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| Open AccessCausal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome
This paper describes the largest genome-wide association study to date on polycystic ovary syndrome (PCOS), a common reproductive disorder in women. Six genetic loci—including known targets of cancer chemotherapy—were identified, and the authors infer causal and balancing selection mechanisms involved in PCOS risk and susceptibility.
- Felix R. Day
- , David A. Hinds
- & John R. B. Perry
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| Open AccessGenome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations
Polycystic Ovary Sydrome is a highly heritable, complex reproductive disorder with unknown underlying genetic factors. Here Hayes and Urbanek et al. identify three loci in European women strongly associated with neuroendocrine changes and disease susceptibility.
- M. Geoffrey Hayes
- , Margrit Urbanek
- & Andrea Dunaif
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| Open AccessGanoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota
Ganoderma lucidumis a medicinal mushroom used in Traditional Chinese Medicine with putative anti-diabetic properties. Here, the authors show that polysaccharides from a water extract of this mushroom exert beneficial metabolic effects by modulating the composition of the gut microbiota in mice.
- Chih-Jung Chang
- , Chuan-Sheng Lin
- & Hsin-Chih Lai
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Article
| Open AccessPI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling
The kinase PI3K is crucial for insulin signalling in the liver but the roles of individual PI3K isoforms are largely unclear. Using mice that lack class II PI3K isoform γ (PI3K-C2γ), the authors here show that PI3K-C2γ selectively activates endosomal Akt2 by regulating the localized production of PIP2.
- Laura Braccini
- , Elisa Ciraolo
- & Emilio Hirsch
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| Open AccessNELL-1 in the treatment of osteoporotic bone loss
The growth factor NELL-1 induces bone formation during development, but its role in osteoporosis is unknown. This study shows that NELL-1 binding to integrin ß1 induces Wnt/ß-catenin signalling in the bone and restores bone mineral density in osteoporotic mice and sheep, suggesting the therapeutic potential of NELL-1 for the treatment of bone loss.
- Aaron W. James
- , Jia Shen
- & Chia Soo
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Article
| Open AccessA Mendelian randomization study of the effect of type-2 diabetes on coronary heart disease
In order to effectively design interventions, it is useful to understand the complex interplay between multiple syndromes. Here, Ahmad et al. use genome-wide association study data and Mendelian randomisation to examine the influence of Type 2 diabetes and fasting glucose levels on coronary heart disease.
- Omar S. Ahmad
- , John A. Morris
- & J. Brent Richards
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Hepatic insulin signalling is dispensable for suppression of glucose output by insulin in vivo
Insulin and the transcription factor FoxO1 are key regulators of hepatic glucose metabolism. Here, Titchenell et al. provide evidence for the existence of an insulin-dependent extrahepatic pathway that is fully capable of regulating hepatic glucose production in the absence of hepatic FoxO1.
- Paul M. Titchenell
- , Qingwei Chu
- & Morris J. Birnbaum
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Article
| Open AccessFTO influences adipogenesis by regulating mitotic clonal expansion
Mutations in the FTO gene have been linked to obesity. Here, Merkestein et al. provide in vitro and in vivo evidence that FTOdirectly regulates adipogenesis in mice at the stage of mitotic clonal expansion, likely by modulating the expression of the transcription factor RUNX1T1.
- Myrte Merkestein
- , Samantha Laber
- & Roger D. Cox
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| Open AccessReduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2requirement for antiviral response in insulin-producing cells.
- Kenichi Izumi
- , Keiichiro Mine
- & Seiho Nagafuchi
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Pharmacological inhibition of Dock5 prevents osteolysis by affecting osteoclast podosome organization while preserving bone formation
Small-molecule C21 inhibits Rac GTPase activation by Dock5, which decreases osteoclast activity in vitro. Using three mouse models where bone loss is caused by hyperactive osteoclasts, Vives et al. show that C21 treatment safely and efficiently prevents osteoporosis while preserving bone formation.
- Virginie Vives
- , Gaëlle Cres
- & Anne Blangy
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| Open AccessLow-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility
Both rare and common variants contribute to the aetiology of complex traits such as type 2 diabetes (T2D). Here, the authors examine the effect of coding variation on glycaemic traits and T2D, and identify low-frequency variation in GLP1Rsignificantly associated with these traits.
- Jennifer Wessel
- , Audrey Y Chu
- & Mark O Goodarzi
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| Open AccessAn integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins
Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.
- Wei Yuan
- , Yudong Xia
- & Tim D. Spector
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Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents
Cilia are hair-like protuberances on the cellular surface that have been implicated in sensing and signal transduction. Here Gerdes et al. show cilia are involved in insulin signalling and secretion in pancreatic β-cells of rodents, and suggest that ciliary dysfunction could contribute to type 2 diabetes.
- Jantje M. Gerdes
- , Sonia Christou-Savina
- & Per-Olof Berggren
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| Open AccessOptical control of insulin release using a photoswitchable sulfonylurea
Sulfonylureas are widely used anti-diabetic drugs, which promote insulin release by blocking a pancreatic ion channel. Here the authors create a photoswitchable sulfonylurea derivative and use it to control insulin release from cultured cells and isolated pancreatic islets by illumination with blue light.
- Johannes Broichhagen
- , Matthias Schönberger
- & Dirk Trauner
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Integrated control of hepatic lipogenesis versus glucose production requires FoxO transcription factors
The transcription factors FoxoO1 and Srebp-1 control hepatic glucose and lipid production, respectively. Here, Haeusler et al.propose a model that integrates glucose and lipid regulation in the normal and diabetic liver under the unifying control of FoxO transcription factors.
- Rebecca A. Haeusler
- , Kirsten Hartil
- & Domenico Accili
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Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes
The mechanisms underlying the relationship between autophagy and metabolism remain unclear. Here, the authors demonstrate that mice with a systemic reduction in the autophagy pathway have an impaired response to metabolic stress, developing insulin resistance and an increase in intracellular lipid content.
- Yu-Mi Lim
- , Hyejin Lim
- & Myung-Shik Lee
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Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis
The protein Mincle can sense pathogens and molecules associated with cell death. Here the authors show that Mincle expressed in macrophages is a mediator of obesity-induced fibrosis and inflammation of adipose tissue, and that Mincle knockout mice are protected from diet-induced metabolic dysfunction.
- Miyako Tanaka
- , Kenji Ikeda
- & Yoshihiro Ogawa
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Article
| Open AccessA rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans
Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3gene strongly associated with plasma triglyceride levels.
- Nicholas J. Timpson
- , Klaudia Walter
- & Hou-Feng Zheng
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Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers
Cellular defects in autophagy contribute to the development of fatty liver in obesity. Here, Park et al.reveal that hepatic autophagy is impaired by chronically elevated cytosolic calcium levels, and show that a clinically approved calcium channel blocker can improve metabolic parameters of obese mice.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9
Elevated blood levels of urate have been linked to metabolic diseases. Here the authors show that the urate transporter, GLUT9, in enterocytes is important for the extrarenal excretion of urate, and that primary hyperuricaemia in mice lacking Glut9 is sufficient to develop metabolic syndrome.
- Brian J DeBosch
- , Oliver Kluth
- & Kelle Moley
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| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice
Retnla is an adipokine with known roles in tissue repair and inflammation. Here Lee et al. show that Retnla also promotes cholesterol metabolism and excretion, thereby lowering blood cholesterol levels and reducing the development of atherosclerosis in mice.
- Mi-Ran Lee
- , Chae-ji Lim
- & Goo Taeg Oh
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FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures
The transcription factor FOXO1 has been shown to control the differentiation of enteroendocrine cells in mice. Here the authors extend these findings to humans by showing that FOXO1-expressing cells also exist in the human gut, and that inhibition of FOXO1 generates insulin-secreting cells in human gut organoid cultures.
- Ryotaro Bouchi
- , Kylie S. Foo
- & Domenico Accili
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Hepatoprotective role of Sestrin2 against chronic ER stress
When exposed to chronic endoplasmic reticulum (ER) stress, cells downregulate protein synthesis by inhibiting mTOR signalling. Park et al.identify Sestrin2 as a transcriptional target of the ER stress pathway and an important mediator of this protective response in the liver.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women
Uterine muscle contracts rhythmically during labour but the underlying electrophysiological mechanisms are not fully understood. The authors of this study show that hERG1 potassium channels reduce human uterine contractions in pregnancy and are suppressed during labour in lean but not in obese women.
- Helena C. Parkington
- , Janet Stevenson
- & Roger Smith
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| Open AccessAmerindian-specific regions under positive selection harbour new lipid variants in Latinos
Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.
- Arthur Ko
- , Rita M. Cantor
- & Päivi Pajukanta
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Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
Mice lacking Toll-like receptor 4 (Tlr4) do not develop diet-induced insulin resistance. Here Jia et al.create two tissue-specific Tlr4 knockouts to demonstrate that hepatic Tlr4, but not Tlr4 expressed in myeloid cells, is driving obesity-induced inflammation and insulin resistance.
- Lin Jia
- , Claudia R. Vianna
- & Joel K. Elmquist
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Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity
Glucocorticoid levels in the body are controlled by an intricate feedback system acting on the hypothalamus. Here the authors provide molecular insight into this process, identifying TrkB signalling in cholecystokinin-GABAergic neurons as a key component of hypothalamic glucocorticoid signalling.
- Mirjam Geibel
- , Sylvia Badurek
- & Liliana Minichiello
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| Open AccessThe serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Hepatic insulin resistance is a hallmark of diabetes, but its aetiology is incompletely understood. Here, Uchimura and colleagues show that the serine protease prostasin cleaves Toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity by modulating TLR4-mediated signalling.
- Kohei Uchimura
- , Manabu Hayata
- & Kenichiro Kitamura
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A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
Allosteric sites are an increasingly used target for drug design. Here, the authors computationally predict an allosteric site in cathepsin K and subsequently identify a small-molecule allosteric modifier.
- Marko Novinec
- , Matevž Korenč
- & Antonio Baici
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| Open AccessMicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
The micro-RNA miR-33 is encoded by an intron of the gene encoding sterol regulatory-binding protein 2 (SREBP-2) and controls cholesterol homoeostasis. Here, Horie et al.identify SREBP-1 as a target of miR-33 and show that deletion of miR-33 promotes diet-induced obesity and liver steatosis in mice.
- Takahiro Horie
- , Tomohiro Nishino
- & Koh Ono
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| Open AccessA closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice
Designer gene circuits allow the controlled expression of proteins in response to specific stimuli. Here, Rössger et al.use synthetic biology approaches to create a fatty-acid biosensor that controls the production of a satiety hormone and use it to control diet-induced obesity in mice.
- Katrin Rössger
- , Ghislaine Charpin-El-Hamri
- & Martin Fussenegger
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| Open AccessAnti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans
Obesity is often associated with increased appetite and food intake, despite normal blood levels of the hunger hormone ghrelin. Here the authors show that ghrelin-reactive antibodies in the blood of obese mice and humans enhance the orexigenic effect of ghrelin by protecting it from degradation.
- Kuniko Takagi
- , Romain Legrand
- & Sergueï O. Fetissov
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Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity
Tempol is an antioxidant that reduces the body weight of mice on a high-fat diet. Li et al.now provide a mechanistic link by demonstrating that tempol affects the intestinal microbiota, which leads to a change in the composition of bile acids and suppression of FXR signalling.
- Fei Li
- , Changtao Jiang
- & Frank J. Gonzalez
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Ecscr regulates insulin sensitivity and predisposition to obesity by modulating endothelial cell functions
The transmembrane protein Ecscr has been implicated in the regulation of endothelial cell signalling. Here, the authors show that Ecscr regulates systemic insulin sensitivity and glucose homeostasis in mice by modulating insulin signalling in endothelial cells.
- Yoshiki Akakabe
- , Masahiro Koide
- & Koji Ikeda
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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome
Consumption of high amounts of glucose leads to the development of insulin resistance and metabolic syndrome. Here, Lanaspa et al.show that the hepatic conversion of glucose into fructose is a key step in the development of glucose-induced metabolic syndrome and fatty liver in mice.
- Miguel A. Lanaspa
- , Takuji Ishimoto
- & Richard J. Johnson
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Article
| Open AccessThe gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43
The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs), which can influence the development of obesity. Here Kimura et al.show that SCFAs act via the receptor GPR43, which acts as a sensor for excessive dietary energy and controls body energy utilization as well as metabolic homoeostasis.
- Ikuo Kimura
- , Kentaro Ozawa
- & Gozoh Tsujimoto
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An atlas of DNA methylomes in porcine adipose and muscle tissues
Epigenetic and genetic factors have a role in obesity but the role of epigenetics in this disease is unclear. Here, Liet al. investigated global DNA methylation patterns in three breeds of pigs that have different fat contents, providing a resource for the further analysis of differentially methylated gene promoters in obesity.
- Mingzhou Li
- , Honglong Wu
- & Ruiqiang Li
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Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production
Erythropoietin circulates in the blood and is essential for erythropoiesis but its role in metabolic homeostasis has not been examined. Tenget al. show that when the erythropoietin receptor is only expressed in erthyroid cells, mice develop obesity and insulin resistance, suggesting that the receptor has a key role in fat mass accumulation.
- Ruifeng Teng
- , Oksana Gavrilova
- & Constance Tom Noguchi
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Article
| Open AccessDisruption of TBP-2 ameliorates insulin sensitivity and secretion without affecting obesity
Thioredoxin binding protein-2 (TBP-2) mutant mice have abnormal insulin sensitivity and secretion. In this study, TBP-2-null obese mice are shown to have improved insulin sensitivity and glucose intolerance, suggesting a potential role for TBP-2 inhibition in diabetes treatment.
- Eiji Yoshihara
- , Shimpei Fujimoto
- & Hiroshi Masutani
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Pseudogene-mediated posttranscriptional silencing of HMGA1 can result in insulin resistance and type 2 diabetes
Pseudogenes are prevalent in the human genome; however, their biological function is relatively unknown. In this study, the high mobility group A1 (HMGA1) pseudogene is shown to destabilizeHMGA1 mRNA. These findings have implications for diabetes, as two patients are reported to express high levels of the HMGA1pseudogene.
- Eusebio Chiefari
- , Stefania Iiritano
- & Antonio Brunetti