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| Open AccessThe transcription factor hepatocyte nuclear factor 4A acts in the intestine to promote white adipose tissue energy storage
HNF4A is a nuclear receptor that regulates liver lipid homeostasis. Here the authors show that HNF4A is not required for intestinal lipid metabolism but controls energy expenditure under diet induced obesity through the fat-induced release of glucose-dependent insulinotropic polypeptide.
- Romain Girard
- , Sarah Tremblay
- & François Boudreau
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Article
| Open AccessClenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells
In this study, the authors demonstrated that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling may prove beneficial as novel antidiabetic drugs.
- Jaroslawna Meister
- , Derek B. J. Bone
- & Jürgen Wess
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Article
| Open AccessOxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
Oxylipins are lipid mediators generated during infection for regulating inflammatory responses, but how they are removed is not completely clear. Here the authors show that cellular oxylipin removal is linked to mitochondria β-oxidation by CPT1, a mitochondria lipid importer protein, to serve as a metabolic checkpoint for oxylipin homeostasis and inflammation.
- Mariya Misheva
- , Konstantinos Kotzamanis
- & Valerie B. O’Donnell
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Article
| Open AccessTotal energy expenditure is repeatable in adults but not associated with short-term changes in body composition
Low total energy expenditure (TEE) has been a hypothesized risk factor for weight gain, but longitudinal repeatability of TEE is incompletely understood. Here the authors report that TEE is repeatable for adults, but not for children, and increases in TEE (adjusted for fat-free mass, fat mass, age and sex) are not associated with body composition changes in short-term longitudinal analyses.
- Rebecca Rimbach
- , Yosuke Yamada
- & John R. Speakman
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Article
| Open AccessGrainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan
Life- and healthspan of organisms can be modulated by dietary, genetic, or pharmacological interventions, which often affect metabolic pathways. Here the authors report that Grainyhead 1 is an evolutionarily conserved, drug-inducible transcription factor that promotes longevity in C. elegans, and thus a potential target for the development of geroprotective drugs.
- Giovanna Grigolon
- , Elisa Araldi
- & Fabian Fischer
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Article
| Open AccessMechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts.
- Ziang Xie
- , Lei Hou
- & Shunwu Fan
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Article
| Open AccessLipid droplet availability affects neural stem/progenitor cell metabolism and proliferation
Lipid droplets (LDs) are central to lipid metabolism, which is known to regulate neural stem cell behavior. Here, the authors show that LDs influence neural stem cell proliferation and metabolic activity and change upon differentiation or quiescence.
- Mergim Ramosaj
- , Sofia Madsen
- & Marlen Knobloch
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Article
| Open AccessGPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1
Activation of thermogenic adipocytes is a strategy to combat metabolic diseases. Here the authors report that GPR180 is a component of TGFβ signalling that promotes thermogenic adipocyte function and mediates the metabolic effects of the adipocyte-secreted factor CTHRC1, and contributes to the regulation of glucose and energy metabolism.
- Lucia Balazova
- , Miroslav Balaz
- & Christian Wolfrum
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Article
| Open AccessFree fatty-acid transport via CD36 drives β-oxidation-mediated hematopoietic stem cell response to infection
Hematopoietic stem cells (HSCs) rapidly expand upon infection, switching their metabolic profile to increase OXPHOS. Here, the authors show in mouse models that infection promotes uptake of long-chain free fatty acids via CD36, which is required for a protective response.
- Jayna J. Mistry
- , Charlotte Hellmich
- & Stuart A. Rushworth
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Article
| Open AccessHigh-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content
Exercise training can be therapeutic but how mitochondria respond remains unclear. Here, the authors use multiple omics techniques to reveal a complex network of non-stoichiometric mitochondrial adaptations that are prioritized or deprioritised during different phases of exercise training.
- Cesare Granata
- , Nikeisha J. Caruana
- & David J. Bishop
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Article
| Open AccessThe multifunctional protein E4F1 links P53 to lipid metabolism in adipocytes
The p53 tumor suppressor is also a regulator of metabolism, but the mechanisms controlling p53-associated metabolic activities remain poorly understood. Here the authors report that the deletion of the multifunctional protein E4F1 is protective against diet-induced obesity in mice, and E4F1 regulates adipocyte lipid metabolism through p53.
- Matthieu Lacroix
- , Laetitia K. Linares
- & Laurent Le Cam
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Article
| Open AccessGP73 is a TBC-domain Rab GTPase-activating protein contributing to the pathogenesis of non-alcoholic fatty liver disease without obesity
Dysregulation of lipid metabolism and transport contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here the authors identify GP73 as a TBC-domain Rab GTPase-activating protein that regulates very low-density lipoprotein export and promotes NAFLD development in mice.
- Yumeng Peng
- , Qiang Zeng
- & Congwen Wei
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Article
| Open AccessAngiogenin mediates paternal inflammation-induced metabolic disorders in offspring through sperm tsRNAs
Paternal environmental inputs can influence various phenotypes in offspring, with important implications for basic biology and public health. Here the authors show that Ang-mediated biogenesis of 5′-tsRNAs in sperm contributes to paternal inflammation-induced metabolic disorders in offspring.
- Yanwen Zhang
- , Li Ren
- & Bin He
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Article
| Open AccessEpigenetic interaction between UTX and DNMT1 regulates diet-induced myogenic remodeling in brown fat
Brown adipocytes contribute to energy balance, and adipocyte development and brown adipocyte thermogenesis are in part regulated by epigenetic modifications. Here the authors report that the histone demethylase Utx maintains brown adipocyte identity via demethylation of PRDM16, which in turn represses myogenic remodelling via DNMT1-mediated Myod1 promoter hypermethylation in mice.
- Fenfen Li
- , Jia Jing
- & Bingzhong Xue
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Article
| Open AccessImprinted lncRNA Dio3os preprograms intergenerational brown fat development and obesity resistance
Maternal obesity predisposes offspring to obesity and metabolic disorders through incompletely understood mechanisms. Here the authors report that Dio3os is an imprinted long-coding RNA that modulates brown adipose tissue development and obesity resistance in the offspring.
- Yan-Ting Chen
- , Qi-Yuan Yang
- & Min Du
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Article
| Open AccessNaked mole-rat brown fat thermogenesis is diminished during hypoxia through a rapid decrease in UCP1
Naked mole-rats are hypoxia-tolerant mammals, and during hypoxia their body temperature decreases via unknown mechanisms. Here the authors report that the hypoxia-induced body temperature decrease in naked mole rats occurs through decreased brown adipose tissue thermogenesis via decreases in a key thermogenic mitochondrial protein: UCP1.
- Hang Cheng
- , Rajaa Sebaa
- & Matthew E. Pamenter
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Article
| Open AccessDiet composition influences the metabolic benefits of short cycles of very low caloric intake
Understanding the contribution of diet composition, calories and length of fasting in health maintenance is still challenging. Here the authors compare the effects of cycles of intermittent very low calorie intake achieved with a plant-based fasting mimicking diet or standard laboratory chow to provide insights into the role played by diet composition in mediating the metabolic benefits of short cycles of very low-calorie intake in mice.
- Alberto Diaz-Ruiz
- , Tyler Rhinesmith
- & Rafael de Cabo
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Article
| Open AccessConstitutive activation of the PI3K-Akt-mTORC1 pathway sustains the m.3243 A > G mtDNA mutation
Heteroplasmic mtDNA mutations cause disease in humans. Here, Chung et al find the PI3K-Akt-mTORC1 pathway constitutively activated in cells with the heteroplasmic m.3243 A > G mutation, and inhibition of the pathway cell autonomously reduces mutant mtDNA load and rescues mitochondrial bioenergetics.
- Chih-Yao Chung
- , Kritarth Singh
- & Michael R. Duchen
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Article
| Open AccessThe transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis
Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.
- Motohiro Sekiya
- , Kenta Kainoh
- & Hitoshi Shimano
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Article
| Open AccessHistone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice
Misregulation of chromatin has been linked to many conditions, including obesity, but the details remain unclear. Here the authors identify the H4 lysine 16 acetyltransferase MOF as a master regulator of glucose metabolism that is required for normal glucose uptake and fat storage.
- Cecilia Pessoa Rodrigues
- , Aindrila Chatterjee
- & Asifa Akhtar
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Article
| Open AccessSynchronization between peripheral circadian clock and feeding-fasting cycles in microfluidic device sustains oscillatory pattern of transcriptome
Chronic desynchronization between physiological and behavioral rhythms has been linked to the onset of metabolic diseases. Here the authors control the cyclic metabolic signals in a microfluidic device to study the effects of the timing, period and frequency of glucose and insulin on the transcriptome of cultured fibroblasts.
- Onelia Gagliano
- , Camilla Luni
- & Nicola Elvassore
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Article
| Open AccessPGRMC1 acts as a size-selective cargo receptor to drive ER-phagic clearance of mutant prohormones
Degradation of misfolded proteins from the endoplasmic reticulum (ER) is important for maintaining proper cellular protein homeostasis. Here, the authors discovered that the ER membrane protein PGRMC1 binds to misfolded prohormones for recruitment into the ER-phagy degradative pathway.
- Yu-Jie Chen
- , Jeffrey Knupp
- & Billy Tsai
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Comment
| Open AccessThe growing need for controlled data access models in clinical proteomics and metabolomics
More and more clinical studies include potentially sensitive human proteomics or metabolomics datasets, but bioinformatics resources for managing the access to these data are not yet available. This commentary discusses current best practices and future perspectives for the responsible handling of clinical proteomics and metabolomics data.
- Thomas M. Keane
- , Claire O’Donovan
- & Juan Antonio Vizcaíno
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Article
| Open AccessBrain adiponectin signaling controls peripheral insulin response in Drosophila
Circulating adiponectin controls sensitivity to insulin in tissues. Here, Arquier et al. show that adiponectin receptor activity in neurons of the Drosophila brain controls insulin response in peripheral tissues via juvenile hormone signaling.
- Nathalie Arquier
- , Marianne Bjordal
- & Pierre Léopold
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Article
| Open AccessExtensive regulation of enzyme activity by phosphorylation in Escherichia coli
While phosphorylation is an essential post-translational modification in eukaryotes only recently the phosphoproteome of prokaryotes has been provided. Here, Schastnaya et al. mutate 52 phosphosites on 23 E. coli enzymes and apply metabolomics to provide evidence for the functional relevance of bacterial phosphorylation events.
- Evgeniya Schastnaya
- , Zrinka Raguz Nakic
- & Uwe Sauer
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Article
| Open AccessBerberine is an insulin secretagogue targeting the KCNH6 potassium channel
Berberine is a compound with glucose-lowering effects in mice and humans. Here, the authors show that in mice berberine has beneficial glycemic effects by promoting insulin secretion, which requires the potassium channel KCNH6 in beta cells, and that berberine can promote insulin secretion in healthy men in a phase 1 clinical trial.
- Miao-Miao Zhao
- , Jing Lu
- & Jin-Kui Yang
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Article
| Open AccessAdipose tissue-derived neurotrophic factor 3 regulates sympathetic innervation and thermogenesis in adipose tissue
Activation of brown adipose tissue thermogenesis increases energy expenditure and promotes weight loss in mice. Here the authors identify neurotrophic factor neurotrophin 3 (NT-3) as an adipokine that regulates sympathetic nervous system growth and innervation in adipose tissue and increases white adipose beiging.
- Xin Cui
- , Jia Jing
- & Hang Shi
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Article
| Open AccessBMP8 and activated brown adipose tissue in human newborns
Brown adipose tissue (BAT) in infants has been studied for more than a century, however, the knowledge about its physiological features is limited. Here, the authors investigate the link between BAT thermogenesis and the regulation of temperature in human new-borns with non-invasive infrared thermography.
- Adela Urisarri
- , Ismael González-García
- & Miguel López
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Article
| Open AccessEndothelium-specific depletion of LRP1 improves glucose homeostasis through inducing osteocalcin
The vascular endothelium contributes to metabolic regulation, however, the underlying mechanisms are not fully understood. Here the authors show that endothelial low-density lipoprotein receptor-related protein 1 regulates glucose homeostasis via osteocalcin expression.
- Hua Mao
- , Luge Li
- & Xinchun Pi
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Article
| Open AccessQuantitative modelling of amino acid transport and homeostasis in mammalian cells
Cytosolic amino acid concentrations are carefully maintained, but how homeostasis occurs is unclear. Here, the authors show that amino acid transporters primarily determine intracellular amino acid levels and develop a model that predicts a perturbation response similar to experimental data.
- Gregory Gauthier-Coles
- , Jade Vennitti
- & Stefan Bröer
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Article
| Open AccessOrexin receptors 1 and 2 in serotonergic neurons differentially regulate peripheral glucose metabolism in obesity
The wake-active orexin system plays a central role in the dynamic regulation of glucose homeostasis. Here the authors report that inactivation of the orexin receptor type 1 or 2 in serotonergic neurons differentially regulate systemic glucose homeostasis in the context of diet induced obesity.
- Xing Xiao
- , Gagik Yeghiazaryan
- & A. Christine Hausen
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Article
| Open AccessDynamics of the compartmentalized Streptomyces chromosome during metabolic differentiation
Streptomyces bacteria have a linear chromosome, with core genes located in the central region and gene clusters for specialized metabolite biosynthesis found in the ‘arms’. Here, Lioy et al. show that such chromosome structure correlates with genetic compartmentalization, and the onset of metabolic differentiation is accompanied by a rearrangement of chromosome architecture.
- Virginia S. Lioy
- , Jean-Noël Lorenzi
- & Stéphanie Bury-Moné
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Article
| Open AccessNTS Prlh overcomes orexigenic stimuli and ameliorates dietary and genetic forms of obesity
Calcitonin receptor-expressing neurons of the nucleus tractus solitarius contribute to long-term control of food intake and body weight. The authors show that a subset of these cells expresses Prlh and that enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity in mice.
- Wenwen Cheng
- , Ermelinda Ndoka
- & Martin G. Myers Jr
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Article
| Open AccessThe pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue
Chlorpyrifos is a widely-used pesticide and a common residue on vegetables and fruits. Here the authors show that at non-neurotoxic doses, chlorpyrifos reduces energy expenditure, by inhibiting diet induced thermogenesis, and promotes obesity and insulin resistance.
- Bo Wang
- , Evangelia E. Tsakiridis
- & Gregory R. Steinberg
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Article
| Open AccessTet2 Controls the Responses of β cells to Inflammation in Autoimmune Diabetes
There are dynamic interactions between immune cells and β cells that lead to β cell destruction in the context of autoimmune diabetes. Here the authors show that TET2, a methylcytosine dioxygenase, can regulate this interaction and deletion of TET2 can prevent the autoimmune destruction of β cells in mice.
- Jinxiu Rui
- , Songyan Deng
- & Kevan C. Herold
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Article
| Open AccessThe enzymatic activity of inositol hexakisphosphate kinase controls circulating phosphate in mammals
Inositol hexakisphosphate kinase (IP6K) is involved in diverse cellular signalling pathways, but the physiological roles of IP6K in vivo remain unknown in mammals. Here, the authors show that the enzymatic activity of IP6K is essential for phosphate regulation in vivo.
- Yusuke Moritoh
- , Shin-ichi Abe
- & Masanori Watanabe
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Article
| Open AccessAdipose tissue hyaluronan production improves systemic glucose homeostasis and primes adipocytes for CL 316,243-stimulated lipolysis
Hyaluronan is a naturally occurring linear polysaccharide that together with collagens, enzymes, and glycoproteins forms the extracellular matrix. Here the authors show that adipose tissue overproduction of Hyaluronan reduces fat accumulation in mice fed high-fat diet and improves systemic glucose homeostasis.
- Yi Zhu
- , Na Li
- & Philipp E. Scherer
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Article
| Open AccessThe sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster
Incretin hormones regulate insulin and glucagon secretion in mammals, but similar peptides have not been characterized in invertebrates. Here the authors show that neuropeptide F functions similar to mammalian incretin in fruit flies, responding to sugar and enhancing insulin-like peptide secretion.
- Yuto Yoshinari
- , Hina Kosakamoto
- & Ryusuke Niwa
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Article
| Open AccessImpact of aging and exercise on skeletal muscle mitochondrial capacity, energy metabolism, and physical function
Aging is associated with a progressive loss of muscle function. Here the authors characterize mitochondrial capacity and muscle function in young and older adults with similar habitual physical activity and also compared to older adults with exercise training or with physical impairment.
- L. Grevendonk
- , N. J. Connell
- & J. Hoeks
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Article
| Open AccessIntestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice
The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.
- Nadejda Bozadjieva-Kramer
- , Jae Hoon Shin
- & Randy J. Seeley
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Article
| Open AccessBrown adipose tissue is the key depot for glucose clearance in microbiota depleted mice
Gut microbiota deficient mice demonstrate enhanced glucose clearance, but which tissues are responsible for this improvement are still unclear. Here the authors report that brown adipose tissue contributes to the enhanced glucose clearance in gut microbiota depleted mice and that this response is dissociated from adaptive thermogenesis.
- Min Li
- , Li Li
- & John R. Speakman
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Article
| Open AccessBeige adipocytes mediate the neuroprotective and anti-inflammatory effects of subcutaneous fat in obese mice
Visceral adiposity is a risk factor for cognitive decline, but subcutaneous adipose tissue (SAT) is not and may be protective. Here, the authors show that beige adipocytes are indispensable for the neuroprotective effects of SAT. Beige fat knockout mice were more susceptible to the neuroimmune and cognitive effects of obesity, and in normal mice, SAT transplants protected against chronic obesity via beige fat-dependent mechanisms.
- De-Huang Guo
- , Masaki Yamamoto
- & Alexis M. Stranahan
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Article
| Open AccessLabel-free imaging for quality control of cardiomyocyte differentiation
Differentiation of hPSCs to cardiomyocytes suffers from high variability. Here the authors report a label-free live cell imaging platform based on autofluorescence imaging to enable the prediction of cardiomyocyte differentiation efficiency from hPSCs.
- Tongcheng Qian
- , Tiffany M. Heaster
- & Melissa C. Skala
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Article
| Open AccessPancreatic Ppy-expressing γ-cells display mixed phenotypic traits and the adaptive plasticity to engage insulin production
The cellular identity and function of the pancreatic polypeptide (Ppy)-producing γ-cells are incompletely understood. Here the authors show that these cells are heterogeneous and display adaptive plasticity to engage in insulin production following β-cell injury, but loss of the Ppy gene or γ-cells in mice does not affect weight or glycemia under basal conditions.
- Marta Perez-Frances
- , Léon van Gurp
- & Pedro L. Herrera
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Article
| Open AccessNeonatal thyroxine activation modifies epigenetic programming of the liver
Whether thyroid hormones affect gene expression via DNA methylation is not well known. Here the authors show that type 2 deiodinase (D2) converts T4 to produce T3, which prevents DNA methylation of discrete areas in the neonatal liver. In the absence of D2, DNA methylation occurs and is associated with reduced chromatin accessibility in promoters and enhancers and affects gene expression.
- Tatiana L. Fonseca
- , Tzintzuni Garcia
- & Antonio C. Bianco
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Article
| Open AccessRole of Tim4 in the regulation of ABCA1+ adipose tissue macrophages and post-prandial cholesterol levels
Diverse macrophage subsets are found in adipose tissue where they regulate its physiology. Here, the authors used single-cell RNA sequencing to analyse the effect of post-prandial lipids on adipose tissue macrophages and identify Tim4 as a regulator of ABCA1+ macrophage function and post-prandial cholesterol transport.
- M. S. Magalhaes
- , P. Smith
- & C. Bénézech
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Article
| Open AccessTemperature heterogeneity correlates with intraspecific variation in physiological flexibility in a small endotherm
Theory predicts that organisms in varied environments should evolve to be more phenotypically flexible. Evidence combining genetic and physiological variation with thermal acclimation experiments shows that the thermogenic flexibility of wild juncos is greatest in populations where temperatures are most variable.
- Maria Stager
- , Nathan R. Senner
- & Zachary A. Cheviron
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Article
| Open AccessGlucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development
Memory T cells are particularly reliant on fatty acid oxidation as a source of energy. Here the authors show this reliance is controlled by AMPK sensing of glucose deprivation that triggers SENP1-Sirt3 signalling, driving fatty acid oxidation and memory differentiation in T cells via deacetylation of YME1L1 to induce mitochondrial fusion.
- Jianli He
- , Xun Shangguan
- & Jinke Cheng
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Article
| Open AccessNeurofibromin regulates metabolic rate via neuronal mechanisms in Drosophila
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in neurofibromin and associated with disruptions in physiology and behavior. Here the authors show that neurofibromin regulates metabolic homeostasis via a discrete brain circuit in a Drosophila model of NF1.
- Valentina Botero
- , Bethany A. Stanhope
- & Seth M. Tomchik