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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 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 AccessAngptl8 mediates food-driven resetting of hepatic circadian clock in mice
The circadian clock regulates rhythms of behavior and physiology and the timing of circadian rhythms in liver is influenced by food intake. Here, the authors identify the hepatokine Angptl8 as a mediator of liver clock food entrainment.
- Siyu Chen
- , Mengyang Feng
- & Chang Liu
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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 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 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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Article
| 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 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 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 AccessHepatic Sdf2l1 controls feeding-induced ER stress and regulates metabolism
Endoplasmic reticulum (ER) stress has been proposed to play a role in metabolic diseases. Here, Sasako and colleagues identify stromal cell-derived factor 2 like 1 (Sdf2l1) as a regulator of the ER stress response to feeding in the liver, and suggest that its downregulation may promote diabetes and hepatic steatosis in humans.
- Takayoshi Sasako
- , Mitsuru Ohsugi
- & Kohjiro Ueki
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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 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 AccessPost-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene
Insulin-related gene (Insig) negatively regulates hepatic fatty acid synthesis, a process involved in development of non-alcoholic fatty liver disease (NAFLD). Here, the authors show that AMPK activation by metformin promotes Insig phosphorylation, stabilizing it and inhibiting lipogenic gene expression. This is protective against steatosis in diabetic mice.
- Yamei Han
- , Zhimin Hu
- & Yu Li
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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 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 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
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Article
| Open AccessNeuronal SIRT1 regulates macronutrient-based diet selection through FGF21 and oxytocin signalling in mice
SIRT1 is a NAD+-dependent deacetylase whose functions have been linked to organismal longevity, aging and metabolism. Here, Matsui and colleagues show that neuronal SIRT1 can affect nutrient-related dietary choice in mice, and this effect is mediated by FGF21 signalling and oxytocin.
- Sho Matsui
- , Tsutomu Sasaki
- & Tadahiro Kitamura
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Article
| Open AccessGenome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation
Thyroid dysfunction is a common public health problem and associated with cardiovascular co-morbidities. Here, the authors carry out genome-wide meta-analysis for thyroid hormone (TH) levels, hyper- and hypothyroidism and identify SLC17A4 as a TH transporter and AADAT as a TH metabolizing enzyme.
- Alexander Teumer
- , Layal Chaker
- & Marco Medici
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Article
| Open AccessThe gut microbiota in infants of obese mothers increases inflammation and susceptibility to NAFLD
Infants born to obese mothers have altered microbiome and increased risk of obesity and NAFLD. Here the authors establish causality by showing that maternal obesity-shaped infant gut microbiome induces macrophage dysfunction, inflammation, and diet-induced metabolic disease in germ-free mice.
- Taylor K. Soderborg
- , Sarah E. Clark
- & Jacob E. Friedman
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Article
| Open AccessSIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression
The onset of mammalian puberty is sensitive to metabolic changes and nutritional status, but the mechanisms underlying this phenomenon are poorly understood. Here the authors show that the epigenetic regulator of transcription, SIRT1, mediates the effects of under and overnutrition on pubertal timing by controlling the expression of Kiss1 in hypothalamic neurons.
- M. J. Vazquez
- , C. A. Toro
- & M. Tena-Sempere
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Article
| Open AccessMetastatic adrenocortical carcinoma displays higher mutation rate and tumor heterogeneity than primary tumors
Adrenocortical cancer (ACC) is a rarely diagnosed and aggressive cancer whose metastatic form has been scarcely studied. Here, the authors study primary and metastatic ACC to investigate genomic heterogeneity, discovering higher mutation rates in metastatic lesions and novel recurrent mutations.
- Sudheer Kumar Gara
- , Justin Lack
- & Electron Kebebew
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Article
| Open AccessDiscovering human diabetes-risk gene function with genetics and physiological assays
The function of genes linked to type 2 diabetes is poorly characterized. Here the authors combine Drosophila genetics and physiology with human islet biology to identify new regulators of insulin secretion including BCL11A.
- Heshan Peiris
- , Sangbin Park
- & Seung K. Kim
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Article
| Open Accessp53 in AgRP neurons is required for protection against diet-induced obesity via JNK1
Emerging studies suggest that p53 is an important regulator of energy metabolism, yet there is little known about the metabolic function of this tumor suppressor in the hypothalamus. Here, authors illustrate that p53, specifically in AgRP neurons, is required for adaptation to diet-induced obesity.
- Mar Quiñones
- , Omar Al-Massadi
- & Ruben Nogueiras
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Article
| Open AccessIdentification of recurrent USP48 and BRAF mutations in Cushing’s disease
In this study the authors report USP48 and BRAF are frequently mutated in USP8 wild-type corticotroph adenomas, and cause Cushing’s disease mainly through promoting the promoter activity of POMC. Inhibition of BRAF may be a promising therapeutic strategy for the treatment of patients with BRAF-mutated corticotroph adenomas.
- Jianhua Chen
- , Xuemin Jian
- & Yongyong Shi
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Article
| Open AccessGenome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes
GWAS have so far identified 129 loci associated with type 2 diabetes (T2D). Here, the authors meta-analyse three large T2D GWA studies which uncovers 42 additional loci, further prioritize 33 functional genes using eQTL and mQTL data and propose regulatory mechanisms for three putative T2D genes.
- Angli Xue
- , Yang Wu
- & Jian Yang
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Article
| Open AccessSingle-dose testosterone administration increases men’s preference for status goods
Testosterone is believed to be involved in social rank-related behavior. Here, the authors show that one dose of testosterone increases men’s preference for “high status” goods and brands, suggesting a role for testosterone in modern consumer behavior in men.
- G. Nave
- , A. Nadler
- & H. Plassmann
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Article
| Open AccessLate-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice
Reduced IGF-1 signaling increases longevity in many organisms. Here, Mao et al. show that administration of an anti-IGF-1R antibody is well tolerated and delays aging in female mice; importantly, late-life targeting is sufficient to achieve the beneficial effects.
- Kai Mao
- , Gabriela Farias Quipildor
- & Derek M. Huffman
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Article
| Open AccessCaffeine-inducible gene switches controlling experimental diabetes
Control of transgene expression should ideally be easy and with minimal side effects. Here the authors present a synthetic biology-based approach in which the caffeine in coffee regulates a genetic circuit controlling glucagon-like peptide 1 expression in diabetic mice.
- Daniel Bojar
- , Leo Scheller
- & Martin Fussenegger
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Article
| Open AccessDominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation
Severe growth hormone insensitivity syndrome (GHIS) with immunodeficiency is caused by autosomal recessive mutations in STAT5B. Here the authors report heterozygous STAT5B mutations with dominant-negative effects, causing mild GHIS without immune defects.
- Jürgen Klammt
- , David Neumann
- & Vivian Hwa
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Article
| Open AccessThe histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity
Steatosis is characterized by initial accumulation of lipids, followed by inflammation and ultimately fibrosis. Here the authors show that the histone demethylase Plant Homeodomain Finger 2 protects liver form steatosis progression by acting as a co-activator of ChREBP, thus, favouring lipid accumulation without inflammation.
- Julien Bricambert
- , Marie-Clotilde Alves-Guerra
- & Renaud Dentin
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Article
| Open AccessTestosterone is an endogenous regulator of BAFF and splenic B cell number
Testosterone deficiency is associated with autoimmunity and increased B cell numbers, but the underlying mechanism is unclear. Here the authors show that testosterone may modulate the production of B cell survival factor BAFF by fibroblastic reticular cells via regulation of splenic neurotransmitter levels.
- Anna S. Wilhelmson
- , Marta Lantero Rodriguez
- & Åsa Tivesten
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Article
| Open AccessDeficiency of PRKD2 triggers hyperinsulinemia and metabolic disorders
Hyperinsulinemia can precede the development of insulin resistance. Here the authors identify a PKD2 mutation that leads to hyperinsulinemia and insulin resistance in Rhesus monkey and show that PKD2 deficiency promotes beta cell insulin secretion by activating L-type Ca2+ channels.
- Yao Xiao
- , Can Wang
- & Xiuqin Zhang
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Article
| Open AccessElucidating the genetic architecture of reproductive ageing in the Japanese population
The timing of female reproductive capacity is influenced by genetic and environmental factors. Here, in genome-wide association studies, the authors identify genetic loci for age at menarche and onset of menopause in Japanese women, and highlight differences with European populations.
- Momoko Horikoshi
- , Felix R. Day
- & John. R. B. Perry
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Article
| Open AccessReduced oxidative capacity in macrophages results in systemic insulin resistance
M1-like polarization of macrophages is thought to control adipose inflammation and associated insulin resistance and metabolic syndrome. Here the authors show that macrophage-specific deletion of the OxPhos-related gene Crif1 results in an M1-like phenotype in mice, and that the effects can be reversed by recombinant GDF15.
- Saet-Byel Jung
- , Min Jeong Choi
- & Minho Shong
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Article
| Open AccessTAp63 contributes to sexual dimorphism in POMC neuron functions and energy homeostasis
Sexual dimorphism exists in a number of physiological processes, including energy homeostasis. Here, the authors show that pro-opiomelanocortin neurons in female mice fire more rapidly than males, and that deletion of the transcription TAp63 leads to a reduced neuronal firing rate and a male-like susceptibility to diet-induced obesity.
- Chunmei Wang
- , Yanlin He
- & Yong Xu
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Article
| Open AccessLRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus
Type 1 diabetes mellitus (T1DM) is characterized by beta cell loss because of an autoimmune attack. Here the authors show that an agonist for LRH-1/NR5A2, a nuclear receptor known to be protective against beta cell apoptosis, inhibits immune-mediated inflammation and hyperglycemia in T1DM mouse models.
- Nadia Cobo-Vuilleumier
- , Petra I. Lorenzo
- & Benoit R. Gauthier
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Article
| Open AccessA novel autophagy enhancer as a therapeutic agent against metabolic syndrome and diabetes
Autophagy plays an important role in metabolic functions and increased autophagic activity may be beneficial for metabolic disorders. Here the authors screen a chemical library for enhancer of autophagic flux and identify small molecules that improve the metabolic profile by increasing lysosomial functions.
- Hyejin Lim
- , Yu-Mi Lim
- & Myung-Shik Lee
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Article
| Open AccessMatriptase-2 deficiency protects from obesity by modulating iron homeostasis
Iron homeostasis dysfunctions have been associated with several metabolic disorders including obesity, steatosis and diabetes. Here the authors demonstrate that the hepcidin repressor matriptase-2 regulates adiposity and its deficiency protects mice against obesity and promotes lipolysis.
- Alicia R. Folgueras
- , Sandra Freitas-Rodríguez
- & Carlos López-Otín
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Article
| Open AccessThe beta secretase BACE1 regulates the expression of insulin receptor in the liver
A soluble form of insulin receptor in human plasma has been previously reported. Here the authors demonstrate that insulin receptor is cleaved by BACE1 that can regulate biological active insulin receptor levels in a glucose concentration-dependent manner, both in physiological and diabetic conditions.
- Paul J. Meakin
- , Anna Mezzapesa
- & Franck Peiretti
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Article
| Open AccessLinear and inverted U-shaped dose-response functions describe estrogen effects on hippocampal activity in young women
While estrogen is known to change hippocampal activity in animals, it is not known if this effect extends to humans. Here, authors vary the doses of estrogen in young women and show that the effects on hippocampal activity can be described by linear and inverted-U shaped dose-response functions.
- Janine Bayer
- , Jan Gläscher
- & Tobias Sommer
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Article
| Open AccessCDK6 inhibits white to beige fat transition by suppressing RUNX1
Beige adipocytes can arise from transdifferentiation of mature white adipocytes. Here the authors identify CDK6 as a key molecule involved in the white-to-beige adipocyte transdifferentiation and, therefore, as a regulator of organismal energy homeostasis in mice.
- Xiaoli Hou
- , Yongzhao Zhang
- & Miaofen G. Hu
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Article
| Open AccessDe novo adipocyte differentiation from Pdgfrβ+ preadipocytes protects against pathologic visceral adipose expansion in obesity
Adipocyte hyperplasia is thought to have beneficial metabolic effects in obesity, but definitive evidence is lacking. Here, Shao et al. promote de novo formation of adipocytes in visceral white adipose tissue (WAT) of adult mice through inducible overexpression of Pparg in Pdgfrβ+ preadipocytes and show that this protects from pathological WAT remodeling.
- Mengle Shao
- , Lavanya Vishvanath
- & Rana K. Gupta