bims-obesme Biomed News
on Obesity metabolism
Issue of 2024‒07‒28
24 papers selected by
Xiong Weng, University of Edinburgh
  1. LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
  2. An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
  3. Ring around the mitochondria.
  4. Tanycytic Transcytosis Inhibition Disrupts Energy Balance, Glucose Homeostasis and Cognitive Function in Male Mice.
  5. Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity.
  6. Identification of BAF60b as a chromatin remodeling checkpoint of diet-induced fatty liver disease.
  7. Epigenetic control of memory formation.
  8. Astrocytes control quiescent NSC reactivation via GPCR signaling-mediated F-actin remodeling.
  9. Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
  10. Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells.
  11. GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to endosomes.
  12. The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation.
  13. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
  14. Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.
  15. Intensive Glucose Control in Critically Ill Patients - How Low Do We Go?
  16. Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis.
  17. Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
  18. DNA fork remodeling proteins, Zranb3 and Smarcal1, are uniquely essential for aging hematopoiesis.
  19. CCN3 maintains bone density during lactation.
  20. Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB.
  21. Metabolomics analyses reveal the liver-protective mechanism of Wang's metabolic formula on metabolic-associated fatty liver disease.
  22. Hepatokines: unveiling the molecular and cellular mechanisms connecting hepatic tissue to insulin resistance and inflammation.
  23. Transcriptomic analysis reveals regulation of adipogenesis via long non-coding RNA, alternative splicing, and alternative polyadenylation.
  24. Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.
  1. Nat Commun. 2024 Jul 20. 15(1): 6126
    LGR signaling mediates muscle-adipose tissue crosstalk and protects against diet-induced insulin resistance.
    Olga Kubrak, Anne F Jørgensen, Takashi Koyama, Mette Lassen, Stanislav Nagy, Jacob Hald, Gianluca Mazzoni, Dennis Madsen, Jacob B Hansen, Martin Røssel Larsen, Michael J Texada, Jakob L Hansen, Kenneth V Halberg, Kim Rewitz.
      Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.
    DOI:  https://doi.org/10.1038/s41467-024-50468-w
  2. Nat Aging. 2024 Jul 23.
    An NAD+-dependent metabolic checkpoint regulates hematopoietic stem cell activation and aging.
    Zehan Song, Sang Hee Park, Wei-Chieh Mu, Yufan Feng, Chih-Ling Wang, Yifei Wang, Marine Barthez, Ayane Maruichi, Jiayue Guo, Fanghan Yang, Anita Wong Lin, Kartoosh Heydari, Claudia C S Chini, Eduardo N Chini, Cholsoon Jang, Danica Chen.
      How hematopoietic stem cells (HSCs) maintain metabolic homeostasis to support tissue repair and regeneration throughout the lifespan is elusive. Here, we show that CD38, an NAD+-dependent metabolic enzyme, promotes HSC proliferation by inducing mitochondrial Ca2+ influx and mitochondrial metabolism in young mice. Conversely, aberrant CD38 upregulation during aging is a driver of HSC deterioration in aged mice due to dysregulated NAD+ metabolism and compromised mitochondrial stress management. The mitochondrial calcium uniporter, a mediator of mitochondrial Ca2+ influx, also supports HSC proliferation in young mice yet drives HSC decline in aged mice. Pharmacological inactivation of CD38 reverses HSC aging and the pathophysiological changes of the aging hematopoietic system in aged mice. Together, our study highlights an NAD+ metabolic checkpoint that balances mitochondrial activation to support HSC proliferation and mitochondrial stress management to enhance HSC self-renewal throughout the lifespan, and links aberrant Ca2+ signaling to HSC aging.
    DOI:  https://doi.org/10.1038/s43587-024-00670-8
  3. Sci Signal. 2024 Jul 23. 17(846): eadr8314
    Ring around the mitochondria.
    Wei Wong.
      Hexokinase 1 forms constricting rings around mitochondria that prevent fission induced by energy stress.
    DOI:  https://doi.org/10.1126/scisignal.adr8314
  4. Mol Metab. 2024 Jul 22. pii: S2212-8778(24)00127-3. [Epub ahead of print] 101996
    Tanycytic Transcytosis Inhibition Disrupts Energy Balance, Glucose Homeostasis and Cognitive Function in Male Mice.
    Manon Duquenne, Eleonora Deligia, Cintia Folgueira, Cyril Bourouh, Emilie Caron, Frank Pfrieger, Markus Schwaninger, Ruben Nogueiras, Jean-Sébastien Annicotte, Monica Imbernon, Vincent Prévot.
      OBJECTIVE: In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance.METHODS: We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice.
    RESULTS: In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice.
    CONCLUSIONS: These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.
    Keywords:  Tanycytes; blood-brain barrier; blood-cerebrospinal fluid barrier; hypothalamus; normal-weight central obesity; transports
    DOI:  https://doi.org/10.1016/j.molmet.2024.101996
  5. Elife. 2024 Jul 22. pii: RP92075. [Epub ahead of print]12
    Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity.
    Christin Krause, Jan H Britsemmer, Miriam Bernecker, Anna Molenaar, Natalie Taege, Nuria Lopez-Alcantara, Cathleen Geißler, Meike Kaehler, Katharina Iben, Anna Judycka, Jonas Wagner, Stefan Wolter, Oliver Mann, Paul Pfluger, Ingolf Cascorbi, Hendrik Lehnert, Kerstin Stemmer, Sonja C Schriever, Henriette Kirchner.
      Background: The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes are still missing.Methods: Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.
    Results: Here, we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5 p was the most associated with whole-body glucose homeostasis and hepatic lipid metabolism. Its target gene LRP6 was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5 p overexpression. Weight loss in obese mice decreased hepatic miR-182-5 p and restored Lrp6 expression and other miR-182-5 p target genes. Hepatic overexpression of miR-182-5 p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.
    Conclusions: By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression of LRP6 by miR-182-5 p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5 p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.
    Funding: This work was supported by research funding from the Deutsche Forschungsgemeinschaft (KI 1887/2-1, KI 1887/2-2, KI 1887/3-1 and CRC-TR296), the European Research Council (ERC, CoG Yoyo LepReSens no. 101002247; PTP), the Helmholtz Association (Initiative and Networking Fund International Helmholtz Research School for Diabetes; MB) and the German Center for Diabetes Research (DZD Next Grant 82DZD09D1G).
    Keywords:  human; liver; medicine; microRNA; mouse; obesity; type 2 diabetes
    DOI:  https://doi.org/10.7554/eLife.92075
  6. Diabetes. 2024 Jul 24. pii: db240002. [Epub ahead of print]
    Identification of BAF60b as a chromatin remodeling checkpoint of diet-induced fatty liver disease.
    Jing Zhong, Xiuyu Ji, Yali Zhao, Yihe Jia, Churui Song, Jinghuan Lv, Yuying Chen, Yanping Zhou, Xue Lv, Zhuoyin Yang, Zheyu Zhang, Qiyao Xu, Weihong Wang, Haiyan Chen, Aoyuan Cui, Yu Li, Zhuo-Xian Meng.
      Overnutrition has gradually become the primary causative factor of nonalcoholic fatty liver disease (NAFLD). However, how nutritional signals are integrated to orchestrate the transcriptional programs important for NAFLD progression remains poorly understood. Here, we identified hepatic BAF60b as a lipid-sensitive subunit of the switch/sucrose-nonfermentable (SWI/SNF) chromatin-remodeling complex and is negatively associated with liver steatosis in mice and humans. Hepatic BAF60b deficiency promotes high-fat diet (HFD)-induced liver steatosis in mice, while transgenic expression of BAF60b in the liver attenuates HFD-induced obesity and NAFLD, both accompanied by a marked regulation of PPARγ expression. Mechanistically, through motif analysis of liver ATAC-Seq and multiple validation experiments, we identified CCAAT/enhancer-binding protein β (C/EBPβ) as the transcription factor that interacts with BAF60b to suppress PPARγ gene expression, thereby controlling hepatic lipid accumulation and NAFLD progression. This work uncovers hepatic BAF60b as a negative regulator of liver steatosis through C/EBPβ dependent chromatin remodeling.
    DOI:  https://doi.org/10.2337/db24-0002
  7. Science. 2024 Jul 26. 385(6707): 367-368
    Epigenetic control of memory formation.
    Sabine Krabbe.
      A neuron's suitability to participate in a memory trace is modulated by its epigenetic state.
    DOI:  https://doi.org/10.1126/science.adq8496
  8. Sci Adv. 2024 Jul 26. 10(30): eadl4694
    Astrocytes control quiescent NSC reactivation via GPCR signaling-mediated F-actin remodeling.
    Kun-Yang Lin, Mahekta R Gujar, Jiaen Lin, Wei Yung Ding, Jiawen Huang, Yang Gao, Ye Sing Tan, Xiang Teng, Low Siok Lan Christine, Pakorn Kanchanawong, Yusuke Toyama, Hongyan Wang.
      The transitioning of neural stem cells (NSCs) between quiescent and proliferative states is fundamental for brain development and homeostasis. Defects in NSC reactivation are associated with neurodevelopmental disorders. Drosophila quiescent NSCs extend an actin-rich primary protrusion toward the neuropil. However, the function of the actin cytoskeleton during NSC reactivation is unknown. Here, we reveal the fine filamentous actin (F-actin) structures in the protrusions of quiescent NSCs by expansion and super-resolution microscopy. We show that F-actin polymerization promotes the nuclear translocation of myocardin-related transcription factor, a microcephaly-associated transcription factor, for NSC reactivation and brain development. F-actin polymerization is regulated by a signaling cascade composed of G protein-coupled receptor Smog, G protein αq subunit, Rho1 guanosine triphosphatase, and Diaphanous (Dia)/Formin during NSC reactivation. Further, astrocytes secrete a Smog ligand folded gastrulation to regulate Gαq-Rho1-Dia-mediated NSC reactivation. Together, we establish that the Smog-Gαq-Rho1 signaling axis derived from astrocytes, an NSC niche, regulates Dia-mediated F-actin dynamics in NSC reactivation.
    DOI:  https://doi.org/10.1126/sciadv.adl4694
  9. Nat Genet. 2024 Jul 24.
    Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression.
    Amin Abedini, Jonathan Levinsohn, Konstantin A Klötzer, Bernhard Dumoulin, Ziyuan Ma, Julia Frederick, Poonam Dhillon, Michael S Balzer, Rojesh Shrestha, Hongbo Liu, Steven Vitale, Andi M Bergeson, Kishor Devalaraja-Narashimha, Paola Grandi, Tanmoy Bhattacharyya, Erding Hu, Steven S Pullen, Carine M Boustany-Kari, Paolo Guarnieri, Anil Karihaloo, Daniel Traum, Hanying Yan, Kyle Coleman, Matthew Palmer, Lea Sarov-Blat, Lori Morton, Christopher A Hunter, Klaus H Kaestner, Mingyao Li, Katalin Susztak.
      Kidneys are intricate three-dimensional structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. We generated high-quality datasets for 81 samples, including single-cell, single-nuclear, spot-level (Visium) and single-cell resolution (CosMx) spatial-RNA expression and single-nuclear open chromatin, capturing cells from healthy, diabetic and hypertensive diseased human kidneys. Combining these data, we identify cell types and map them to their locations within the tissue. Unbiased deconvolution of the spatial data identifies the following four distinct microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex organization of microenvironments in health and disease and find that the fibrotic microenvironment is able to molecularly classify human kidneys and offers an improved prognosis compared to traditional histopathology. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
    DOI:  https://doi.org/10.1038/s41588-024-01802-x
  10. iScience. 2024 Jul 19. 27(7): 110306
    Epidermal growth factor augments the self-renewal capacity of aged hematopoietic stem cells.
    Vivian Y Chang, Yuwei He, Samantha Grohe, Morgan R Brady, Aldi Chan, Rucha S Kadam, Tiancheng Fang, Amara Pang, Katherine Pohl, Evelyn Tran, Michelle Li, Jenny Kan, Yurun Zhang, Josie J Lu, Joshua P Sasine, Heather A Himburg, Peibin Yue, John P Chute.
      Hematopoietic aging is associated with decreased hematopoietic stem cell (HSC) self-renewal capacity and myeloid skewing. We report that culture of bone marrow (BM) HSCs from aged mice with epidermal growth factor (EGF) suppressed myeloid skewing, increased multipotent colony formation, and increased HSC repopulation in primary and secondary transplantation assays. Mice transplanted with aged, EGF-treated HSCs displayed increased donor cell engraftment within BM HSCs and systemic administration of EGF to aged mice increased HSC self-renewal capacity in primary and secondary transplantation assays. Expression of a dominant negative EGFR in Scl/Tal1+ hematopoietic cells caused increased myeloid skewing and depletion of long term-HSCs in 15-month-old mice. EGF treatment decreased DNA damage in aged HSCs and shifted the transcriptome of aged HSCs from genes regulating cell death to genes involved in HSC self-renewal and DNA repair but had no effect on HSC senescence. These data suggest that EGFR signaling regulates the repopulating capacity of aged HSCs.
    Keywords:  Human physiology; cellular physiology; functional aspects of cell biology; molecular medicine; stem cells research
    DOI:  https://doi.org/10.1016/j.isci.2024.110306
  11. Diabetes. 2024 Jul 24. pii: db230802. [Epub ahead of print]
    GAS6 and AXL promote insulin resistance by rewiring insulin signaling and increasing insulin receptor trafficking to endosomes.
    Céline Schott, Amélie Germain, Julie Lacombe, Monica Pata, Denis Faubert, Jonathan Boulais, Peter Carmeliet, Jean-François Côté, Mathieu Ferron.
      Growth-arrest specific 6 (GAS6) is a secreted protein that acts as a ligand for TAM receptors (TYRO3, AXL and MERTK). In humans, GAS6 circulating levels and genetic variations in GAS6 are associated with hyperglycemia and increased risk of type 2 diabetes. However, the mechanisms by which GAS6 influences glucose metabolism are not understood. Here, we show that Gas6 deficiency in mice increases insulin sensitivity and protects from diet-induced insulin resistance. Conversely, increasing GAS6 circulating levels is sufficient to reduce insulin sensitivity in vivo. GAS6 inhibits the activation of the insulin receptor (IR) and reduces insulin response in muscle cells in vitro and in vivo. Mechanistically, AXL and IR form a complex, while GAS6 reprograms signaling pathways downstream of IR. This results in increased IR endocytosis following insulin treatment. This study contributes to a better understanding of the cellular and molecular mechanisms by which GAS6 and AXL influence insulin sensitivity.
    DOI:  https://doi.org/10.2337/db23-0802
  12. Sci Signal. 2024 Jul 23. 17(846): eadh2381
    The kinase ITK controls a Ca2+-mediated switch that balances TH17 and Treg cell differentiation.
    Orchi Anannya, Weishan Huang, Avery August.
      The balance of proinflammatory T helper type 17 (TH17) and anti-inflammatory T regulatory (Treg) cells is crucial for immune homeostasis in health and disease. The differentiation of naïve CD4+ T cells into TH17 and Treg cells depends on T cell receptor (TCR) signaling mediated, in part, by interleukin-2-inducible T cell kinase (ITK), which stimulates mitogen-activated protein kinases (MAPKs) and Ca2+ signaling. Here, we report that, in the absence of ITK activity, naïve murine CD4+ T cells cultured under TH17-inducing conditions expressed the Treg transcription factor Foxp3 and did not develop into TH17 cells. Furthermore, ITK inhibition in vivo during allergic inflammation increased the Treg:TH17 ratio in the lung. These switched Foxp3+ Treg-like cells had suppressive function, and their transcriptomic profile resembled that of differentiated, induced Treg (iTreg) cells, but their chromatin accessibility profiles were intermediate between TH17 and iTreg cells. Like iTreg cells, switched Foxp3+ Treg-like cells had reductions in the expression of genes involved in mitochondrial oxidative phosphorylation and glycolysis, in the activation of the mechanistic target of rapamycin (mTOR) signaling pathway, and in the abundance of the TH17 pioneer transcription factor BATF. This ITK-dependent switch between TH17 and Treg cells depended on Ca2+ signaling but not on MAPKs. These findings suggest potential strategies for fine-tuning TCR signal strength through ITK to control the balance of TH17 and Treg cells.
    DOI:  https://doi.org/10.1126/scisignal.adh2381
  13. Nat Commun. 2024 Jul 21. 15(1): 6152
    Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression.
    Gloria Asantewaa, Emily T Tuttle, Nathan P Ward, Yun Pyo Kang, Yumi Kim, Madeline E Kavanagh, Nomeda Girnius, Ying Chen, Katherine Rodriguez, Fabio Hecht, Marco Zocchi, Leonid Smorodintsev-Schiller, TashJaé Q Scales, Kira Taylor, Fatemeh Alimohammadi, Renae P Duncan, Zachary R Sechrist, Diana Agostini-Vulaj, Xenia L Schafer, Hayley Chang, Zachary R Smith, Thomas N O'Connor, Sarah Whelan, Laura M Selfors, Jett Crowdis, G Kenneth Gray, Roderick T Bronson, Dirk Brenner, Alessandro Rufini, Robert T Dirksen, Aram F Hezel, Aaron R Huber, Joshua Munger, Benjamin F Cravatt, Vasilis Vasiliou, Calvin L Cole, Gina M DeNicola, Isaac S Harris.
      Cells rely on antioxidants to survive. The most abundant antioxidant is glutathione (GSH). The synthesis of GSH is non-redundantly controlled by the glutamate-cysteine ligase catalytic subunit (GCLC). GSH imbalance is implicated in many diseases, but the requirement for GSH in adult tissues is unclear. To interrogate this, we have developed a series of in vivo models to induce Gclc deletion in adult animals. We find that GSH is essential to lipid abundance in vivo. GSH levels are highest in liver tissue, which is also a hub for lipid production. While the loss of GSH does not cause liver failure, it decreases lipogenic enzyme expression, circulating triglyceride levels, and fat stores. Mechanistically, we find that GSH promotes lipid abundance by repressing NRF2, a transcription factor induced by oxidative stress. These studies identify GSH as a fulcrum in the liver's balance of redox buffering and triglyceride production.
    DOI:  https://doi.org/10.1038/s41467-024-50454-2
  14. Metabolism. 2024 Jul 20. pii: S0026-0495(24)00206-3. [Epub ahead of print] 155979
    Cardiomyocyte LGR6 alleviates ferroptosis in diabetic cardiomyopathy via regulating mitochondrial biogenesis.
    Mengmeng Zhao, Zican Shen, Zihui Zheng, Yao Xu, Jishou Zhang, Jianfang Liu, Shanshan Peng, Jun Wan, Juan-Juan Qin, Menglong Wang.
      AIMS: The majority of people with diabetes are susceptible to cardiac dysfunction and heart failure, and conventional drug therapy cannot correct the progression of diabetic cardiomyopathy. We assessed the potential role and therapeutic value of LGR6 (G protein-coupled receptor containing leucine-rich repeats 6) in diabetic cardiomyopathy.METHODS AND RESULTS: Type 2 diabetes models were established using high-fat diet/streptozotocin-induced diabetes in mice. LGR6 knockout mice were generated. Recombinant adeno-associated virus serotype 9 carrying LGR6 under the cardiac troponin T promoter was injected into diabetic mice. Cardiomyocytes incubated with high glucose (HG) were used to imitate diabetic cardiomyopathy in vitro. The molecular mechanism was explored through RNA sequencing and a chromatin immunoprecipitation assay. We found that LGR6 expression was upregulated in diabetic hearts and HL1 cardiomyocytes treated with HG. The LGR6 knockout aggravated, but cardiomyocyte-specific LGR6 overexpression ameliorated, cardiac dysfunction and remodeling in diabetic mice. Mechanistically, in vivo and in vitro experiments revealed that LGR6 deletion aggravated, whereas LGR6 overexpression alleviated, ferroptosis and disrupted mitochondrial biogenesis by regulating STAT3/Pgc1a signaling. STAT3 inhibition and Pgc1a activation abrogated LGR6 knockout-induced mitochondrial dysfunction and ferroptosis in diabetic mice. In addition, LGR6 activation by recombinant RSPO3 treatment ameliorated cardiac dysfunction, ferroptosis and mitochondrial dysfunction in diabetic mice.
    CONCLUSIONS: We identified a previously undescribed signaling pathway of the LGR6-STAT3-Pgc1a axis that plays a critical role in ferroptosis and mitochondrial disorders during diabetic cardiomyopathy and provides an option for treatment of diabetic hearts.
    Keywords:  Diabetic cardiomyopathy; Ferroptosis; LGR6; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.metabol.2024.155979
  15. NEJM Evid. 2024 Aug;3(8): EVIDe2400196
    Intensive Glucose Control in Critically Ill Patients - How Low Do We Go?
    Shohinee Sarma.
      
    DOI:  https://doi.org/10.1056/EVIDe2400196
  16. Nat Cardiovasc Res. 2024 Feb 01. 3 221-242
    Identification of a non-canonical chemokine-receptor pathway suppressing regulatory T cells to drive atherosclerosis.
    Yvonne Döring, Emiel P C van der Vorst, Yi Yan, Carlos Neideck, Xavier Blanchet, Yvonne Jansen, Manuela Kemmerich, Soyolmaa Bayasgalan, Linsey J F Peters, Michael Hristov, Kiril Bidzhekov, Changjun Yin, Xi Zhang, Julian Leberzammer, Ya Li, Inhye Park, Maria Kral, Katrin Nitz, Laura Parma, Selin Gencer, Andreas Habenicht, Alexander Faussner, Daniel Teupser, Claudia Monaco, Lesca Holdt, Remco T A Megens, Dorothee Atzler, Donato Santovito, Philipp von Hundelshausen, Christian Weber.
      CCL17 is produced by conventional dendritic cells (cDCs), signals through CCR4 on regulatory T cells (Tregs), and drives atherosclerosis by suppressing Treg functions through yet undefined mechanisms. Here we show that cDCs from CCL17-deficient mice display a pro-tolerogenic phenotype and transcriptome that is not phenocopied in mice lacking its cognate receptor CCR4. In the plasma of CCL17-deficient mice, CCL3 was the only decreased cytokine/chemokine. We found that CCL17 signaled through CCR8 as an alternate high-affinity receptor, which induced CCL3 expression and suppressed Treg functions in the absence of CCR4. Genetic ablation of CCL3 and CCR8 in CD4+ T cells reduced CCL3 secretion, boosted FoxP3+ Treg numbers, and limited atherosclerosis. Conversely, CCL3 administration exacerbated atherosclerosis and restrained Treg differentiation. In symptomatic versus asymptomatic human carotid atheroma, CCL3 expression was increased, while FoxP3 expression was reduced. Together, we identified a non-canonical chemokine pathway whereby CCL17 interacts with CCR8 to yield a CCL3-dependent suppression of atheroprotective Tregs.
    Keywords:  atherosclerosis; chemokine receptors; chemokines; regulatory T cells
    DOI:  https://doi.org/10.1038/s44161-023-00413-9
  17. Nature. 2024 Jul 24.
    Neoantigen-specific cytotoxic Tr1 CD4 T cells suppress cancer immunotherapy.
    Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Naveen Sharma, Tian-Tian Liu, Vladimir Sukhov, Maria Firulyova, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Andres M Salazar, Robert Burns, Helio A Costa, Kelly D Moynihan, Yik Andy Yeung, Ivana Djuretic, Ton N Schumacher, Kathleen C F Sheehan, Marco Colonna, James P Allison, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber.
      CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified them as type 1 regulatory T (Tr1) cells expressing IL-10, granzyme B, perforin, CCL5 and LILRB4. Tumour-specific Tr1 cells suppressed tumour rejection induced by anti-PD1, LDVax or adoptively transferred tumour-specific effector T cells. Mechanistically, HDVax-induced Tr1 cells selectively killed MHC-II tumour antigen-presenting type 1 conventional dendritic cells (cDC1s), leading to low numbers of cDC1s in tumours. We then documented modalities to overcome this inhibition, specifically via anti-LILRB4 blockade, using a CD8-directed IL-2 mutein, or targeted loss of cDC2/monocytes. Collectively, these data show that cytotoxic Tr1 cells, which maintain peripheral tolerance, also inhibit antitumour responses and thereby function to impede immune control of cancer.
    DOI:  https://doi.org/10.1038/s41586-024-07752-y
  18. Aging Cell. 2024 Jul 23. e14281
    DNA fork remodeling proteins, Zranb3 and Smarcal1, are uniquely essential for aging hematopoiesis.
    Saul Kushinsky, Matthew V Puccetti, Clare M Adams, Irina Shkundina, Nikkole James, Brittany M Mahon, Peter Michener, Christine M Eischen.
      Over a lifetime, hematopoietic stem and progenitor cells (HSPCs) are forced to repeatedly proliferate to maintain hematopoiesis, increasing their susceptibility to DNA damaging replication stress. However, the proteins that mitigate this stress, protect HSPC replication, and prevent aging-driven dysregulation are unknown. We report two evolutionarily conserved, ubiquitously expressed chromatin remodeling enzymes with similar DNA replication fork reversal biochemical functions, Zranb3 and Smarcal1, have surprisingly specialized roles in distinct HSPC populations. While both proteins actively mitigate replication stress and prevent DNA damage and breaks during lifelong hematopoiesis, the loss of either resulted in distinct biochemical and biological consequences. Notably, defective long-term HSC function, revealed with bone marrow transplantation, caused hematopoiesis abnormalities in young mice lacking Zranb3. Aging significantly worsened these hematopoiesis defects in Zranb3-deficient mice, including accelerating the onset of myeloid-biased hematopoietic dysregulation to early in life. Such Zranb3-deficient HSPC abnormalities with age were driven by accumulated DNA damage and replication stress. Conversely, Smarcal1 loss primarily negatively affected progenitor cell functions that were exacerbated with aging, resulting in a lymphoid bias. Simultaneous loss of both Zranb3 and Smarcal1 compounded HSPC defects. Additionally, HSPC DNA replication fork dynamics had unanticipated HSPC type and age plasticity that depended on the stress and Zranb3 and/or Smarcal1. Our data reveal both Zranb3 and Smarcal1 have essential HSPC cell intrinsic functions in lifelong hematopoiesis that protect HSPCs from replication stress and DNA damage in unexpected, unique ways.
    Keywords:  DNA replication stress; Smarcal1; Zranb3; aging; hematopoiesis; hematopoietic stem and progenitor cells (HSPC)
    DOI:  https://doi.org/10.1111/acel.14281
  19. Nat Rev Endocrinol. 2024 Jul 23.
    CCN3 maintains bone density during lactation.
    Claire Greenhill.
      
    DOI:  https://doi.org/10.1038/s41574-024-01023-6
  20. Proc Natl Acad Sci U S A. 2024 Jul 30. 121(31): e2314760121
    Ammonia transporter RhBG initiates downstream signaling and functional responses by activating NFκB.
    Saurabh Mishra, Nicole Welch, Shashi Shekhar Singh, Khuraijam Dhanachandra Singh, Annette Bellar, Avinash Kumar, Lars N Deutz, Maxmillian D Hanlon, Sashi Kant, Sumitava Dastidar, Hailee Patel, Vandana Agrawal, Amy H Attaway, Ryan Musich, George R Stark, Francesco Saverio Tedesco, George A Truskey, I David Weiner, Sadashiva S Karnik, Srinivasan Dasarathy.
      Transceptors, solute transporters that facilitate intracellular entry of molecules and also initiate intracellular signaling events, have been primarily studied in lower-order species. Ammonia, a cytotoxic endogenous metabolite, is converted to urea in hepatocytes for urinary excretion in mammals. During hyperammonemia, when hepatic metabolism is impaired, nonureagenic ammonia disposal occurs primarily in skeletal muscle. Increased ammonia uptake in skeletal muscle is mediated by a membrane-bound, 12 transmembrane domain solute transporter, Rhesus blood group-associated B glycoprotein (RhBG). We show that in addition to its transport function, RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB. We also show that ammonia-induced MyD88 signaling is independent of the canonical toll-like receptor-initiated mechanism of MyD88-dependent NFκB activation. In silico, in vitro, and in situ experiments show that the conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. In skeletal muscle from human patients, human-induced pluripotent stem cell-derived myotubes, and myobundles show an interaction of RhBG-MyD88 during hyperammonemia. Using complementary experimental and multiomics analyses in murine myotubes and mice with muscle-specific RhBG or MyD88 deletion, we show that the RhBG-MyD88 interaction is essential for the activation of NFkB but not ammonia transport. Our studies show a paradigm of substrate-dependent regulation of transceptor function with the potential for modulation of cellular responses in mammalian systems by decoupling transport and signaling functions of transceptors.
    Keywords:  NFkB; hyperammonemia; skeletal muscle; solute transporter; transceptor
    DOI:  https://doi.org/10.1073/pnas.2314760121
  21. Heliyon. 2024 Jul 15. 10(13): e33418
    Metabolomics analyses reveal the liver-protective mechanism of Wang's metabolic formula on metabolic-associated fatty liver disease.
    Suhong Chen, Jiahui Huang, Yuzhen Huang, Chengliang Zhou, Ning Wang, Linnan Zhang, Zehua Zhang, Bo Li, Xinglishang He, Kungen Wang, Yihui Zhi, Guiyuan Lv, Shuhua Shen.
      Wang's metabolic formula (WMF) is a traditional Chinese medicine formula developed under the guidance of Professor Kungen Wang. WMF has been clinically utilized for several years. However, the therapeutic mechanism of WMF in treating metabolic-associated fatty liver disease (MAFLD) remains unclear. In this study, we performed phytochemical analysis on WMF using LC-MS. To study the role of WMF in MAFLD, we orally administered WMF (20.6 g/kg) to male MAFLD mice induced by a high-cholesterol high-fat diet (HCHFD). Then pathological, biochemical, and metabolomic analyses were performed. The main components of WMF are chlorogenic acid, geniposide, albiflorin, paeoniflorin, and calycosin-7-O-glucoside. MAFLD mice treated with WMF exhibited significant improvements in obesity, abnormal lipid metabolism, inflammation, and liver pathology. WMF decreased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG) levels in the serum of MAFLD mice while increasing high-density lipoprotein cholesterol (HDL-c) levels. WMF lowered liver TG levels and inflammatory factors (IL-1β, IL-6, TNF-α, and NF-κB). Metabolomic analysis of the liver annotated 78 differentially regulated metabolites enriched in four pathways: glycerophospholipid metabolism, retinol metabolism, PPAR signaling pathway, and choline metabolism. Western blot experiments showed that WMF increased the expression of PPAR-α, PPAR-β, and RXR in the liver while decreasing the expression of RAR. The study demonstrates that WMF has a solid preventive and therapeutic effect on MAFLD. The anti-inflammatory and regulation of abnormal liver metabolism activities of WMF involve retinol metabolism and the PPAR signaling pathway.
    Keywords:  MAFLD; Metabolomics; PPAR signaling pathway; Retinol metabolism; TCM; Wang's metabolic formula (WMF)
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e33418
  22. Acta Diabetol. 2024 Jul 20.
    Hepatokines: unveiling the molecular and cellular mechanisms connecting hepatic tissue to insulin resistance and inflammation.
    Xiaolei Miao, Arian Alidadipour, Vian Saed, Firooze Sayyadi, Yasaman Jadidi, Maryam Davoudi, Fatemeh Amraee, Nastaran Jadidi, Reza Afrisham.
      Insulin resistance arising from Non-Alcoholic Fatty Liver Disease (NAFLD) stands as a prevalent global ailment, a manifestation within societies stemming from individuals' suboptimal dietary habits and lifestyles. This form of insulin resistance emerges as a pivotal factor in the development of type 2 diabetes mellitus (T2DM). Emerging evidence underscores the significant role of hepatokines, as hepatic-secreted hormone-like entities, in the genesis of insulin resistance and eventual onset of type 2 diabetes. Hepatokines exert influence over extrahepatic metabolism regulation. Their principal functions encompass impacting adipocytes, pancreatic cells, muscles, and the brain, thereby playing a crucial role in shaping body metabolism through signaling to target tissues. This review explores the most important hepatokines, each with distinct influences. Our review shows that Fetuin-A promotes lipid-induced insulin resistance by acting as an endogenous ligand for Toll-like receptor 4 (TLR-4). FGF21 reduces inflammation in diabetes by blocking the nuclear translocation of nuclear factor-κB (NF-κB) in adipocytes and adipose tissue, while also improving glucose metabolism. ANGPTL6 enhances AMPK and insulin signaling in muscle, and suppresses gluconeogenesis. Follistatin can influence insulin resistance and inflammation by interacting with members of the TGF-β family. Adropin show a positive correlation with phosphoenolpyruvate carboxykinase 1 (PCK1), a key regulator of gluconeogenesis. This article delves into hepatokines' impact on NAFLD, inflammation, and T2DM, with a specific focus on insulin resistance. The aim is to comprehend the influence of these recently identified hormones on disease development and their underlying physiological and pathological mechanisms.
    Keywords:  Diabetes; Hepatokines; Inflammation; Insulin resistance; Liver; Obesity
    DOI:  https://doi.org/10.1007/s00592-024-02335-9
  23. Sci Rep. 2024 Jul 23. 14(1): 16964
    Transcriptomic analysis reveals regulation of adipogenesis via long non-coding RNA, alternative splicing, and alternative polyadenylation.
    Salwa Mohd Mostafa, Luyang Wang, Bin Tian, Joel Graber, Claire Moore.
      Obesity is characterized by dysregulated adipogenesis that leads to increased number and/or size of adipocytes. Understanding the molecular mechanisms governing adipogenesis is therefore key to designing therapeutic interventions against obesity. In our study, we analyzed 3'-end sequencing data that we generated from human preadipocytes and adipocytes, as well as previously published RNA-seq datasets, to elucidate mechanisms of regulation via long non-coding RNA (lncRNA), alternative splicing (AS) and alternative polyadenylation (APA). We discovered lncRNAs that have not been previously characterized but may be key regulators of white adipogenesis. We also detected 100 AS events and, using motif enrichment analysis, identified RNA binding proteins (RBPs) that could mediate exon skipping-the most prevalent AS event. In addition, we show that usage of alternative poly(A) sites in introns or 3'-UTRs of key adipogenesis genes leads to isoform diversity, which can have significant biological consequences on differentiation efficiency. We also identified RBPs that may modulate APA and defined how 3'-UTR APA can regulate gene expression through gain or loss of specific microRNA binding sites. Taken together, our bioinformatics-based analysis reveals potential therapeutic avenues for obesity through manipulation of lncRNA levels and the profile of mRNA isoforms via alternative splicing and polyadenylation.
    DOI:  https://doi.org/10.1038/s41598-024-67648-9
  24. Elife. 2024 Jul 25. pii: e84532. [Epub ahead of print]13
    Hippo pathway-mediated YAP1/TAZ inhibition is essential for proper pancreatic endocrine specification and differentiation.
    Yifan Wu, Kunhua Qin, Yi Xu, Shreya Rajhans, Truong Vo, Kevin M Lopez, Jun Liu, Michael H Nipper, Janice Deng, Xue Yin, Logan R Ramjit, Zhenqing Ye, Yu Luan, H Efsun Arda, Pei Wang.
      The Hippo pathway plays a central role in tissue development and homeostasis. However, the function of Hippo in pancreatic endocrine development remains obscure. Here, we generated novel conditional genetically engineered mouse models to examine the roles of Hippo pathway-mediated YAP1/TAZ inhibition in the development stages of endocrine specification and differentiation. While YAP1 protein was localized to the nuclei in bipotent progenitor cells, Neurogenin 3 expressing endocrine progenitors completely lost YAP1 expression. Using genetically engineered mouse models, we found that inactivation of YAP1 requires both an intact Hippo pathway and Neurogenin 3 protein. Gene deletion of Lats1 and 2 kinases (Lats1&2) in endocrine progenitor cells of developing mouse pancreas using Neurog3Cre blocked endocrine progenitor cell differentiation and specification, resulting in reduced islets size and a disorganized pancreas at birth. Loss of Lats1&2 in Neurogenin 3 expressing cells activated YAP1/TAZ transcriptional activity and recruited macrophages to the developing pancreas. These defects were rescued by deletion of Yap1/Wwtr1 genes, suggesting that tight regulation of YAP1/TAZ by Hippo signaling is crucial for pancreatic endocrine specification. In contrast, deletion of Lats1&2 using β-cell-specific Ins1CreER resulted in a phenotypically normal pancreas, indicating that Lats1&2 are indispensable for differentiation of endocrine progenitors but not for that of β-cells. Our results demonstrate that loss of YAP1/TAZ expression in the pancreatic endocrine compartment is not a passive consequence of endocrine specification. Rather, Hippo pathway-mediated inhibition of YAP1/TAZ in endocrine progenitors is a prerequisite for endocrine specification and differentiation.
    Keywords:  Hippo signaling; development; developmental biology; differentiation; endocrine progenitors; mouse; pancreas; specification
    DOI:  https://doi.org/10.7554/eLife.84532
This page is being maintained by Thomas Krichel. It was last updated on 2024‒08‒11 at 5:29.