bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2021‒11‒14
sixteen papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute
  1. Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
  2. The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.
  3. Overview of the regulation of the class IA PI3K/AKT pathway by SUMO.
  4. Raptor is critical for increasing the mitochondrial proteome and skeletal muscle force during hypertrophy.
  5. A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing.
  6. MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.
  7. Cell type ontologies of the Human Cell Atlas.
  8. MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.
  9. A Robust Protocol for CRISPR-Cas9 Gene Editing in Human Suspension Cell Lines.
  10. CRISPR-Cas9 Genome Editing of Primary Human Vascular Cells In Vitro.
  11. PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients.
  12. Optical Control of Phosphoinositide Binding: Rapid Activation of Subcellular Protein Translocation and Cell Signaling.
  13. The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function.
  14. Nutritional reprogramming of mouse liver proteome is dampened by metformin, resveratrol, and rapamycin.
  15. Elevated circulating follistatin associates with an increased risk of type 2 diabetes.
  16. AdipoAtlas: A reference lipidome for human white adipose tissue.
  1. PLoS Genet. 2021 Nov;17(11): e1009876
    Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype.
    Ralitsa R Madsen, Emily C Erickson, Oscar M Rueda, Xavier Robin, Carlos Caldas, Alex Toker, Robert K Semple, Bart Vanhaesebroeck.
      A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a "biphasic" relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CAH1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.
    DOI:  https://doi.org/10.1371/journal.pgen.1009876
  2. J Mol Cell Biol. 2021 Nov 09. pii: mjab073. [Epub ahead of print]
    The regulatory subunits of PI3K, p85α and p85β, differentially affect BRD7-mediated regulation of insulin signaling.
    Junsik M Lee, Renyan Liu, Sang Won Park.
      Bromodomain-containing protein 7 (BRD7) has been shown to interact with the regulatory subunit of phosphatidylinositol 3-kinase (PI3K), p85, in the insulin signaling pathway. Here, we show that upregulation of hepatic BRD7 improves glucose homeostasis even in the absence of either p85 isoform, p85α or p85β. However, BRD7 leads to differential activation of downstream effector proteins in the insulin signaling pathway depending on which isoform of p85 is present. In the presence of only p85α, BRD7 overexpression increases phosphorylation of insulin receptor upon insulin stimulation, without increasing the recruitment of p85 to insulin receptor substrate. Overexpression of BRD7 also increases activation of Akt in response to insulin but does not affect basal phosphorylation levels of Akt. Meanwhile, the phosphorylation of glycogen synthase kinase 3β (GSK3β) is increased by overexpression of BRD7. On the other hand, in the presence of only p85β, BRD7 overexpression does not affect phosphorylation levels of insulin receptor, and Akt phosphorylation is not affected by insulin stimulation following BRD7 upregulation. However, BRD7 overexpression leads to increased basal phosphorylation levels of Akt and GSK3β. These data demonstrate that BRD7's action on glucose homeostasis does not require the presence of both p85 isoforms, and p85α and p85β have unique roles in insulin signaling in the liver.
    Keywords:  Akt; BRD7; PI3K; insulin signaling
    DOI:  https://doi.org/10.1093/jmcb/mjab073
  3. Semin Cell Dev Biol. 2021 Nov 06. pii: S1084-9521(21)00275-5. [Epub ahead of print]
    Overview of the regulation of the class IA PI3K/AKT pathway by SUMO.
    Santiago Vidal, Yanis Hichem Bouzaher, Ahmed El Motiam, Rocío Seoane, Carmen Rivas.
      The phosphatidylinositol-3-kinase (PI3K)/AKT pathway is a major regulator of metabolism, migration, survival, proliferation, and antiviral immunity. Both an overactivation and an inhibition of the PI3K/AKT pathway are related to different pathologies. Activation of this signaling pathway is tightly controlled through a multistep process and its deregulation can be associated with aberrant post-translational modifications including SUMOylation. Here, we review the complex modulation of the PI3K/AKT pathway by SUMOylation and we discuss its putative involvement in human disease.
    Keywords:  AKT; PI3K; PTEN; SUMO; p110; p85
    DOI:  https://doi.org/10.1016/j.semcdb.2021.10.012
  4. FASEB J. 2021 Dec;35(12): e22031
    Raptor is critical for increasing the mitochondrial proteome and skeletal muscle force during hypertrophy.
    Martina Baraldo, Leonardo Nogara, Georgia Ana Dumitras, Achille Homère Tchampda Dondjang, Alessia Geremia, Marco Scalabrin, Clara Türk, Frederik Telkamp, Lorena Zentilin, Mauro Giacca, Marcus Krüger, Bert Blaauw.
      Loss of skeletal muscle mass and force is of critical importance in numerous pathologies, like age-related sarcopenia or cancer. It has been shown that the Akt-mTORC1 pathway is critical for stimulating adult muscle mass and function, however, it is unknown if mTORC1 is the only mediator downstream of Akt and which intracellular processes are required for functional muscle growth. Here, we show that loss of Raptor reduces muscle hypertrophy after Akt activation and completely prevents increases in muscle force. Interestingly, the residual hypertrophy after Raptor deletion can be completely prevented by administration of the mTORC1 inhibitor rapamycin. Using a quantitative proteomics approach we find that loss of Raptor affects the increases in mitochondrial proteins, while rapamycin mainly affects ribosomal proteins. Taken together, these results suggest that mTORC1 is the key mediator of Akt-dependent muscle growth and its regulation of the mitochondrial proteome is critical for increasing muscle force.
    Keywords:  Raptor; hypertrophy; mTOR; mitochondria; rapamycin; skeletal muscle
    DOI:  https://doi.org/10.1096/fj.202101054RR
  5. Nat Commun. 2021 Nov 11. 12(1): 6512
    A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing.
    Sanju Sinha, Karina Barbosa, Kuoyuan Cheng, Mark D M Leiserson, Prashant Jain, Anagha Deshpande, David M Wilson, Bríd M Ryan, Ji Luo, Ze'ev A Ronai, Joo Sang Lee, Aniruddha J Deshpande, Eytan Ruppin.
      Recent studies have reported that genome editing by CRISPR-Cas9 induces a DNA damage response mediated by p53 in primary cells hampering their growth. This could lead to a selection of cells with pre-existing p53 mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing p53 mutations by CRISPR-Cas9. We next demonstrate that similar to p53, wildtype KRAS may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing KRAS-mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing p53 or KRAS mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing p53 and KRAS mutations.
    DOI:  https://doi.org/10.1038/s41467-021-26788-6
  6. Sci Adv. 2021 Nov 12. 7(46): eabi6439
    MAPK6-AKT signaling promotes tumor growth and resistance to mTOR kinase blockade.
    Qinbo Cai, Wolong Zhou, Wei Wang, Bingning Dong, Dong Han, Tao Shen, Chad J Creighton, David D Moore, Feng Yang.
      [Figure: see text].
    DOI:  https://doi.org/10.1126/sciadv.abi6439
  7. Nat Cell Biol. 2021 Nov;23(11): 1129-1135
    Cell type ontologies of the Human Cell Atlas.
    David Osumi-Sutherland, Chuan Xu, Maria Keays, Adam P Levine, Peter V Kharchenko, Aviv Regev, Ed Lein, Sarah A Teichmann.
      Massive single-cell profiling efforts have accelerated our discovery of the cellular composition of the human body while at the same time raising the need to formalize this new knowledge. Here, we discuss current efforts to harmonize and integrate different sources of annotations of cell types and states into a reference cell ontology. We illustrate with examples how a unified ontology can consolidate and advance our understanding of cell types across scientific communities and biological domains.
    DOI:  https://doi.org/10.1038/s41556-021-00787-7
  8. Immunity. 2021 Nov 03. pii: S1074-7613(21)00448-9. [Epub ahead of print]
    MTHFD2 is a metabolic checkpoint controlling effector and regulatory T cell fate and function.
    Ayaka Sugiura, Gabriela Andrejeva, Kelsey Voss, Darren R Heintzman, Xincheng Xu, Matthew Z Madden, Xiang Ye, Katherine L Beier, Nowrin U Chowdhury, Melissa M Wolf, Arissa C Young, Dalton L Greenwood, Allison E Sewell, Shailesh K Shahi, Samantha N Freedman, Alanna M Cameron, Patrik Foerch, Tim Bourne, Juan C Garcia-Canaveras, John Karijolich, Dawn C Newcomb, Ashutosh K Mangalam, Joshua D Rabinowitz, Jeffrey C Rathmell.
      Antigenic stimulation promotes T cell metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) regulates de novo purine synthesis and signaling in activated T cells to promote proliferation and inflammatory cytokine production. In pathogenic T helper-17 (Th17) cells, MTHFD2 prevented aberrant upregulation of the transcription factor FoxP3 along with inappropriate gain of suppressive capacity. MTHFD2 deficiency also promoted regulatory T (Treg) cell differentiation. Mechanistically, MTHFD2 inhibition led to depletion of purine pools, accumulation of purine biosynthetic intermediates, and decreased nutrient sensor mTORC1 signaling. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. MTHFD2 is thus a metabolic checkpoint to integrate purine metabolism with pathogenic effector cell signaling and is a potential therapeutic target within 1C metabolism pathways.
    Keywords:  CD4(+) T cells; CRISPR screen; MTHFD2; T cell differentiation; inflammation; mTORC1; metabolic checkpoint; methylation; one carbon metabolism; purine metabolism
    DOI:  https://doi.org/10.1016/j.immuni.2021.10.011
  9. Curr Protoc. 2021 Nov;1(11): e286
    A Robust Protocol for CRISPR-Cas9 Gene Editing in Human Suspension Cell Lines.
    Joanna D Wardyn, Allison S Y Chan, Anand D Jeyasekharan.
      The implementation of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 systems in mammalian cells has sparked an exciting new era in targeted gene editing. CRISPR-Cas9 technologies allow gene function to be interrogated by gene deletions, mutations, and truncations, and by epitope tagging and promoter activity modulation. Many robust protocols have been published to date on CRISPR-Cas9 techniques, however, most of these focus on adherent cell lines. Suspension cell lines, typically of hematolymphoid origin, such as Jurkat, Daudi, and TOLEDO, pose unique challenges to the setup of CRISPR experiments. Here, using B cell lymphoma cells as a primary model, we describe a comprehensive protocol for targeted gene manipulations using the CRISPR-Cas9 system in suspension cells. We also highlight necessary optimization steps to make this approach universal to other suspension cell lines. We first describe a detailed protocol for transient expression of the Cas9 nuclease and guide RNAs. We then suggest workflows for obtaining single-cell clones and for screening for successful homozygous knockout (KO) clones in suspension lines. This protocol aims to serve as a comprehensive resource to facilitate gene editing experiments for users starting CRISPR-Cas9 gene editing protocols on suspension cell lines or those looking to optimize their current workflows. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Transient CRISPR Cas9-gRNA delivery for gene knockout by NeonTM electroporation Support Protocol 1: Designing and preparing gene-specific gRNA Support Protocol 2: Preparation of conditioned medium and culture vessels for single-cell FACS Alternate Protocol 1: Transient CRISPR Cas9-gRNA delivery for gene knockout by Nepagene electroporator Basic Protocol 2: FACS and single-cell clone generation Alternate Protocol 2: Manual cell dilution to obtain single-cell clones Basic Protocol 3: Confirming indels status in single-cell clones by PCR on genomic DNA and Sanger sequencing.
    Keywords:  B cell lymphoma; CRISPR-Cas9; electroporation; gRNA; gene editing; knockout; mammalian; suspension cell lines
    DOI:  https://doi.org/10.1002/cpz1.286
  10. Curr Protoc. 2021 Nov;1(11): e291
    CRISPR-Cas9 Genome Editing of Primary Human Vascular Cells In Vitro.
    Deepak S Atri, Vivian S Lee-Kim, Shamsudheen K Vellarikkal, Oscar Sias-Garcia, Mounica Yanamandala, Gavin R Schniztler, Rajat M Gupta.
      Genome editing of primary human cells with CRISPR-Cas9 is a powerful tool to study gene function. For many cell types, there are efficient protocols for editing with optimized plasmids for Cas9 and sgRNA expression. Vascular cells, however, remain refractory to plasmid-based delivery of CRISPR machinery for in vitro genome editing due to low transfection efficiency, poor expression of the Cas9 machinery, and toxic effects of the selection antibiotics. Here, we describe a method for high-efficiency editing of primary human vascular cells in vitro using nucleofection for direct delivery of sgRNA:Cas9-NLS ribonucleoprotein complexes. This method is more rapid and its high editing efficiency eliminates the need for additional selection steps. The edited cells can be employed in diverse applications, such as gene expression measurement or functional assays to assess various genetic perturbation effects in vitro. This method proves effective in vascular cells that are refractory to standard genome manipulation techniques using viral plasmid delivery. We anticipate that this technique will be applied to other non-vascular cell types that face similar barriers to efficient genome editing. © 2021 Wiley Periodicals LLC. Basic Protocol: CRISPR-Cas9 genome editing of primary human vascular cells in vitro.
    Keywords:  CRISPR; Cas9; endothelial cells; genome editing; vascular smooth muscle cells
    DOI:  https://doi.org/10.1002/cpz1.291
  11. Cancers (Basel). 2021 Nov 04. pii: 5535. [Epub ahead of print]13(21):
    PI3Kδ Inhibitors as Immunomodulatory Agents for the Treatment of Lymphoma Patients.
    Chiara Tarantelli, Lisa Argnani, Pier Luigi Zinzani, Francesco Bertoni.
      The development of small molecules able to block specific or multiple isoforms of phosphoinositide 3-kinases (PI3K) has already been an active field of research for many years in the cancer field. PI3Kδ inhibitors are among the targeted agents most extensively studied for the treatment of lymphoma patients and PI3Kδ inhibitors are already approved by regulatory agencies. More recently, it became clear that the anti-tumor activity of PI3K inhibitors might not be due only to a direct effect on the cancer cells but it can also be mediated via inhibition of the kinases in non-neoplastic cells present in the tumor microenvironment. T-cells represent an important component of the tumor microenvironment and they comprise different subpopulations that can have both anti- and pro-tumor effects. In this review article, we discuss the effects that PI3Kδ inhibitors exert on the immune system with a particular focus on the T-cell compartment.
    Keywords:  B-cells; PI3K inhibitors; T-cells; cancer; chemokine; immune checkpoint inhibitors; lymphoma; macrophages; tumor
    DOI:  https://doi.org/10.3390/cancers13215535
  12. ACS Synth Biol. 2021 Nov 08.
    Optical Control of Phosphoinositide Binding: Rapid Activation of Subcellular Protein Translocation and Cell Signaling.
    Amy Ryan, Gerald R V Hammond, Alexander Deiters.
      Cells utilize protein translocation to specific compartments for spatial and temporal regulation of protein activity, in particular in the context of signaling processes. Protein recognition and binding to various subcellular membranes is mediated by a network of phosphatidylinositol phosphate (PIP) species bearing one or multiple phosphate moieties on the polar inositol head. Here, we report a new, highly efficient method for optical control of protein localization through the site-specific incorporation of a photocaged amino acid for steric and electrostatic disruption of inositol phosphate recognition and binding. We demonstrate general applicability of the approach by photocaging two unrelated proteins, sorting nexin 3 (SNX3) and the pleckstrin homology (PH) domain of phospholipase C delta 1 (PLCδ1), with two distinct PIP binding domains and distinct subcellular localizations. We have established the applicability of this methodology through its application to Son of Sevenless 2 (SOS2), a signaling protein involved in the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) cascade. Upon fusing the photocaged plasma membrane-targeted construct PH-enhanced green fluorescent protein (EGFP), to the catalytic domain of SOS2, we demonstrated light-induced membrane localization of the construct resulting in fast and extensive activation of the ERK signaling pathway in NIH 3T3 cells. This approach can be readily extended to other proteins, with minimal protein engineering, and provides a method for acute optical control of protein translocation with rapid and complete activation.
    Keywords:  endosome localization; membrane localization; optochemical biology; optogenetics; phosphatidylinositol phosphate
    DOI:  https://doi.org/10.1021/acssynbio.1c00328
  13. Nat Cell Biol. 2021 Nov;23(11): 1136-1147
    The RNA helicase Ddx21 controls Vegfc-driven developmental lymphangiogenesis by balancing endothelial cell ribosome biogenesis and p53 function.
    Katarzyna Koltowska, Kazuhide S Okuda, Marleen Gloger, Maria Rondon-Galeano, Elizabeth Mason, Jiachen Xuan, Stefanie Dudczig, Huijun Chen, Hannah Arnold, Renae Skoczylas, Neil I Bower, Scott Paterson, Anne Karine Lagendijk, Gregory J Baillie, Ignaty Leshchiner, Cas Simons, Kelly A Smith, Wolfram Goessling, Joan K Heath, Richard B Pearson, Elaine Sanij, Stefan Schulte-Merker, Benjamin M Hogan.
      The development of a functional vasculature requires the coordinated control of cell fate, lineage differentiation and network growth. Cellular proliferation is spatiotemporally regulated in developing vessels, but how this is orchestrated in different lineages is unknown. Here, using a zebrafish genetic screen for lymphatic-deficient mutants, we uncover a mutant for the RNA helicase Ddx21. Ddx21 cell-autonomously regulates lymphatic vessel development. An established regulator of ribosomal RNA synthesis and ribosome biogenesis, Ddx21 is enriched in sprouting venous endothelial cells in response to Vegfc-Flt4 signalling. Ddx21 function is essential for Vegfc-Flt4-driven endothelial cell proliferation. In the absence of Ddx21, endothelial cells show reduced ribosome biogenesis, p53 and p21 upregulation and cell cycle arrest that blocks lymphangiogenesis. Thus, Ddx21 coordinates the lymphatic endothelial cell response to Vegfc-Flt4 signalling by balancing ribosome biogenesis and p53 function. This mechanism may be targetable in diseases of excessive lymphangiogenesis such as cancer metastasis or lymphatic malformation.
    DOI:  https://doi.org/10.1038/s41556-021-00784-w
  14. Cell Metab. 2021 Nov 06. pii: S1550-4131(21)00528-3. [Epub ahead of print]
    Nutritional reprogramming of mouse liver proteome is dampened by metformin, resveratrol, and rapamycin.
    David G Le Couteur, Samantha M Solon-Biet, Benjamin L Parker, Tamara Pulpitel, Amanda E Brandon, Nicholas J Hunt, Jibran A Wali, Rahul Gokarn, Alistair M Senior, Gregory J Cooney, David Raubenheimer, Victoria C Cogger, David E James, Stephen J Simpson.
      Nutrient sensing pathways influence metabolic health and aging, offering the possibility that diet might be used therapeutically, alone or with drugs targeting these pathways. We used the Geometric Framework for Nutrition to study interactive and comparative effects of diet and drugs on the hepatic proteome in mice across 40 dietary treatments differing in macronutrient ratios, energy density, and drug treatment (metformin, rapamycin, resveratrol). There was a strong negative correlation between dietary energy and the spliceosome and a strong positive correlation between dietary protein and mitochondria, generating oxidative stress at high protein intake. Metformin, rapamycin, and resveratrol had lesser effects than and dampened responses to diet. Rapamycin and metformin reduced mitochondrial responses to dietary protein while the effects of carbohydrates and fat were downregulated by resveratrol. Dietary composition has a powerful impact on the hepatic proteome, not just on metabolic pathways but fundamental processes such as mitochondrial function and RNA splicing.
    Keywords:  Geometric Framework; Nutrition; caloric restriction; liver; macronutrients; metformin; mitochondria; proteome; rapamycin; resveratrol; spliceosome
    DOI:  https://doi.org/10.1016/j.cmet.2021.10.016
  15. Nat Commun. 2021 Nov 10. 12(1): 6486
    Elevated circulating follistatin associates with an increased risk of type 2 diabetes.
    Chuanyan Wu, Yan Borné, Rui Gao, Maykel López Rodriguez, William C Roell, Jonathan M Wilson, Ajit Regmi, Cheng Luan, Dina Mansour Aly, Andreas Peter, Jürgen Machann, Harald Staiger, Andreas Fritsche, Andreas L Birkenfeld, Rongya Tao, Robert Wagner, Mickaël Canouil, Mun-Gwan Hong, Jochen M Schwenk, Emma Ahlqvist, Minna U Kaikkonen, Peter Nilsson, Angela C Shore, Faisel Khan, Andrea Natali, Olle Melander, Marju Orho-Melander, Jan Nilsson, Hans-Ulrich Häring, Erik Renström, Claes B Wollheim, Gunnar Engström, Jianping Weng, Ewan R Pearson, Paul W Franks, Morris F White, Kevin L Duffin, Allan Arthur Vaag, Markku Laakso, Norbert Stefan, Leif Groop, Yang De Marinis.
      The hepatokine follistatin is elevated in patients with type 2 diabetes (T2D) and promotes hyperglycemia in mice. Here we explore the relationship of plasma follistatin levels with incident T2D and mechanisms involved. Adjusted hazard ratio (HR) per standard deviation (SD) increase in follistatin levels for T2D is 1.24 (CI: 1.04-1.47, p < 0.05) during 19-year follow-up (n = 4060, Sweden); and 1.31 (CI: 1.09-1.58, p < 0.01) during 4-year follow-up (n = 883, Finland). High circulating follistatin associates with adipose tissue insulin resistance and non-alcoholic fatty liver disease (n = 210, Germany). In human adipocytes, follistatin dose-dependently increases free fatty acid release. In genome-wide association study (GWAS), variation in the glucokinase regulatory protein gene (GCKR) associates with plasma follistatin levels (n = 4239, Sweden; n = 885, UK, Italy and Sweden) and GCKR regulates follistatin secretion in hepatocytes in vitro. Our findings suggest that GCKR regulates follistatin secretion and that elevated circulating follistatin associates with an increased risk of T2D by inducing adipose tissue insulin resistance.
    DOI:  https://doi.org/10.1038/s41467-021-26536-w
  16. Cell Rep Med. 2021 Oct 19. 2(10): 100407
    AdipoAtlas: A reference lipidome for human white adipose tissue.
    Mike Lange, Georgia Angelidou, Zhixu Ni, Angela Criscuolo, Jürgen Schiller, Matthias Blüher, Maria Fedorova.
      Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodeling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodeling at the molecular level, we provide in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. We generate a human WAT reference lipidome by performing tissue-tailored preanalytical and analytical workflows, which allow accurate identification and semi-absolute quantification of 1,636 and 737 lipid molecular species, respectively. Deep lipidomic profiling allows identification of main lipid (sub)classes undergoing depot-/phenotype-specific remodeling. Previously unanticipated diversity of WAT ceramides is now uncovered. AdipoAtlas reference lipidome serves as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.
    Keywords:  LC-MS/MS; ceramides; human white adipose tissue; lipid identification; lipid metabolism; lipidomics; obesity; plasmalogens; semi-absolute lipid quantification; sphingolipids; subcutaneous white adipose tissue; triacylglycerols; visceral white adipose tissue
    DOI:  https://doi.org/10.1016/j.xcrm.2021.100407
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