Featured
-
-
Article
| Open AccessMitochondrial aconitase suppresses immunity by modulating oxaloacetate and the mitochondrial unfolded protein response
Mitochondrial function has been linked to immunity but the role of the Krebs’s cycle in regards the immune response is not well characterised. Here the authors show that Krebs’s cycle enzyme ACO2 suppresses immunity via modulation of oxaloacetate and the mitochondrial unfolded protein response.
- Eunah Kim
- , Andrea Annibal
- & Seung-Jae V. Lee
-
Article
| Open AccessGut microbiota Turicibacter strains differentially modify bile acids and host lipids
Mechanisms by which the gut microbiota affects its host are a main research focus. Here, Lynch et al. characterize bile acid modifications performed by a prevalent bacterial taxon from the gut, the genus Turicibacter, and found they broadly altered host lipids, connecting Turicibacter functions and host physiology.
- Jonathan B. Lynch
- , Erika L. Gonzalez
- & Elaine Y. Hsiao
-
Article
| Open AccessSignaling mechanisms in renal compensatory hypertrophy revealed by multi-omics
The authors used a multi-omic approach in a mouse unilateral nephrectomy model to identify signaling processes associated with compensatory hypertrophy of the renal proximal tubule. The results indicate that PPARα is an important determinant of proximal tubule cell size and is a likely mediator of compensatory proximal tubule hypertrophy.
- Hiroaki Kikuchi
- , Chung-Lin Chou
- & Mark A. Knepper
-
Article
| Open AccessEmbryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes
Environmental conditions during pregnancy contribute to offspring metabolic disease. Here, the authors show that immune cells reprogrammed in utero by maternal vitamin D deficiency increase lifetime diabetes risk in the offspring and are sufficient to transplant diabetes.
- Jisu Oh
- , Amy E. Riek
- & Carlos Bernal-Mizrachi
-
Article
| Open AccessClinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation
Porcine kidney xenotransplantation is accelerating towards clinical testing. Here the authors present preclinical results examining xenograft growth and participation in renal endocrine pathways that can be used to inform clinical study design.
- Daniel J. Firl
- , Grace Lassiter
- & Katherine C. Hall
-
Article
| Open AccessExcessive copper impairs intrahepatocyte trafficking and secretion of selenoprotein P
Selenium and copper are two essential trace elements whose homeostasis and distribution is regulated by hepatic release of selenoprotein P (SELENOP) and ceruloplasmin, respectively. Here, the authors show that excessive copper results in hepatic SELENOP accumulation in the trans Golgi which might limit the selenium transport to peripheral organs.
- Maria Schwarz
- , Caroline E. Meyer
- & Anna P. Kipp
-
Article
| Open AccessA multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase
While dimethylarginine dimethylaminohydrolase 1 (DDAH1) is known to metabolize the endogenous inhibitor of nitric oxide synthases, asymmetric dimethylarginine (ADMA), the function of DDAH2 has remained controversial. Here, the authors present several lines of evidence that DDAH2 does not hydrolyze ADMA.
- Vinitha N. Ragavan
- , Pramod C. Nair
- & Roman N. Rodionov
-
Article
| Open AccessStructural mechanism of intracellular autoregulation of zinc uptake in ZIP transporters
Zinc uptake and regulation are vital in all life forms. Here, authors describe a dimer of a ZIP-family zinc transporter in an inward-facing, inhibited conformation. A built-in zinc sensor is proposed to sense the intracellular zinc content to autoregulate zinc uptake across membranes.
- Changxu Pang
- , Jin Chai
- & Qun Liu
-
Article
| Open AccessSERCA2 phosphorylation at serine 663 is a key regulator of Ca2+ homeostasis in heart diseases
Despite advances in cardioprotection, new therapeutic strategies precluding ischemia-reperfusion injury of patients are still needed. Here, the authors show that preventing serine 663 phosphorylation of SERCA2, significantly increases its activity and protects against cell death, by counteracting cytosolic and mitochondrial Ca2+ overload.
- Fabrice Gonnot
- , Laura Boulogne
- & Ludovic Gomez
-
Article
| Open AccessRare phenomena of central rhythm and pattern generation in a case of complete spinal cord injury
The existence of dedicated spinal circuits generating locomotion in humans has remained controversial. Here, the authors study distinct forms of spontaneous and induced rhythmic leg activity in a paralyzed individual, providing insight into spinal rhythmogenesis and pattern formation.
- Karen Minassian
- , Aymeric Bayart
- & Ursula S. Hofstoetter
-
Article
| Open AccessDurable contraception in the female domestic cat using viral-vectored delivery of a feline anti-Müllerian hormone transgene
This study demonstrates the safety and long-term efficacy of a single-dose, injectable contraceptive in female domestic cats. Treated females remained contracepted for over two years, and did not ovulate or produce kittens when paired with males.
- Lindsey M. Vansandt
- , Marie-Charlotte Meinsohn
- & David Pépin
-
Article
| Open AccessNative American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain
Drugs that rescue function of episodic ataxia 1 (EA1) mutant potassium channels are lacking. Here, Manville et al identify and describe the molecular basis for Native American botanical ataxia remedies that directly rescue EA1 mutant channels.
- Rían W. Manville
- , J. Alfredo Freites
- & Geoffrey W. Abbott
-
Article
| Open AccessNeutrophil-derived catecholamines mediate negative stress effects on bone
Authors present both preclinical data in mice and clinical data from humans in support of the hypothesis that stress negatively affects bone growth and repair. These effects are mediated by neutrophil-derived catecholamines inhibiting cartilage-to-bone transition via β2-adrenoceptor signaling in chondrocytes.
- Miriam E. A. Tschaffon-Müller
- , Elena Kempter
- & Stefan O. Reber
-
Article
| Open AccessCFP1 governs uterine epigenetic landscapes to intervene in progesterone responses for uterine physiology and suppression of endometriosis
Progesterone (P4) signalling is involved in physiological control of the endometrium and contributes to the pathogenesis of endometrial diseases such as endometriosis. Here the authors report that CFP1, a regulator of histone methylation, controls endometrial responses to P4 and lack of endometrial CFP1 leads to failure of embryo implantation and exacerbated experimental endometriosis in mice.
- Seung Chel Yang
- , Mira Park
- & Haengseok Song
-
Article
| Open AccessDevelopment of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding
Despite the therapeutic interest in targeting CDK2, developing a selective CDK2 inhibitor has been challenging. Here, the authors describe a potent and selective CDK2 inhibitor that binds an allosteric pocket, preventing activating protein partners from binding and showing potential as a contraceptive.
- Erik B. Faber
- , Luxin Sun
- & Gunda I. Georg
-
Article
| Open AccessM1BP is an essential transcriptional activator of oxidative metabolism during Drosophila development
The transcriptional regulation of mitochondrial oxidative phosphorylation gene expression is poorly understood. Using the developing Drosophila flight muscle, the authors identify the transcription factor M1BP as a new major regulator of this process.
- Gabriela Poliacikova
- , Marine Barthez
- & Andrew J. Saurin
-
Article
| Open AccessSenescent immune cells accumulation promotes brown adipose tissue dysfunction during aging
With increasing age, brown adipose tissue (BAT) becomes characterized by increased adiposity and immune cell infiltration but reduced thermogenic capacity. Here the authors report that bone marrow-derived pro-inflammatory and senescent S100A8+ immune cells accumulate in BAT of male rats and mice during aging and contribute to BAT dysfunction.
- Xu Feng
- , Liwen Wang
- & Haiyan Zhou
-
Article
| Open AccessTranscriptional coactivation by EHMT2 restricts glucocorticoid-induced insulin resistance in a study with male mice
Glucocorticoids are known to induce insulin resistance via transcriptional activation of genes related to liver gluconeogenesis and insulin resistance. Here the authors report that in male mice treated with glucocorticoids, the transcriptional co-regulator EHMT2 is involved in the induction of Irs2 (a gene promoting insulin action) to restrict the extent of insulin resistance in the liver.
- Rebecca A. Lee
- , Maggie Chang
- & Jen-Chywan Wang
-
Article
| Open AccessDax1 modulates ERα-dependent hypothalamic estrogen sensing in female mice
Estrogen controls female fertility in part via restraining or promoting kisspeptin (Kiss1)-neuron activity in the arcuate hypothalamic nucleus and the AVPV hypothalamic nucleus, respectively. Here the authors report that estrogen receptor alpha (ERα) interacts with the genome and the nuclear receptor co-repressor NR0B1 (DAX1) to manifest region-specific actions on Kiss1 expression.
- Jose M. Ramos-Pittol
- , Isabel Fernandes-Freitas
- & Bryn M. Owen
-
Article
| Open AccessNatural killer cells and innate lymphoid cells 1 tune anxiety-like behavior and memory in mice via interferon-γ and acetylcholine
The meningeal compartment communicates with the brain to modulate homeostatic functions. Here, the authors demonstrate that natural killer (NK) cells and innate lymphoid cells (ILC) 1 shape synaptic neuronal transmission and affect mouse behavior.
- Stefano Garofalo
- , Germana Cocozza
- & Cristina Limatola
-
Article
| Open AccessUpregulation of breathing rate during running exercise by central locomotor circuits in mice
The neuronal basis for respiratory augmentation during running is poorly understood. Here, the authors identify two neuronal pathways by which the central locomotor network can upregulate respiratory rate in running mice.
- Coralie Hérent
- , Séverine Diem
- & Julien Bouvier
-
Article
| Open AccessPlatelet-derived chemokines promote skeletal muscle regeneration by guiding neutrophil recruitment to injured muscles
Skeletal muscle has a remarkable capacity to regenerate in response to injury, but it is not entirely understood how this regeneration initiates. Here, Graca et al. show that platelet-secreted chemokines promote the early steps of muscle regeneration by recruiting neutrophils to injured muscles.
- Flavia A. Graca
- , Anna Stephan
- & Myriam Labelle
-
Article
| Open AccessUsing mass spectrometry imaging to map fluxes quantitatively in the tumor ecosystem
Isotopologue spectral analysis was originally designed to assess metabolic fluxes from bulk samples. Here, the authors adapted this approach to infer fluxes from discrete regions in tissue by using mass spectrometry imaging, showing increased fatty acid synthesis flux in brain tumors of mice.
- Michaela Schwaiger-Haber
- , Ethan Stancliffe
- & Gary J. Patti
-
Article
| Open AccessEndothelial cell-derived stem cell factor promotes lipid accumulation through c-Kit-mediated increase of lipogenic enzymes in brown adipocytes
Although it is known that cellular crosstalk between endothelial cells and brown adipocytes is essential, it remains poorly understood. Here the authors show that SCF derived from the surrounding endothelial cells promotes lipid accumulation in BAT by enhancing lipogenic enzymes in through c-Kit activation.
- Hyuek Jong Lee
- , Jueun Lee
- & Gou Young Koh
-
Article
| Open AccessGenetically prolonged beige fat in male mice confers long-lasting metabolic health
Beige adipocytes quickly transition into white adipocytes upon the removal of stimuli, limiting their therapeutic potential for chronic metabolic diseases. In this study, the authors show that inhibiting Cdkn2a-Becn1 mediated autophagy can maintain beige adipocytes and provide long term metabolic health benefits in mice.
- Ruifan Wu
- , Jooman Park
- & Yuwei Jiang
-
Article
| Open AccessSpectro-spatial features in distributed human intracranial activity proactively encode peripheral metabolic activity
How human brain activity relates to peripheral metabolism is not known. Here, the authors find that intracranial activity is strongly coupled to peripheral glucose variations across multiple brain regions and is sufficient for decoding of glucose levels.
- Yuhao Huang
- , Jeffrey B. Wang
- & Casey H. Halpern
-
Article
| Open AccessAnatomical and functional maturation of the mid-gestation human enteric nervous system
Dershowitz and colleagues assess second trimester human fetal enteric nervous system development and function. They describe structural reorganization of the enteric nervous system that corresponds to gastrointestinal motility onset in ex vivo preparations.
- Lori B. Dershowitz
- , Li Li
- & Julia A. Kaltschmidt
-
Article
| Open AccessResveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1
Resveratrol intervention improves lipid homeostasis, but how it can target multiple organs with very low bioavailability remains elusive. Here, the authors report that gut microbiota-bile acids are linked to the hypolipidemic effect of resveratrol via inhibiting the intestinal FXR/SR-B1 signalling pathway.
- Juan Pang
- , Fitore Raka
- & Tianru Jin
-
Article
| Open AccessMale reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity
We know that nutrition and obesity can impact male fertility, but specific dietary guidelines for men trying to conceive don’t exist. Here the authors show that diet composition is likely more important than body fat in influencing reproductive traits and each macronutrient has different impacts.
- A. J. Crean
- , S. Afrin
- & T. Pini
-
Article
| Open AccessIdentification of biomarkers for glycaemic deterioration in type 2 diabetes
There is an urgent need for biomarkers for type 2 diabetes progression that provide a deeper understanding of the disease process. Here, the authors identify biomarkers in three molecular classes, replicate them in other cohorts and explore top protein biomarkers in detail in functional studies.
- Roderick C. Slieker
- , Louise A. Donnelly
- & Guy A. Rutter
-
Article
| Open AccessReduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice
Adipose tissue thermogenesis plays a role in appropriate response to cold exposure through incompletely understood mechanisms. Here the authors report that acute cold exposure increases the serum levels of bradykinin, which induces brown adipose tissue thermogenesis and white adipose tissue browning in male mice.
- Fei Xiao
- , Haizhou Jiang
- & Feifan Guo
-
Perspective
| Open AccessA precision environmental health approach to prevention of human disease
Precision environmental health leverages environmental and system-level data to understand underlying environmental causes of disease, identify biomarkers of exposure, and develop new prevention and intervention strategies. In this Perspective, the authors provide real-life illustrations of the utility of precision environmental health approaches and identify current challenges in the field.
- Andrea Baccarelli
- , Dana C. Dolinoy
- & Cheryl Lyn Walker
-
Article
| Open AccessMitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria
Mitochondria modulate both normal and premature aging, yet if primary oxidative phosphorylation deficiency can cause progeria has been unclear. Here, the authors show that mice with severe isolated respiratory complex III deficiency display cellular senescence and juvenile-onset segmental progeria.
- Janne Purhonen
- , Rishi Banerjee
- & Jukka Kallijärvi
-
Article
| Open AccessA small secreted protein NICOL regulates lumicrine-mediated sperm maturation and male fertility
Mammalian sperm need to be matured in the epididymis to achieve potential for fertility. Here the authors identify NICOL as a secreted protein that acts on the epididymis to trigger its functional differentiation and induce sperm maturation.
- Daiji Kiyozumi
- , Kentaro Shimada
- & Masahito Ikawa
-
Article
| Open AccessGlucocorticoid activation of anti-inflammatory macrophages protects against insulin resistance
Obesity and a high-fat diet can lead to insulin resistance in a process involving macrophage-mediated inflammation of adipose tissue. Here the authors show that glucocorticoid receptor-deficient macrophages have an elevated inflammatory response which aggravates insulin resistance implicating that glucocorticoids promote insulin-sensitizing actions via adipose tissue macrophages during obesity.
- Giorgio Caratti
- , Ulrich Stifel
- & Jan P. Tuckermann
-
Article
| Open AccessARRDC5 expression is conserved in mammalian testes and required for normal sperm morphogenesis
Male organisms produce huge numbers of sperm each day, with defects in the process resulting infertility. Here they show that arrestin domain-containing 5 (ARRDC5) is a testis-specific molecule required for mammalian spermatogenesis.
- Mariana I. Giassetti
- , Deqiang Miao
- & Jon M. Oatley
-
Article
| Open AccessDerepression may masquerade as activation in ligand-gated ion channels
Ligand-gated ion channels are activated/opened by agonists. Tessier et al. show that agonists can inhibit the inhibition of intrinsic basal activity, and thus that activation may instead be the manifestation of a derepression mechanism.
- Christian J. G. Tessier
- , Johnathon R. Emlaw
- & Corrie J. B. daCosta
-
Article
| Open AccessAstrocytic chloride is brain state dependent and modulates inhibitory neurotransmission in mice
Astrocytes act as a dynamic Cl− reservoir regulating Cl− homeostasis in the CNS. Astrocytic Cl− is high and stable during sleep, it is lower during wakefulness and fluctuates in response to sensory input and motor activity. Efflux of Cl− from astrocytes supports inhibitory transmission in the CNS.
- Verena Untiet
- , Felix R. M. Beinlich
- & Maiken Nedergaard
-
Article
| Open AccessNAD+ repletion with niacin counteracts cancer cachexia
The loss of nicotinamide adenine dinucleotide is reported to be associated with muscle mitochondrial dysfunction in murine cancer models. Here the authors show that niacin supplementation improves mitochondrial metabolism and reduces muscle wasting in mouse models of cachexia.
- Marc Beltrà
- , Noora Pöllänen
- & Fabio Penna
-
Article
| Open AccessThe C-terminal tail of polycystin-1 suppresses cystic disease in a mitochondrial enzyme-dependent fashion
Mutations in the gene encoding PC1 cause ADPKD, a common genetic renal disease. Here, the authors show that expression of the C-terminal 200 amino acids of the large PC1 protein in mouse models of ADPKD suppresses cystic disease through an interaction with the mitochondrial enzyme NNT.
- Laura Onuchic
- , Valeria Padovano
- & Michael J. Caplan
-
Article
| Open AccessCharacterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology
The neural mechanisms underpinning ketamine’s dissociative and antidepressant effects remain poorly understood. Here, the authors analyzed ketamine-induced brain dynamics with intracranial recordings in humans and found that ketamine engages different brain areas in distinct frequency-dependent patterns that may relate to its dissociative and antidepressant effects.
- Fangyun Tian
- , Laura D. Lewis
- & Patrick L. Purdon
-
Article
| Open AccessTime-of-day defines NAD+ efficacy to treat diet-induced metabolic disease by synchronizing the hepatic clock in mice
The timing of NAD + supply determines its efficacy to treat metabolic disease. Here, the authors show that increasing NAD + at the early active phase maximizes weight loss and glucose regulation in mice. NAD + can displace the phase of the liver clock which can cause circadian misalignment.
- Quetzalcoatl Escalante-Covarrubias
- , Lucía Mendoza-Viveros
- & Lorena Aguilar-Arnal
-
Article
| Open AccessThe rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice
Many transcriptomic pathways in the liver show circadian rhythms, which have been reported to be disrupted in aged mice. Here the authors report that the expression of transcription factor Egr-1 decreases and its rhythm is shifted with age in the liver of male mice, and that deletion of Egr-1 results in increased liver fat accumulation.
- Jing Wu
- , Dandan Bu
- & Chao-Jun Li
-
Article
| Open AccessA defect in mitochondrial protein translation influences mitonuclear communication in the heart
The heart requires high levels of mitochondria to sustain function, and mitochondrial stressors can be transmitted to the nucleus and reprogram metabolism. Here, the authors show that a mitochondrial ribosomal protein is important for heart development in mice by increasing nuclear Klf15 expression.
- Feng Gao
- , Tian Liang
- & Jinghai Chen
-
Article
| Open AccessBitter taste cells in the ventricular walls of the murine brain regulate glucose homeostasis
The median eminence (ME) at the base of the brain controls body homeostasis. Here, the authors describe a functional tanycyte subpopulation at the ME which tastes the surrounding milieu, responds to metabolic signals and regulates glucose homeostasis.
- Qiang Yu
- , Igor Gamayun
- & Ulrich Boehm
-
Article
| Open AccessAdipocyte YTH N(6)-methyladenosine RNA-binding protein 1 protects against obesity by promoting white adipose tissue beiging in male mice
Activation of white adipose tissue (WAT) thermogenesis alleviates obesity-associated metabolic disorders in rodents. Here the authors report that the m6 A RNA modification reader YTHDF1 promotes WAT thermogenesis in a study with male mice, and may be a potential target for the treatment of obesity.
- Sujun Yan
- , Xiaoling Zhou
- & Xiangwei Gao
-
Article
| Open AccessSAPS3 subunit of protein phosphatase 6 is an AMPK inhibitor and controls metabolic homeostasis upon dietary challenge in male mice
Inhibition of AMPK leads to metabolic perturbations yet how AMPK is inactivated is not fully understood. Here the authors show protein phosphatase 6 subunit SAPS3 is a negative regulator of AMPK and loss of SAPS3 activates AMPK and protects male mice against overnutrition.
- Ying Yang
- , Michael A. Reid
- & Mei Kong
-
Article
| Open AccessDe novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics
The function of de novo lipogenesis (DNL) in adipocytes has been a mystery as it contributes little to fat storage in these cells. Here, the authors show that DNL is a critical source of fatty acids for membrane-expanding processes like autophagy.
- Leslie A. Rowland
- , Adilson Guilherme
- & Michael P. Czech
-
Article
| Open AccessMicrobiota alters the metabolome in an age- and sex- dependent manner in mice
Commensal microbes contribute considerably to mammalian metabolism. Here the authors report the relative contributions of microbiome, age and sex to metabolism throughout the body and uncover age- and sex- specificity in how microbes affect metabolite levels in mice.
- Kirsty Brown
- , Carolyn A. Thomson
- & Kathy D. McCoy