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Horvath, Carla; Wolfrum, Christian; Pelczar, Pawel
doi: 10.1038/s42255-024-01087-8pmid: 39160335
Despite the high utility and widespread use of Cre driver lines, lack of Cre specificity, Cre-induced toxicity or poor experimental design can affect experimental results and conclusions. Such pitfalls must be considered before embarking on any Cre-based studies in metabolic research.
doi: 10.1038/s42255-024-01111-xpmid: 39112721
Liu et al. found that different subgroups of GABAergic neurons in mouse basal forebrain exert opposite impacts on food consumption, highlighting the complex interaction of basal forebrain and hypothalamus for regulating homeostatic and hedonic aspects of feeding.
doi: 10.1038/s42255-024-01120-wpmid: 39261627
The metabolic sensor enzyme OGT dynamically O-GlcNAcylates hexokinase 1 (HK1). This modification enhances the localization of HK1 to mitochondria in response to glucose flux and facilitates the formation of a glycolytic metabolon on the mitochondrial outer membrane, leading to increased rates of both glycolytic and mitochondrial ATP production.
doi: 10.1038/s42255-024-01102-ypmid: 39256591
Adults with overweight or obesity who have been exercising regularly for at least a few years have distinct structural and biological characteristics in their abdominal subcutaneous adipose tissue. These changes could underlie improved cardiometabolic health outcomes in this population, when compared with well-matched sedentary adults with overweight or obesity.
doi: 10.1038/s42255-024-01117-5pmid: 39169272
Pancreatic β-cells do not appear to require interactions with neighbouring non-β-cells (α-cells, δ-cells and γ-cells) to regulate insulin secretion. These results are clinically relevant and support the development of treatments for diabetes that involve the generation of β-like cells alone, whether from pluripotent cells or by in situ conversion of non-β-cells.
McGettrick, A. F.; Bourner, L. A.; Dorsey, F. C.; O’Neill, L. A. J.
doi: 10.1038/s42255-024-01092-xpmid: 39060560
The metabolite itaconate has emerged as an important immunoregulator with roles in antibacterial defence, inhibition of inflammation and, more recently, as an inhibitory factor in obesity. Itaconate is one of the most upregulated metabolites in inflammatory macrophages. It is produced owing to the disturbance of the tricarboxylic acid cycle and the diversion of aconitate to itaconate via the enzyme aconitate decarboxylase 1. In immunology, initial studies concentrated on the role of itaconate in inflammatory macrophages where it was shown to be inhibitory, but this has expanded as the impact of itaconate on other cell types is starting to emerge. This review focuses on itaconate as a key immunoregulatory metabolite and describes its diverse mechanisms of action and its many impacts on the immune and inflammatory responses and in cancer. We also examine the clinical relevance of this immunometabolite and its therapeutic potential for immune and inflammatory diseases.
Sivanand, Sharanya; Gultekin, Yetis; Winter, Peter S.; Vermeulen, Sidney Y.; Tchourine, Konstantine M.; Abbott, Keene L.; Danai, Laura V.; Gourgue, Florian; Do, Brian T.; Crowder, Kayla; Kunchok, Tenzin; Lau, Allison N.; Darnell, Alicia M.; Jefferson, Alexandria; Morita, Satoru;
Saavedra, Pedro H. V.; Trzeciak, Alissa J.; Lipshutz, Allie; Daman, Andrew W.; O’Neal, Anya J.; Liu, Zong-Lin; Wang, Zhaoquan; Romero-Pichardo, Jesús E.; Rojas, Waleska Saitz; Zago, Giulia; van den Brink, Marcel R. M.; Josefowicz, Steven Z.; Lucas, Christopher D.; Anderson, Christopher J.;
Buglakova, Elena; Ekelöf, Måns; Schwaiger-Haber, Michaela; Schlicker, Lisa; Molenaar, Martijn R.; Shahraz, Mohammed; Stuart, Lachlan; Eisenbarth, Andreas; Hilsenstein, Volker; Patti, Gary J.; Schulze, Almut; Snaebjornsson, Marteinn T.; Alexandrov, Theodore
doi: 10.1038/s42255-024-01118-4pmid: 39251875
Showing 1 to 10 of 18 Articles
doi: 10.1038/s42255-024-01105-9pmid: 39160333
Metastases arise from subsets of cancer cells that disseminate from the primary tumour1,2. The ability of cancer cells to thrive in a new tissue site is influenced by genetic and epigenetic changes that are important for disease initiation and progression, but these factors alone do not predict if and where cancers metastasize3,4. Specific cancer types metastasize to consistent subsets of tissues, suggesting that primary tumour-associated factors influence where cancers can grow. We find primary and metastatic pancreatic tumours have metabolic similarities and that the tumour-initiating capacity and proliferation of both primary-derived and metastasis-derived cells is favoured in the primary site relative to the metastatic site. Moreover, propagating cells as tumours in the lung or the liver does not enhance their relative ability to form large tumours in those sites, change their preference to grow in the primary site, nor stably alter aspects of their metabolism relative to primary tumours. Primary liver and lung cancer cells also exhibit a preference to grow in their primary site relative to metastatic sites. These data suggest cancer tissue of origin influences both primary and metastatic tumour metabolism and may impact where cancer cells can metastasize.
doi: 10.1038/s42255-024-01107-7pmid: 39122784
The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4–7.
While heterogeneity is a key feature of cancer, understanding metabolic heterogeneity at the single-cell level remains a challenge. Here we present 13C-SpaceM, a method for spatial single-cell isotope tracing that extends the previously published SpaceM method with detection of 13C6-glucose-derived carbons in esterified fatty acids. We validated 13C-SpaceM on spatially heterogeneous models using liver cancer cells subjected to either normoxia-hypoxia or ATP citrate lyase depletion. This revealed substantial single-cell heterogeneity in labelling of the lipogenic acetyl-CoA pool and in relative fatty acid uptake versus synthesis hidden in bulk analyses. Analysing tumour-bearing brain tissue from mice fed a 13C6-glucose-containing diet, we found higher glucose-dependent synthesis of saturated fatty acids and increased elongation of essential fatty acids in tumours compared with healthy brains. Furthermore, our analysis uncovered spatial heterogeneity in lipogenic acetyl-CoA pool labelling in tumours. Our method enhances spatial probing of metabolic activities in single cells and tissues, providing insights into fatty acid metabolism in homoeostasis and disease.