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| Open AccessPTH induces bone loss via microbial-dependent expansion of intestinal TNF+ T cells and Th17 cells
T cells are involved in the bone loss induced by parathyroid hormone (PTH), but their origin is unknown. Here, the authors show that the intestinal microbiota is required for PTH to induce bone loss and describes mechanisms for microbiota-mediated gut–bone crosstalk in mouse models of hyperparathyroidism.
- Mingcan Yu
- , Abdul Malik Tyagi
- & Roberto Pacifici
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Article
| Open AccessGenetic deletion of mast cell serotonin synthesis prevents the development of obesity and insulin resistance
Serotonin inhibits adipose tissue thermogenesis. Here the authors show that obese mice housed in thermoneutrality have increased mast cell serotonin synthesis, and that inhibiting this pathway through deletion of mast cell Tph1 increases white adipose tissue browning and protects against diet-induced obesity, insulin resistance and liver steatosis.
- Julian M. Yabut
- , Eric M. Desjardins
- & Gregory R. Steinberg
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Article
| Open AccessEndothelial ZEB1 promotes angiogenesis-dependent bone formation and reverses osteoporosis
An endothelial cell subtype, expressing endomucin and CD31, has been reported to couple angiogenesis with osteogenesis. Here, the authors show that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice
- Rong Fu
- , Wen-Cong Lv
- & Zhao-Qiu Wu
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Article
| Open AccessThe RNA-binding protein HuR is a negative regulator in adipogenesis
Human antigen R (HuR) is an RNA binding protein that promotes mRNA stability. Here the authors show that HuR represses adipogenesis in white and brown adipose tissue by stabilizing Insig1 and other targets.
- Diana Teh Chee Siang
- , Yen Ching Lim
- & Dan Xu
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Article
| Open AccessPredicting optical coherence tomography-derived diabetic macular edema grades from fundus photographs using deep learning
Diabetic eye disease is a cause of preventable blindness and accurate and timely referral of patients with diabetic macular edema is important to start treatment. Here the authors present a deep learning model that can predict the presence of diabetic macular edema from color fundus photographs with superior specificity and positive predictive value compared to retinal specialists.
- Avinash V. Varadarajan
- , Pinal Bavishi
- & Dale R. Webster
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Article
| Open AccessIdentification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism
Anti-resorptive bone therapies also inhibit bone formation, as osteoclasts secrete factors that stimulate bone formation by osteoblasts. Here, the authors identify osteoclast-secreted factors that couple bone resorption to bone formation in healthy subjects, and show that osteoclast-derived DPP4 may be a factor coupling bone resorption to energy metabolism.
- Megan M. Weivoda
- , Chee Kian Chew
- & Sundeep Khosla
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Article
| Open AccessTissue-infiltrating macrophages mediate an exosome-based metabolic reprogramming upon DNA damage
DNA damage is associated with metabolic disorders, but the mechanism in unclear. Here, the authors show that persistent DNA damage induced by lack of the endonuclease XPF-ERCC1 triggers extracellular vesicle biogenesis in tissue infiltrating macrophages, and that vesicle uptake stimulates glucose uptake in recipient cells, leading to increased inflammation.
- Evi Goulielmaki
- , Anna Ioannidou
- & George A. Garinis
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Article
| Open AccessGenetic correlations of psychiatric traits with body composition and glycemic traits are sex- and age-dependent
Psychiatric disorders are often accompanied by alterations in BMI and body composition due to changes in eating behaviour and physical activity. Here, Hübel et al. study the genetic overlap between these traits and find that genetic correlations between psychiatric disorders and body composition are sex-specific and evident only in adulthood.
- Christopher Hübel
- , Héléna A. Gaspar
- & Gerome Breen
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Article
| Open AccessFlagellin-elicited adaptive immunity suppresses flagellated microbiota and vaccinates against chronic inflammatory diseases
Gut microbiota alterations, including enrichment of flagellated bacteria, are associated with metabolic syndrome and chronic inflammatory diseases. Here, Tran et al. show, in mice, that elicitation of mucosal anti-flagellin antibodies protects against experimental colitis and ameliorates diet-induced obesity.
- Hao Q. Tran
- , Ruth E. Ley
- & Benoit Chassaing
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Article
| Open AccessLeptin induces TNFα-dependent inflammation in acquired generalized lipodystrophy and combined Crohn’s disease
The adipokine leptin modulates intestinal inflammation in mice. Here the authors describe a patient with inflammatory bowel disease and lipodystrophy, providing evidence that leptin aggravates intestinal inflammation with proinflammatory effects on leukocytes that are reversible by TNFα blockade.
- Jörn F. Ziegler
- , Chotima Böttcher
- & Carl Weidinger
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Article
| Open AccessNAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome
The molecular mechanisms of mitochondrial dysfunction in the premature ageing Werner syndrome were elusive. Here the authors show that NAD+ depletion-induced impaired mitophagy contributes to this phenomenon, shedding light on potential therapeutics.
- Evandro F. Fang
- , Yujun Hou
- & Vilhelm A. Bohr
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Article
| Open AccessZwitterionically modified alginates mitigate cellular overgrowth for cell encapsulation
Cellular overgrowth and fibrosis in the foreign body response can compromise the function of transplanted cells. Here, the authors report on the zwitterionically modified alginates for the encapsulation of cells to reduce cellular overgrowth and demonstrate application in mice, dogs and pigs.
- Qingsheng Liu
- , Alan Chiu
- & Minglin Ma
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Article
| Open AccessElevated aldosterone and blood pressure in a mouse model of familial hyperaldosteronism with ClC-2 mutation
Mutations in the chloride channel ClC-2 have been associated with familial forms of hyperaldosteronism. Here, Schewe et al. generated a mouse model carrying the most common mutation found in patients and find it recapitulates key features of the disease, providing a unique tool for future studies on its pathogenesis.
- Julia Schewe
- , Eric Seidel
- & Ute Scholl
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Article
| Open AccessMulti-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration
Sleep duration is associated with an adverse lipid profile. Here, the authors perform genome-wide gene-by-sleep interaction analysis and find 49 previously unreported lipid loci when considering short or long total sleep time.
- Raymond Noordam
- , Maxime M. Bos
- & Susan Redline
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Article
| Open AccessNeratinib protects pancreatic beta cells in diabetes
Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.
- Amin Ardestani
- , Sijia Li
- & Kathrin Maedler
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Article
| Open AccessPhosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion
Elevated inorganic phosphate levels promote excessive parathyroid hormone secretion, which contributes to the aetiology of secondary hyperparathyroidism. Here, the authors show that phosphate directly inhibits the calcium-sensing receptor, the main regulator of parathyroid hormone secretion.
- Patricia P. Centeno
- , Amanda Herberger
- & Donald T. Ward
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Article
| Open AccessPathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism
Mutations in the chloride channel ClC-2 have been found in primary aldosteronism (PA). Here, Göppner et al. generate transgenic mice expressing a mutant form of ClC-2 that displays increased chloride currents like patient mutations, and find it recapitulates the key pathological features of PA.
- Corinna Göppner
- , Ian J. Orozco
- & Thomas J. Jentsch
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Article
| Open AccessEngineering transferrable microvascular meshes for subcutaneous islet transplantation
The success of engineered tissue depends on the integration of a dense vascular network to supply nutrients and remove waste products. Here the authors design high density microvascular meshes made through an anchored self-assembly mechanism, and use these meshes to support subcutaneous pancreatic islet survival in a mouse diabetes model.
- Wei Song
- , Alan Chiu
- & Minglin Ma
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| Open AccessDynamic changes of muscle insulin sensitivity after metabolic surgery
Surgical weight-loss interventions improve insulin sensitivity via incompletely understood mechanisms. Here the authors assess skeletal muscle epigenetic changes in individuals with obesity following metabolic surgery and compare them with data from individuals without obesity.
- Sofiya Gancheva
- , Meriem Ouni
- & Michael Roden
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Article
| Open AccessComponents of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology
While many pleiotropic genetic loci have been identified, how they contribute to phenotypes across traits and diseases is unclear. Here, the authors propose decomposition of genetic associations (DeGAs), which uses singular value decomposition, to characterize the underlying latent structure of genetic associations of 2,138 phenotypes.
- Yosuke Tanigawa
- , Jiehan Li
- & Manuel A. Rivas
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Article
| Open AccessGut-associated IgA+ immune cells regulate obesity-related insulin resistance
The effect of diet-induced obesity on intestinal B cell populations is not well understood despite emerging evidence of a critical role for the intestinal immune system in contributing to insulin resistance. Here, the authors show important functions of IgA in regulating metabolic disease and for intestinal immunity in modulating systemic glucose metabolism.
- Helen Luck
- , Saad Khan
- & Daniel A. Winer
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Article
| Open AccessS100A9 extends lifespan in insulin deficiency
Insulin replacement is a valuable therapy for insulin deficiency, however, other therapies are being investigated to restore metabolic homeostasis. Here, the authors identify S100A9 as a leptin induced circulating cue that improves glucose and lipid homeostasis and extends survival in insulin deficient mice.
- Giorgio Ramadori
- , Sanda Ljubicic
- & Roberto Coppari
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Article
| Open AccessLysosomal degradation of newly formed insulin granules contributes to β cell failure in diabetes
Impaired beta-cell insulin secretion is a key pathological feature of type 2 diabetes. Here, the authors describe metabolic stress induced lysosomal degradation of newly formed insulin granules, independent of macroautophagy, as a potential mechanism for beta-cell dysfunction.
- Adrien Pasquier
- , Kevin Vivot
- & Romeo Ricci
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Article
| Open AccessAdipose group 1 innate lymphoid cells promote adipose tissue fibrosis and diabetes in obesity
Whether adipose ILC1s regulate adipose tissue fibrogenesis is unknown. Here, the authors report a direct role of adipose ILC1s in adipose tissue fibrogenesis and provide insights into the mechanisms of local immune dysfunction in obesity-associated metabolic disorders.
- Hongdong Wang
- , Lei Shen
- & Yan Bi
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Article
| Open AccessZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response
Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.
- Adebowale A. Adeyemo
- , Norann A. Zaghloul
- & Charles N. Rotimi
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Article
| Open AccessPatient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders
Defective CFTR protein, responsible for Cystic Fibrosis (CF), is highly expressed in pancreatic ductal epithelial cells (PDECs) but their impact on insulin secreting pancreatic islets is not fully understood. Here the authors develop a non-CF and CF patient derived pancreas-on-a-chip model to study how CF affects insulin secretion.
- Kyu Shik Mun
- , Kavisha Arora
- & Anjaparavanda P. Naren
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Article
| Open AccessAdipocyte β-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis
Beta3-adrenergic receptor signaling regulates adipose tissue browning. Here, the authors show that barr2 regulates internalization of beta3-adrenergic receptors and that mice lacking barr2 in adipocytes are protected from diet-induced weight gain and metabolic complications.
- Sai P. Pydi
- , Shanu Jain
- & Jürgen Wess
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Article
| Open AccessIAPP toxicity activates HIF1α/PFKFB3 signaling delaying β-cell loss at the expense of β-cell function
Type 2 diabetes is associated with islet amyloid deposits derived from islet amyloid polypeptide (IAPP) expressed by β-cells. Here the authors show that IAPP misfolded protein stress induces the hypoxia inducible factor 1 alpha injury repair pathway and activates survival metabolic changes mediated by PFKFB3.
- Chiara Montemurro
- , Hiroshi Nomoto
- & Slavica Tudzarova
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| Open AccessAn integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis
Our understanding of the functional link between differential DNA methylation and type 2 diabetes and obesity remains limited. Here the authors present a blood-based EWAS of fasting glucose and insulin among 4808 non-diabetic Europeans and identify nine CpGs not previously implicated in glucose, insulin homeostasis and diabetes.
- Jun Liu
- , Elena Carnero-Montoro
- & Cornelia M. van Duijn
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Article
| Open AccessDiabetes causes marked inhibition of mitochondrial metabolism in pancreatic β-cells
Pancreatic beta-cell glucose metabolism is coupled to insulin secretion. Here the authors set out to characterize changes in beta-cell metabolism in hyperglycemia which may contribute to insufficient insulin secretion in type 2 diabetes and, using a multi-omics approach, find that mitochondrial metabolism is perturbed.
- Elizabeth Haythorne
- , Maria Rohm
- & Frances M. Ashcroft
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Article
| Open AccessAntidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler
Mitochondrial uncoupling is a treatment strategy for metabolic diseases that reduces the efficiency of mitochondrial oxidative phosphorylation and ATP generation. Here the authors characterize the pharmacokinetic and therapeutic properties of the liver-localized mitochondrial uncoupler OPC-163493, which leads to amelioration of diabetes and hypertension in several rodent disease models.
- Naohide Kanemoto
- , Takashi Okamoto
- & Seiji Sato
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Article
| Open AccessPancreatic islet chromatin accessibility and conformation reveals distal enhancer networks of type 2 diabetes risk
Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.
- William W. Greenwald
- , Joshua Chiou
- & Kyle J. Gaulton
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Article
| Open AccessMajor vault protein suppresses obesity and atherosclerosis through inhibiting IKK–NF-κB signaling mediated inflammation
Metabolic diseases are associated with chronic, low-grade inflammation. Here the authors show that major vault protein (MVP) suppresses NF-κB signalling in macrophages via an IRAK1–TRAF6 axis and that loss of MVP in myeloid cells exacerbates the inflammatory response in mice fed a high fat diet.
- Jingjing Ben
- , Bin Jiang
- & Qi Chen
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Article
| Open AccessSteroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis
Neurons expressing pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here the authors show that Steroid Receptor Coactivator-1 (SRC-1) regulates the function of Pomc expressing neurons, and that rare heterozygous variants found in obese individuals lead to loss of SRC-1 function.
- Yongjie Yang
- , Agatha A. van der Klaauw
- & Yong Xu
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Article
| Open AccessTG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone
Parathyroid hormone (PTH) is used to treat osteoporosis, but its therapeutic mechanism remains unclear. Here, the authors show that Tgif1 is a PTH target gene, and that its deletion impairs the function of osteoblasts and PTH-induced bone formation in mice.
- Hiroaki Saito
- , Andreas Gasser
- & Eric Hesse
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Article
| Open AccessGenome-scale Capture C promoter interactions implicate effector genes at GWAS loci for bone mineral density
GWAS have identified numerous genetic loci for bone mineral density (BMD) and fracture risk. Here, the authors map these variants to putative target genes using ATAC-seq and Capture C of human osteoblasts and confirm ING3 and EPDR1 as BMD genes in in vitro osteoblast differentiation experiments.
- Alessandra Chesi
- , Yadav Wagley
- & Struan F. A. Grant
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Article
| Open AccessAdenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons
Glucagon-like peptide 1 (GLP-1) is released from intestinal L-cells following nutrient uptake and enhances insulin release as well as promotes satiety. Here, the authors demonstrate that GLP-1 secreting cells release ATP and that this stimulates nodose neurons and enterocytes in a paracrine manner in vitro.
- Van B. Lu
- , Juraj Rievaj
- & Frank Reimann
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Article
| Open AccessMeasuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader
Assessment of luteinising hormone pulsatility is important in the diagnosis of reproductive disorders. Here the authors develop a DNA aptamer-based electrochemical analysis integrated into a robotic platform for high-throughput and sensitive analysis.
- Shaolin Liang
- , Andrew B. Kinghorn
- & Julian A. Tanner
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Article
| Open AccessInhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production
The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
- T. M. Zaved Waise
- , Mozhgan Rasti
- & Tony K. T. Lam
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Article
| Open AccessGrowth hormone regulates neuroendocrine responses to weight loss via AgRP neurons
Reduction in food intake elicits neuroendocrine adaptations to counterregulate the negative energy balance, e.g. via reduction in leptin levels. Here, the authors identify an additional starvation signal, growth hormone (GH). Blocking GH receptor attenuates the fall of whole body energy expenditure during food deprivation in mice.
- Isadora C. Furigo
- , Pryscila D. S. Teixeira
- & J. Donato Jr
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Article
| Open AccessDehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats
The use of sodium-glucose transport protein 2 (SGLT2) inhibitors for the treatment of diabetes has been associated with euglycemic ketoacidosis and increased glucose production and glucagon secretion. Here Perry et al. show that these effects rely on both insulinopenia and dehydration, and thus suggest ways to manage the side effects associated with the use of SGLT2 inhibitors.
- Rachel J. Perry
- , Aviva Rabin-Court
- & Gerald I. Shulman
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Article
| Open AccessGenome-wide gene-based analyses of weight loss interventions identify a potential role for NKX6.3 in metabolism
Individuals show large variability in their capacity to lose weight and maintain this weight. Here, the authors perform GWAS in two weight loss intervention cohorts and identify two genetic loci associated with weight loss that are taken forward for Bayesian fine-mapping and functional assessment in flies.
- Armand Valsesia
- , Qiao-Ping Wang
- & Jörg Hager
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Article
| Open AccessTAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression
Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
- Jun-Ha Hwang
- , A Rum Kim
- & Jeong-Ho Hong
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Article
| Open AccessGenome-wide association study of body fat distribution identifies adiposity loci and sex-specific genetic effects
Obesity and the distribution of fat within the body are risk factors for cardiometabolic diseases. Here, Rask-Andersen et al. perform GWAS for bio-electrical impedance measurements in UK Biobank participants and identify 29 novel independent loci for fat distribution and a high degree of sex-heterogeneity.
- Mathias Rask-Andersen
- , Torgny Karlsson
- & Åsa Johansson
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Article
| Open AccessE47 modulates hepatic glucocorticoid action
Glucocorticoids (GCs) are widely used anti-inflammatory drugs; however, long-term treatment causes metabolic side effects. Here, the authors show that E47 is a modulator of glucocorticoid receptor activity for a subset of target genes in mouse liver, and that loss of E47 protects mice from hyperglycemia and hepatic steatosis in response to GCs.
- M. Charlotte Hemmer
- , Michael Wierer
- & N. Henriette Uhlenhaut
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Article
| Open AccessEstrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones
Estrogen promotes negative energy balance and preserves skeletal physiology. Here the authors show that loss of estrogen signalling after ablating estrogen receptor alpha (ERa) in specific hypothalamic neuronal populations leads to a marked sex-dependent increase in bone mass in female mice.
- Candice B. Herber
- , William C. Krause
- & Holly A. Ingraham
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Article
| Open AccessAn inflammatory-CCRK circuitry drives mTORC1-dependent metabolic and immunosuppressive reprogramming in obesity-associated hepatocellular carcinoma
Obesity increases the risk of hepatocellular carcinoma (HCC) especially in men. Here the authors find a potential mechanistic explanation by showing that, in mice, obesity-induced STAT3 cooperates with the androgen receptor to activate the mTORC pathway through up regulation of CCRK, resulting in hepatic steatosis worsening and HCC development via metabolic and immune reprogramming.
- Hanyong Sun
- , Weiqin Yang
- & Alfred S. L. Cheng
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Article
| Open AccessMettl3-mediated m6A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis
mRNA modifications have been shown to regulate mammalian development and disease. Here the authors show that the m6A methyltransferase Mettl3 ensures translational efficiency of the mesenchymal stem cell lineage allocator Pth1r, promoting osteogenesis and protecting from osteoporosis.
- Yunshu Wu
- , Liang Xie
- & Quan Yuan
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Article
| Open AccessLong term but not short term exposure to obesity related microbiota promotes host insulin resistance
Gut microbiota impact host metabolism and gut microbiome composition reflects dietary habits. Here the authors show that, in animals fed obesogenic diets, changes in gut microbiota precede changes in glucose homeostasis. Importantly, long term exposure of the host to the changed microbiota is required to impair glucose homeostasis.
- Kevin P. Foley
- , Soumaya Zlitni
- & Jonathan D. Schertzer