of donors' islets exhibited the highest insulin response to glucose, moderate response to amino acid, and minimal response to fatty acid. However, 9% of donors' islets had amino acid responses, and 8% had fatty acid responses that were larger than their glucose-stimulated insulin responses. We leveraged this heterogeneity and used multi-omics to identify molecular correlates of nutrient responsiveness, as well as proteins and mRNAs altered in type 2 diabetes. We also examined nutrient-stimulated insulin release from stem cell-derived islets and observed responsiveness to fat but not carbohydrate or protein-potentially a hallmark of immaturity. Understanding the diversity of insulin responses to carbohydrate, protein, and fat lays the groundwork for personalized nutrition.
    Keywords:  RNA-seq; human islets; insulin secretion; macronutrients; proteomics; stem cell-derived islets; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2024.06.001
  6. Nat Commun. 2024 Jul 05. 15(1): 5664
    GTPBP8 plays a role in mitoribosome formation in human mitochondria.
    Miriam Cipullo, Genís Valentín Gesé, Shreekara Gopalakrishna, Annika Krueger, Vivian Lobo, Maria A Pirozhkova, James Marks, Petra Páleníková, Dmitrii Shiriaev, Yong Liu, Jelena Misic, Yu Cai, Minh Duc Nguyen, Abubakar Abdelbagi, Xinping Li, Michal Minczuk, Markus Hafner, Daniel Benhalevy, Aishe A Sarshad, Ilian Atanassov, B Martin Hällberg, Joanna Rorbach.
      Mitochondrial gene expression relies on mitoribosomes to translate mitochondrial mRNAs. The biogenesis of mitoribosomes is an intricate process involving multiple assembly factors. Among these factors, GTP-binding proteins (GTPBPs) play important roles. In bacterial systems, numerous GTPBPs are required for ribosome subunit maturation, with EngB being a GTPBP involved in the ribosomal large subunit assembly. In this study, we focus on exploring the function of GTPBP8, the human homolog of EngB. We find that ablation of GTPBP8 leads to the inhibition of mitochondrial translation, resulting in significant impairment of oxidative phosphorylation. Structural analysis of mitoribosomes from GTPBP8 knock-out cells shows the accumulation of mitoribosomal large subunit assembly intermediates that are incapable of forming functional monosomes. Furthermore, fPAR-CLIP analysis reveals that GTPBP8 is an RNA-binding protein that interacts specifically with the mitochondrial ribosome large subunit 16 S rRNA. Our study highlights the role of GTPBP8 as a component of the mitochondrial gene expression machinery involved in mitochondrial large subunit maturation.
    DOI:  https://doi.org/10.1038/s41467-024-50011-x
  7. Cell Rep. 2024 Jun 27. pii: S2211-1247(24)00731-9. [Epub ahead of print]43(7): 114403
    BACH1 inhibits senescence, obesity, and short lifespan by ferroptotic FGF21 secretion.
    Hironari Nishizawa, Mitsuyo Matsumoto, Mie Yamanaka, Riko Irikura, Kazuma Nakajima, Keisuke Tada, Yoshiaki Nakayama, Morichika Konishi, Nobuyuki Itoh, Ryo Funayama, Keiko Nakayama, Kazuhiko Igarashi.
      Ferroptosis is a type of regulated cell death characterized by iron-dependent lipid peroxidation. A model cell system is constructed to induce ferroptosis by re-expressing the transcription factor BACH1, a potent ferroptosis inducer, in immortalized mouse embryonic fibroblasts (iMEFs). The transfer of the culture supernatant from ferroptotic iMEFs activates the proliferation of hepatoma cells and other fibroblasts and suppresses cellular senescence-like features. The BACH1-dependent secretion of the longevity factor FGF21 is increased in ferroptotic iMEFs. The anti-senescent effects of the culture supernatant from these iMEFs are abrogated by Fgf21 knockout. BACH1 activates the transcription of Fgf21 by promoting ferroptotic stress and increases FGF21 protein expression by suppressing its autophagic degradation through transcriptional Sqstm1 and Lamp2 repression. The BACH1-induced ferroptotic FGF21 secretion suppresses obesity in high-fat diet-fed mice and the short lifespan of progeria mice. The inhibition of these aging-related phenotypes can be physiologically significant regarding ferroptosis.
    Keywords:  BACH1; CP: Metabolism; DAMPs; FGF21; aging; cell death; cellular senescence; ferroptosis; longevity; obesity; α-klotho
    DOI:  https://doi.org/10.1016/j.celrep.2024.114403
  8. Trends Endocrinol Metab. 2024 Jul 02. pii: S1043-2760(24)00176-0. [Epub ahead of print]
    Why do some individuals with obesity remain metabolically healthy?
    Christoph Buettner, Kenichi Sakamoto, Mary A Butera.
      A recent study by Peterson et al. that characterized individuals with metabolically healthy obesity (MHO) or metabolically unhealthy obesity (MUO) in depth provides insights into the potential pathogenesis of MUO that accounts for much of the cardiometabolic disease and excess mortality caused by the obesity epidemic.
    Keywords:  cardiometabolic health; insulin resistance; metabolically healthy obesity (MHO); metabolically unhealthy obesity (MUO)
    DOI:  https://doi.org/10.1016/j.tem.2024.06.015
  9. Cell Death Dis. 2024 Jul 04. 15(7): 479
    Differential signalling requirements for RIPK1-dependent pyroptosis in neutrophils and macrophages.
    See Jie Yow, Safwah Nasuha Rosli, Paul E Hutchinson, Kaiwen W Chen.
      TLR4 and TNFR1 signalling promotes potent proinflammatory signal transduction events, thus, are often hijacked by pathogenic microorganisms. We recently reported that myeloid cells retaliate Yersinia blockade of TAK1/IKK signalling by triggering RIPK1-dependent caspase-8 activation that promotes downstream GSDMD and GSDME-mediated pyroptosis in macrophages and neutrophils respectively. However, the upstream signalling events for RIPK1 activation in these cells are not well defined. Here, we demonstrate that unlike in macrophages, RIPK1-driven pyroptosis and cytokine priming in neutrophils are driven through TNFR1 signalling, while TLR4-TRIF signalling is dispensable. Furthermore, we demonstrate that activation of RIPK1-dependent pyroptosis in neutrophils during Yersinia infection requires IFN-γ priming, which serves to induce surface TNFR1 expression and amplify soluble TNF secretion. In contrast, macrophages utilise both TNFR1 and TLR4-TRIF signalling to trigger cell death, but only require TRIF but not autocrine TNFR1 for cytokine production. Together, these data highlight the emerging theme of cell type-specific regulation in cell death and immune signalling in myeloid cells.
    DOI:  https://doi.org/10.1038/s41419-024-06871-8
  10. Nat Commun. 2024 Jul 03. 15(1): 5602
    KAT8-mediated H4K16ac is essential for sustaining trophoblast self-renewal and proliferation via regulating CDX2.
    Shilei Bi, Lijun Huang, Yongjie Chen, Zhenhua Hu, Shanze Li, Yifan Wang, Baoying Huang, Lizi Zhang, Yuanyuan Huang, Beibei Dai, Lili Du, Zhaowei Tu, Yijing Wang, Dan Xu, Xiaotong Xu, Wen Sun, Julia Kzhyshkowska, Haibin Wang, Dunjin Chen, Fengchao Wang, Shuang Zhang.
      Abnormal trophoblast self-renewal and differentiation during early gestation is the major cause of miscarriage, yet the underlying regulatory mechanisms remain elusive. Here, we show that trophoblast specific deletion of Kat8, a MYST family histone acetyltransferase, leads to extraembryonic ectoderm abnormalities and embryonic lethality. Employing RNA-seq and CUT&Tag analyses on trophoblast stem cells (TSCs), we further discover that KAT8 regulates the transcriptional activation of the trophoblast stemness marker, CDX2, via acetylating H4K16. Remarkably, CDX2 overexpression partially rescues the defects arising from Kat8 knockout. Moreover, increasing H4K16ac via using deacetylase SIRT1 inhibitor, EX527, restores CDX2 levels and promoted placental development. Clinical analysis shows reduced KAT8, CDX2 and H4K16ac expression are associated with recurrent pregnancy loss (RPL). Trophoblast organoids derived from these patients exhibit impaired TSC self-renewal and growth, which are significantly ameliorated with EX527 treatment. These findings suggest the therapeutic potential of targeting the KAT8-H4K16ac-CDX2 axis for mitigating RPL, shedding light on early gestational abnormalities.
    DOI:  https://doi.org/10.1038/s41467-024-49930-6
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