bims-obesme Biomed News
on Obesity metabolism
Issue of 2024‒06‒09
nine papers selected by
Xiong Weng, University of Edinburgh
  1. Single-cell analysis reveals a subpopulation of adipose progenitor cells that impairs glucose homeostasis.
  2. Diacylglycerol kinase delta overexpression improves glucose clearance and protects against the development of obesity.
  3. PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
  4. Two-stage evolution of mammalian adipose tissue thermogenesis.
  5. Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation.
  6. A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
  7. Proteomic Analysis of Signaling Pathways Modulated by FABP5 in Macrophages.
  8. Microbial metabolite butyrate modulates granzyme B in tolerogenic IL-10 producing Th1 cells to regulate intestinal inflammation.
  9. The evolution of thermogenesis in mammals.
  1. Nat Commun. 2024 Jun 06. 15(1): 4827
    Single-cell analysis reveals a subpopulation of adipose progenitor cells that impairs glucose homeostasis.
    Hongdong Wang, Yanhua Du, Shanshan Huang, Xitai Sun, Youqiong Ye, Haixiang Sun, Xuehui Chu, Xiaodong Shan, Yue Yuan, Lei Shen, Yan Bi.
      Adipose progenitor cells (APCs) are heterogeneous stromal cells and help to maintain metabolic homeostasis. However, the influence of obesity on human APC heterogeneity and the role of APC subpopulations on regulating glucose homeostasis remain unknown. Here, we find that APCs in human visceral adipose tissue contain four subsets. The composition and functionality of APCs are altered in patients with type 2 diabetes (T2D). CD9+CD55low APCs are the subset which is significantly increased in T2D patients. Transplantation of these cells from T2D patients into adipose tissue causes glycemic disturbance. Mechanistically, CD9+CD55low APCs promote T2D development through producing bioactive proteins to form a detrimental niche, leading to upregulation of adipocyte lipolysis. Depletion of pathogenic APCs by inducing intracellular diphtheria toxin A expression or using a hunter-killer peptide improves obesity-related glycemic disturbance. Collectively, our data provide deeper insights in human APC functionality and highlights APCs as a potential therapeutic target to combat T2D. All mice utilized in this study are male.
    DOI:  https://doi.org/10.1038/s41467-024-48914-w
  2. Metabolism. 2024 Jun 04. pii: S0026-0495(24)00166-5. [Epub ahead of print] 155939
    Diacylglycerol kinase delta overexpression improves glucose clearance and protects against the development of obesity.
    Maxence Jollet, Flavia Tramontana, Lake Q Jiang, Melissa L Borg, Mladen Savikj, Michael S Kuefner, Julie Massart, Thais de Castro Barbosa, Louise Mannerås-Holm, Antonio Checa, Nicolas J Pillon, Alexander V Chibalin, Marie Björnholm, Juleen R Zierath.
      BACKGROUND AND AIM: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C signaling by converting DAG to phosphatidic acid. DGKδ (type II isozyme) downregulation causes insulin resistance, metabolic inflexibility, and obesity. Here we determined whether DGKδ overexpression prevents these metabolic impairments.METHODS: We generated a transgenic mouse model overexpressing human DGKδ2 under the myosin light chain promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG mice and wild-type littermates fed chow or high-fat diet (HFD). Mice were also provided free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes.
    RESULTS: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance and increased skeletal muscle glycogen content. DGKδ TG mice were protected against HFD-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulated the beneficial effects of exercise on metabolic outcomes. DGKδ overexpression and exercise had a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle revealed common gene ontology signatures of exercise and DGKδ overexpression that were related to lipid storage, extracellular matrix, and glycerophospholipids biosynthesis pathways.
    CONCLUSION: Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.
    Keywords:  Exercise; Glucose metabolism; Lipid metabolism; Lipid species; Obesity
    DOI:  https://doi.org/10.1016/j.metabol.2024.155939
  3. Nat Commun. 2024 Jun 06. 15(1): 4847
    PNPLA3 is a triglyceride lipase that mobilizes polyunsaturated fatty acids to facilitate hepatic secretion of large-sized very low-density lipoprotein.
    Scott M Johnson, Hanmei Bao, Cailin E McMahon, Yongbin Chen, Stephanie D Burr, Aaron M Anderson, Katja Madeyski-Bengtson, Daniel Lindén, Xianlin Han, Jun Liu.
      The I148M variant of PNPLA3 is closely associated with hepatic steatosis. Recent evidence indicates that the I148M mutant functions as an inhibitor of PNPLA2/ATGL-mediated lipolysis, leaving the role of wild-type PNPLA3 undefined. Despite showing a triglyceride hydrolase activity in vitro, PNPLA3 has yet to be established as a lipase in vivo. Here, we show that PNPLA3 preferentially hydrolyzes polyunsaturated triglycerides, mobilizing polyunsaturated fatty acids for phospholipid desaturation and enhancing hepatic secretion of triglyceride-rich lipoproteins. Under lipogenic conditions, mice with liver-specific knockout or acute knockdown of PNPLA3 exhibit aggravated liver steatosis and reduced plasma VLDL-triglyceride levels. Similarly, I148M-knockin mice show decreased hepatic triglyceride secretion during lipogenic stimulation. Our results highlight a specific context whereby the wild-type PNPLA3 facilitates the balance between hepatic triglyceride storage and secretion, and suggest the potential contribution of a loss-of-function by the I148M variant to the development of fatty liver disease in humans.
    DOI:  https://doi.org/10.1038/s41467-024-49224-x
  4. Science. 2024 Jun 07. 384(6700): 1111-1117
    Two-stage evolution of mammalian adipose tissue thermogenesis.
    Susanne Keipert, Michael J Gaudry, Maria Kutschke, Michaela Keuper, Margeoux A S Dela Rosa, Yiming Cheng, José M Monroy Kuhn, Rutger Laterveer, Camila A Cotrim, Peter Giere, Fabiana Perocchi, Regina Feederle, Paul G Crichton, Dominik Lutter, Martin Jastroch.
      Brown adipose tissue (BAT) is a heater organ that expresses thermogenic uncoupling protein 1 (UCP1) to maintain high body temperatures during cold stress. BAT thermogenesis is considered an overarching mammalian trait, but its evolutionary origin is unknown. We show that adipose tissue of marsupials, which diverged from eutherian mammals ~150 million years ago, expresses a nonthermogenic UCP1 variant governed by a partial transcriptomic BAT signature similar to that found in eutherian beige adipose tissue. We found that the reconstructed UCP1 sequence of the common eutherian ancestor displayed typical thermogenic activity, whereas therian ancestor UCP1 is nonthermogenic. Thus, mammalian adipose tissue thermogenesis may have evolved in two distinct stages, with a prethermogenic stage in the common therian ancestor linking UCP1 expression to adipose tissue and thermal stress. We propose that in a second stage, UCP1 acquired its thermogenic function specifically in eutherians, such that the onset of mammalian BAT thermogenesis occurred only after the divergence from marsupials.
    DOI:  https://doi.org/10.1126/science.adg1947
  5. Nat Commun. 2024 Jun 05. 15(1): 4792
    Microbiota regulates the TET1-mediated DNA hydroxymethylation program in innate lymphoid cell differentiation.
    Xusheng Zhang, Xintong Gao, Zhen Liu, Fei Shao, Dou Yu, Min Zhao, Xiwen Qin, Shuo Wang.
      Innate lymphoid cell precursors (ILCPs) develop into distinct subsets of innate lymphoid cells (ILCs) with specific functions. The epigenetic program underlying the differentiation of ILCPs into ILC subsets remains poorly understood. Here, we reveal the genome-wide distribution and dynamics of the DNA methylation and hydroxymethylation in ILC subsets and their respective precursors. Additionally, we find that the DNA hydroxymethyltransferase TET1 suppresses ILC1 but not ILC2 or ILC3 differentiation. TET1 deficiency promotes ILC1 differentiation by inhibiting TGF-β signaling. Throughout ILCP differentiation at postnatal stage, gut microbiota contributes to the downregulation of TET1 level. Microbiota decreases the level of cholic acid in the gut, impairs TET1 expression and suppresses DNA hydroxymethylation, ultimately resulting in an expansion of ILC1s. In adult mice, TET1 suppresses the hyperactivation of ILC1s to maintain intestinal homeostasis. Our findings provide insights into the microbiota-mediated epigenetic programming of ILCs, which links microbiota-DNA methylation crosstalk to ILC differentiation.
    DOI:  https://doi.org/10.1038/s41467-024-48794-0
  6. Nat Aging. 2024 Jun 07.
    A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.
    Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo Efeyan.
      The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.
    DOI:  https://doi.org/10.1038/s43587-024-00635-x
  7. J Pharmacol Exp Ther. 2024 Jun 07. pii: JPET-AR-2023-002006. [Epub ahead of print]
    Proteomic Analysis of Signaling Pathways Modulated by FABP5 in Macrophages.
    Faniya Doswell, John D Haley, Martin Kaczocha.
      While acute inflammation serves essential functions in maintaining tissue homeostasis, chronic inflammation is causally linked to many diseases. Macrophages are a major cell-type that orchestrates inflammatory processes. During inflammation, macrophages undergo polarization and activation, thereby mobilizing pro-inflammatory and anti-inflammatory transcriptional programs that regulate ensuing macrophage functions. Fatty acid binding protein 5 (FABP5) is a lipid chaperone highly expressed in macrophages. FABP5 deletion is implicated in driving macrophages towards an anti-inflammatory phenotype, yet signaling pathways regulated by macrophage-FABP5 have not been systematically profiled. We leveraged proteomic and phosphoproteomic approaches to characterize pathways modulated by FABP5 in M1 and M2 polarized bone marrow derived macrophages (BMDMs). Stable isotope labeling by amino acids (SILAC) based analysis of M1 and M2 polarized wild-type (WT) and FABP5 knockout (KO) BMDMs revealed numerous differentially regulated proteins and phosphoproteins. FABP5 deletion impacted downstream pathways associated with inflammation, cytokine production, oxidative stress, and kinase activity. Toll-like receptor 2 (TLR2) emerged as a novel target of FABP5 and pharmacological FABP5 inhibition blunted TLR2-mediated activation of downstream pathways, ascribing a novel role for FABP5 in TLR2 signaling. This study represents a comprehensive characterization of the impact of FABP5 deletion upon the proteomic and phosphoproteomic landscape of M1 and M2 polarized BMDMs. Loss of FABP5 altered pathways implicated in inflammatory responses, macrophage function, and TLR2 signaling. This work provides a foundation for future studies seeking to investigate the therapeutic potential of FABP5 inhibition in pathophysiological states resulting from dysregulated inflammatory signaling. Significance Statement This work employed quantitative proteomic and phosphoproteomic approaches to characterize the proteomic profiles of bone marrow derived macrophages obtained from wild-type and fatty acid binding protein 5 (FABP5) knockout mice. Our findings revealed multiple differentially regulated pathways in M1 and M2 polarized FABP5 knockout macrophages compared to wild-type controls, notably those related to inflammation. These results expand our understanding of FABP5 function in macrophages and support recent studies highlighting the therapeutic potential of targeting macrophage FABP5 to treat inflammatory diseases.
    Keywords:  fatty acid metabolism; inflammation; macrophages; proteomics
    DOI:  https://doi.org/10.1124/jpet.123.002006
  8. Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2363020
    Microbial metabolite butyrate modulates granzyme B in tolerogenic IL-10 producing Th1 cells to regulate intestinal inflammation.
    Wenjing Yang, Tianming Yu, Xia Liu, Suxia Yao, Kamil Khanipov, George Golovko, Danyvid Olivares-Villagómez, Yingzi Cong.
      CD4+ T cells play a critical role in regulating autoimmune diseases, and intestinal microbial metabolites control various immune responses. Granzyme B (GzmB)-producing CD4+ T cells have been recently reported to participate in the pathogenesis of autoimmune diseases. Here, we found that GzmbB-deficient CD4+ T cells induced more severe colitis in Rag1-/- mice than wild-type (WT) CD4+ T cells. Germ-free (GF) mice exhibited a lower expression of GzmB in intestinal CD4+ T cells compared to specific pathogen-free (SPF) mice. Intestinal microbial metabolite butyrate increased GzmB expression in CD4+ T cells, especially in IL-10-producing Th1 cells, through HDAC inhibition and GPR43, but not GPR41 and GPR109a. Butyrate-treated GzmB-deficient CD4+ T cells demonstrated more severe colitis compared to butyrate-treated WT CD4+ T cells in the T cell transfer model. Butyrate altered intestinal microbiota composition, but altered microbiota did not mediate butyrate induction of intestinal CD4+ T cell expression of GzmB in mice. Blimp1 was involved in the butyrate induction of GzmB in IL-10-producing Th1 cells. Glucose metabolism, including glycolysis and pyruvate oxidation, mediated butyrate induction of GzmB in Th1 cells. In addition, we found that IKZF3 and NR2F6 regulated GzmB expression induced by butyrate. Together, our studies underscored the critical role of GzmB in mediating gut bacterial metabolite butyrate regulation of T cell tolerance at the mucosal surface.
    Keywords:  GzmB; Microbiota; colitis; glucose metabolism
    DOI:  https://doi.org/10.1080/19490976.2024.2363020
  9. Science. 2024 Jun 07. 384(6700): 1065-1066
    The evolution of thermogenesis in mammals.
    Katharine R Grabek, Ryan J Sprenger.
      Comparative genomics elucidates the steps enabling heat production in fat tissue.
    DOI:  https://doi.org/10.1126/science.adp8782
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