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| Open AccessLoss of SUMO-specific protease 2 causes isolated glucocorticoid deficiency by blocking adrenal cortex zonal transdifferentiation in mice
SUMOylation is a mechanism of posttranslational modification involved in eukaryotic cell homeostasis. Here the authors report that mice unable to control SUMOylation in the adrenal cortex develop a selective defect in glucocorticoid production due to disrupted differentiation of cells involved in steroid hormone synthesis.
- Damien Dufour
- , Typhanie Dumontet
- & Antoine Martinez
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Article
| Open AccessHedgehog-mediated gut-taste neuron axis controls sweet perception in Drosophila
Food regulates taste perception, but the underlying molecular mechanisms are not clear. Here, the authors reveal that sugar intake in Drosophila induces the gut to secrete Hedgehog into the circulation that suppresses sweet taste, sugar perception and preference.
- Yunpo Zhao
- , Mohammed A. Khallaf
- & Mattias Alenius
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| Open AccessHepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Dysregulation of the post-translational modification neddylation has been implicated in liver diseases such as fibrosis and hepatocellular carcinoma. Here the authors report that hepatic neddylation deficiency via genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1) causes acute liver failure due to mitochondrial dysfunction and aberrant activation of NF-κB-inducing kinase in mice.
- Cheng Xu
- , Hongyi Zhou
- & Weiqin Chen
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Article
| Open AccessSIRT7 suppresses energy expenditure and thermogenesis by regulating brown adipose tissue functions in mice
Sirtuins have been reported to positively regulate brown adipose tissue thermogenesis. Here the authors report that brown adipocytic SIRT7 suppresses whole-body energy expenditure and thermogenesis in mice, potentially by attenuating batokine gene expressions and Ucp1 mRNA translation.
- Tatsuya Yoshizawa
- , Yoshifumi Sato
- & Kazuya Yamagata
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Article
| Open AccessA brown fat-enriched adipokine Adissp controls adipose thermogenesis and glucose homeostasis
The signaling mechanisms regulating adipose thermogenesis have not been fully elucidated. Here, the authors show that a brown fat-enriched adipokine ADISSP promotes adipose thermogenesis and improves metabolic health independently of b-adrenergic receptor.
- Qingbo Chen
- , Lei Huang
- & Yong-Xu Wang
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Article
| Open AccessDeconstruction of a hypothalamic astrocyte-white adipocyte sympathetic axis that regulates lipolysis in mice
The role of non-neuronal glial cells in the regulation of adipose tissue function are incompletely understood. Here the authors report that stimulation of mediobasal hypothalamic astrocytes promotes inguinal white adipose tissue lipolysis in mice, dependent on the activation of the pro-opiomelanocortin neurons.
- Dan Chen
- , Yong Qi
- & Yunlei Yang
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Article
| Open AccessThe circadian clock influences T cell responses to vaccination by regulating dendritic cell antigen processing
Circadian rhythms are known to impact a range of biological processes including in the immune system. Here the authors show how circadian rhythms modulate the T cell response to vaccination via regulation of dendritic cell metabolism.
- Mariana P. Cervantes-Silva
- , Richard G. Carroll
- & Annie M. Curtis
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Article
| Open AccessG protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis
Rare variants in the G-protein coupled receptor 151 (GPR151) gene in humans are associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here, the authors show that GPR151 regulates the process of hepatic gluconeogenesis and affects whole-body glucose metabolism.
- Ewa Bielczyk-Maczynska
- , Meng Zhao
- & Joshua W. Knowles
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Article
| Open AccessSecreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice
Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.
- Xuanchun Wang
- , Yanliang Li
- & Chong Wee Liew
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Article
| Open AccessReduced secretion of neuronal growth regulator 1 contributes to impaired adipose-neuronal crosstalk in obesity
Adipose tissue is an important secretory organ, but less is known about the secretory activity of perivascular fat. Here the authors use proteomics analysis on secretomes from perivascular fat to identify neuronal growth regulator 1 as an adipocyte-derived neurotrophic factor, whose decreased secretion in obesity results in a loss of sympathetic innervation of adipose depots in mice.
- Elisa Duregotti
- , Christina M. Reumiller
- & Manuel Mayr
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Article
| Open AccessOsteoblast/osteocyte-derived interleukin-11 regulates osteogenesis and systemic adipogenesis
Here, the authors identify interleukin-11 as a mediator of bone-adipose crosstalk during mechanical loading of the bone. Interleukin-11 secreted by the bone acts as a hormone to regulate fat metabolism, in addition to having an autocrine-paracrine effect on bone itself.
- Bingzi Dong
- , Masahiro Hiasa
- & Toshio Matsumoto
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Article
| Open AccessSphingosine 1-phosphate mediates adiponectin receptor signaling essential for lipid homeostasis and embryogenesis
Cells and organisms requires proper membrane composition, which the cell must modulate as membrane lipids are primary acquired from the diet. Here, Ruiz et al. identify a conserved pathway connecting the fluidity regulators AdipoR1/2 with fatty acid desaturase SCD to mediate membrane homeostasis.
- Mario Ruiz
- , Ranjan Devkota
- & Marc Pilon
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Article
| Open AccessAltered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells
Chronic hyperglycemia impairs insulin secretion from pancreatic beta cells in diabetes. Here, the authors reveal that a glucose metabolite is responsible and show lowering glucose metabolism during hyperglycemia prevents loss of beta-cell function.
- Elizabeth Haythorne
- , Matthew Lloyd
- & Frances M. Ashcroft
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Article
| Open AccessA conserved megaprotein-based molecular bridge critical for lipid trafficking and cold resilience
Environmental temperature changes can alter cell membrane lipid composition but the mechanisms underlying this conserved mechanism are unclear. Here, the authors identify the megaprotein LPD-3 in C. elegans as critical for normal phospholipid distribution and cold resilience.
- Changnan Wang
- , Bingying Wang
- & Dengke K. Ma
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Article
| Open AccessParkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes
Parkin plays a role in mitophagy and has been shown to control adipose tissue browning and thermogenesis. Here the authors report that Parkin coordinates mitophagy with Pgc1α-mediated mitochondrial biogenesis in white adipocytes to regulate adiposity.
- Timothy M. Moore
- , Lijing Cheng
- & Zhenqi Zhou
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Article
| Open AccessIdentification of evolutionarily conserved regulators of muscle mitochondrial network organization
Mitochondrial networks are carefully positioned to facilitate energy distribution within muscle cells. Here they show that energetic demands and conserved transcription factors regulate mitochondrial network organization and contractile phenotypes independently in Drosophila.
- Prasanna Katti
- , Peter T. Ajayi
- & Brian Glancy
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Article
| Open AccessPhosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice
A truncating variant of 17β-hydroxysteroid dehydrogenase-13 (17β-HSD13), a lipid droplet -associated protein, associates with lower risk of chronic liver disease. Here the authors identify a phosphorylation site in 17β-HSD13 which promotes lipolysis, and report that a knock-in mouse with a 17β-HSD13 mutant defective for phosphorylation is more susceptible to nonalcoholic steatohepatitis.
- Wen Su
- , Sijin Wu
- & Youfei Guan
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Article
| Open AccessAnalytical and computational workflow for in-depth analysis of oxidized complex lipids in blood plasma
Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.
- Angela Criscuolo
- , Palina Nepachalovich
- & Maria Fedorova
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Article
| Open AccessPlasma membrane flipping of Syntaxin-2 regulates its inhibitory action on insulin granule exocytosis
Kang and colleagues find that plasma membrane flipping of Syntaxin-2 from inside (inhibitory) to outside (relief of inhibition) of pancreatic β-cells helps fine-tune insulin secretion. Increasing this flipping efficiency can alleviate the impaired insulin secretion in diabetes.
- Fei Kang
- , Li Xie
- & Herbert Y. Gaisano
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Article
| Open AccessHepatic thyroid hormone signalling modulates glucose homeostasis through the regulation of GLP-1 production via bile acid-mediated FXR antagonism
Thyroid hormones regulate systemic glucose metabolism through incompletely understood mechanisms. Here the authors report that hepatic thyroid hormone receptor β mediates the effects of the thyroid hormone T3 on systemic glucose homeostasis by modulating GLP-1 levels through suppression of hepatic CYP8B1 expression and bile acid mediated inhibition of intestinal FXR signalling.
- Ying Yan
- , Zhoumin Niu
- & Hao Ying
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Article
| Open AccessREDD1 promotes obesity-induced metabolic dysfunction via atypical NF-κB activation
The stress response protein REDD1 is regulates inflammation and energy metabolism. Here the authors report that global or adipocyte-specific deletion of REDD1 inhibits diet induced obesity, insulin resistance, liver steatosis and inflammation in mice, at least in part via reduced atypical NF-κB activation.
- Dong-Keon Lee
- , Taesam Kim
- & Young-Myeong Kim
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Article
| Open AccessWnt4 is heterogeneously activated in maturing β-cells to control calcium signaling, metabolism and function
Diabetes is characterized by loss or dysfunction of pancreatic β-cells. Here the authors show that the signalling protein WNT4 is heterogeneously activated by β-cells during their postnatal maturation with WNT4 positive cells being more mature, and that inactivating WNT4 in β-cells after maturation impairs beta-cell function.
- Keiichi Katsumoto
- , Siham Yennek
- & Anne Grapin-Botton
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Article
| Open AccessThe hypoxia response pathway promotes PEP carboxykinase and gluconeogenesis in C. elegans
The hypoxia response pathway can counter pathological damage caused by low oxygen availability. Here the authors employ a multiomics approach to show how the pathway reprograms metabolism towards gluconeogenesis to combat oxidative stress.
- Mehul Vora
- , Stephanie M. Pyonteck
- & Christopher Rongo
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Article
| Open AccessTLCD1 and TLCD2 regulate cellular phosphatidylethanolamine composition and promote the progression of non-alcoholic steatohepatitis
The regulation of cellular phosphatidylethanolamine (PE) acyl chain composition is poorly understood. Here, the authors show that TLCD1 and TLCD2 proteins mediate the formation of monounsaturated fatty acid-containing PE species and promote the progression of non-alcoholic steatohepatitis.
- Kasparas Petkevicius
- , Henrik Palmgren
- & Xiao-Rong Peng
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Article
| Open AccessPhosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling
The insulin signalling cascade can be inhibited by phosphatases, including Ser/Thr protein phosphatase 2A (PP2A). Here the authors show that Alpha4, a regulator of the PP2A catalytic subunit, modulates insulin receptor tyrosine phosphorylation via the YBX-1/PTP1B pathway and is involved in maintenance of adipose tissue homeostasis and systemic metabolism.
- Masaji Sakaguchi
- , Shota Okagawa
- & Eiichi Araki
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Article
| Open AccessChronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue
Dietary sugar intake may contribute to the development non-alcoholic fatty liver disease. Here the authors investigated the effects of chronic dietary sucrose on the liver-adipose-microbiome axis in mice, and report that sex is a moderating factor that influences sucrose-driven lipid storage in the liver and adipose tissue lipolysis.
- Erin J. Stephenson
- , Amanda S. Stayton
- & Joan C. Han
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Article
| Open AccessThe Hippo pathway links adipocyte plasticity to adipose tissue fibrosis
Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
- Hongyu Shen
- , Xun Huang
- & Yifu Qiu
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Article
| Open AccessDeletion of skeletal muscle Akt1/2 causes osteosarcopenia and reduces lifespan in mice
Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.
- Takayoshi Sasako
- , Toshihiro Umehara
- & Kohjiro Ueki
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Article
| Open AccessLipid biosynthesis enzyme Agpat5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion
During hypoglycemia, glucagon secretion is part of the mechanism needed to restore normal blood glucose levels. Here, Strembitska et al. report that sensing of hypoglycemia by AgRP neurons requires Agpat5, an enzyme which prevents fatty acids from entering the mitochondria for ATP production, ensuring correct neuronal activation and glucagon secretion.
- Anastasiya Strembitska
- , Gwenaël Labouèbe
- & Bernard Thorens
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Article
| Open AccessSARS-CoV-2 infects adipose tissue in a fat depot- and viral lineage-dependent manner
Visceral adiposity is a risk factor for severe COVID-19, and infection of adipose tissue by SARS-CoV-2 has been reported. Here the authors confirm that human adipose tissue is a possible site for SARS-CoV-2 infection, but the degree of adipose tissue infection and the way adipocytes respond to the virus depend on the adipose tissue depot and the viral strain.
- Tatiana Dandolini Saccon
- , Felippe Mousovich-Neto
- & Marcelo A. Mori
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Article
| Open AccessMicroRNA-7 regulates melanocortin circuits involved in mammalian energy homeostasis
The hypothalamus controls systemic energy homeostasis. Here, the authors show that loss of microRNA-7 in hypothalamic neurons causes obesity, increased growth and endocrine dysfunction in mice, and report genetic evidence that links microRNA-7 to height and adiposity in humans.
- Mary P. LaPierre
- , Katherine Lawler
- & Markus Stoffel
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Article
| Open AccessTFEB regulates sulfur amino acid and coenzyme A metabolism to support hepatic metabolic adaptation and redox homeostasis
Matye el al. show that coenzyme-A and glutathione deficiency in NAFLD limits fatty acid oxidation and antioxidant defence capacity. The nutrient sensing transcription factor EB induces autophagy–lysosome proteolysis and methionine cycle-transsulfuration to maintain hepatic cysteine, coenzyme-A and glutathione availability.
- David Matye
- , Sumedha Gunewardena
- & Tiangang Li
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Article
| Open AccessFatty acids homeostasis during fasting predicts protection from chemotherapy toxicity
Fasting has been reported to protect from chemotherapy-associated toxicity. Here, the authors show that fatty acid profiles in erythrocyte membranes and gene expression from peripheral blood mononuclear cells are associated to the fasting-mediated benefits during cancer treatment in mice and patients.
- Marta Barradas
- , Adrián Plaza
- & Pablo J. Fernandez-Marcos
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Article
| Open AccessActivation of the insulin receptor by an insulin mimetic peptide
Genetic mutations of insulin receptor (IR) cause severe insulin resistance syndromes with no current treatment or cure. Here, the authors present that insulin-independent IR activation mechanism by peptide agonist which activate non-functional IR mutants that cause the insulin resistance syndromes.
- Junhee Park
- , Jie Li
- & Eunhee Choi
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Article
| Open AccessMulti-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models
In animal models, maternal obesity is associated with development of neurodevelopmental disorder like phenotypes. Here the authors show in a macaque model that in obese dams, cell-free fetal DNA methylation, inflammatory cytokines, and metabolites correlated with infant brain DNA methylation, lipids, and metabolites.
- Benjamin I. Laufer
- , Yu Hasegawa
- & Janine M. LaSalle
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Article
| Open AccessSirtuin 6 inhibition protects against glucocorticoid-induced skeletal muscle atrophy by regulating IGF/PI3K/AKT signaling
Chronic stress induces skeletal muscle atrophy via upregulation of glucocorticoid levels. Here, the authors show that SIRT6 transcriptionally regulates glucocorticoid-induced muscle atrophy by modulating IGF/PI3K/AKT signalling.
- Sneha Mishra
- , Claudia Cosentino
- & Nagalingam R. Sundaresan
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Article
| Open AccessNo evidence of brown adipose tissue activation after 24 weeks of supervised exercise training in young sedentary adults in the ACTIBATE randomized controlled trial
Exercise modulates brown adipose tissue (BAT) metabolism in murine models. Here the authors report that there is no evidence that 24 weeks of supervised exercise training modulates BAT volume or function in young sedentary adults in the ACTIBATE randomized controlled trial.
- Borja Martinez-Tellez
- , Guillermo Sanchez-Delgado
- & Jonatan R. Ruiz
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Article
| Open AccessEarly macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
Interferon Regulatory Factor 5 levels have been shown to increase in adipose tissue macrophages in diet-induced obesity. Here authors show that IRF5 transcriptionally represses the Growth Hormone Inducible Transmembrane Protein gene encoding a mitochondrial protein important for oxidative respiration in macrophages, thus driving the detrimental metabolic changes observed in obesity.
- L. Orliaguet
- , T. Ejlalmanesh
- & F. Alzaid
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Article
| Open AccessAdipocytes control food intake and weight regain via Vacuolar-type H+ ATPase
Energy metabolism is dysregulated in obesity, and some if these changes persist after weight loss and may contribute to weight regain. Here the authors report that a vacuolar-type H+ ATPase, ATP6v0a1, is induced in adipocytes during obesity and persists after weight loss, and regulates food intake and weight gain in C. elegans and mice.
- Rizaldy C. Zapata
- , Maria Carretero
- & Olivia Osborn
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Article
| Open AccessNanoscale segregation of channel and barrier claudins enables paracellular ion flux
Meshworks of claudin polymers control the paracellular transport and barrier properties of epithelial tight junctions. Here, the authors show different claudin nanoscale organization principles, finding that claudin segregation enables barrier formation and paracellular ion flux across tight junctions.
- Hannes Gonschior
- , Christopher Schmied
- & Martin Lehmann
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Article
| Open AccessFerritin-mediated iron detoxification promotes hypothermia survival in Caenorhabditis elegans and murine neurons
Strategies to improve cold resistance are of potential biomedical interest. Here the authors demonstrate that ferritin-mediated detoxification of iron, preventing the generation of reactive oxygen species, promotes cold survival in both Caenorhabditis elegans and cultured mammalian neurons.
- Tina Pekec
- , Jarosław Lewandowski
- & Rafal Ciosk
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Article
| Open AccessIron mobilization during lactation reduces oxygen stores in a diving mammal
Here, the authors show that Weddell seal mothers mobilize endogenous iron stores during lactation to provide to pups, resulting in iron concentrations in milk 100x higher than terrestrial mammals. This was associated with reduced dive durations in the mother, a cost of reproduction.
- Michelle R. Shero
- , Amy L. Kirkham
- & Jennifer M. Burns
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Article
| Open AccessPhenylalanine impairs insulin signaling and inhibits glucose uptake through modification of IRβ
Whether amino acids act on cellular insulin signaling remains unclear. Here, the authors find that phenylalanine modifies insulin receptor beta (IRβ) and inactivates insulin signaling and glucose uptake and positively correlated with T2D onset.
- Qian Zhou
- , Wan-Wan Sun
- & Shi-Min Zhao
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Article
| Open AccessA temperature-regulated circuit for feeding behavior
Feeding behavior is modulated by ambient temperature, as lower temperatures increase the necessity for energy intake and vice versa. Here the authors identify neuronal pathways that control feeding in a temperature-dependent manner.
- Shaowen Qian
- , Sumei Yan
- & Yi Zhou
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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Article
| Open AccessHepatic non-parenchymal S100A9-TLR4-mTORC1 axis normalizes diabetic ketogenesis
Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin.
- Gloria Ursino
- , Giorgio Ramadori
- & Roberto Coppari
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Article
| Open AccessAdipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism
Dysregulation of plasmalogen metabolism in adipose tissue is associated with metabolic diseases. Here the authors characterize the role of adipocyte TMEM86A as a lysoplasmalogenase and show its deletion is protective against high fat diet induced metabolic disease, an effect that can be recapitulated by plasmenyl lysophosphatidylethanolamine 18:0 supplementation.
- Yoon Keun Cho
- , Young Cheol Yoon
- & Yun-Hee Lee
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Article
| Open AccessTranslational fidelity and growth of Arabidopsis require stress-sensitive diphthamide biosynthesis
Diphthamide is a post-translationally modified histidine residue present in animal and yeast TRANSLATION ELONGATION FACTOR2. Here the authors show that diphthamide modification of eEF2 is conserved in Arabidopsis thaliana and contributes to translational fidelity and growth via cell proliferation.
- Hongliang Zhang
- , Julia Quintana
- & Ute Krämer
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Article
| Open AccessTRIM24 is an insulin-responsive regulator of P-bodies
Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.
- Wen Wei
- , Qiaoli Chen
- & Shuai Chen