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| Open AccessA miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning
White adipocytes can be stimulated to express thermogenic genes in a process known as beiging. Here, the authors show that miR-327 is downregulated during beiging, which releases FGF10 from inhibition and supports beige adipocyte formation via signaling through FGFR2.
- Carina Fischer
- , Takahiro Seki
- & Yihai Cao
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Article
| Open AccessAncestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice
Early life exposure to endocrine disrupting chemicals has been linked to increased adiposity during adulthood. Here Chamorro-García et al. show that ancestral exposure to the obesogen tributyltin causes obesity in untreated F4 generation male descendants by inducing heritable changes in genome architecture that promote a thrifty phenotype.
- Raquel Chamorro-Garcia
- , Carlos Diaz-Castillo
- & Bruce Blumberg
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Article
| Open AccessAuditory closed-loop stimulation of EEG slow oscillations strengthens sleep and signs of its immune-supportive function
Circulating hormones undergo fluctuations during sleep. Here, the authors increase electroencephalographic slow oscillations (SO) during sleep in men using an auditory closed-loop stimulation, and show that the circulating level of cortisol, aldosterone and immune cell count can be altered.
- Luciana Besedovsky
- , Hong-Viet V. Ngo
- & Jan Born
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| Open AccessIn vivo transplantation of 3D encapsulated ovarian constructs in rats corrects abnormalities of ovarian failure
Cell-based hormone replacement therapy (cHRT) may be an alternative therapy to pharmacological (p)HRT. Here, the authors show that implanted 3D bioengineered ovarian constructs of granulosa and theca cells in ovariectomized rats recapitulate native cell interactions and improve efficacy compared to similar doses of pHRT.
- Sivanandane Sittadjody
- , Justin M. Saul
- & Emmanuel C. Opara
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| Open AccessHepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
During obesity, chronic inflammation leads to insulin resistance and diabetes. Here, Brenachot et al. show that Protein Tyrosine Phosphatase Receptor Gamma is upregulated in obesity by inflammatory signals and correlates with insulin resistance in humans. Its deletion in mouse models of obesity and inflammation ameliorates insulin resistance by suppressing glucose production.
- Xavier Brenachot
- , Giorgio Ramadori
- & Roberto Coppari
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| Open AccessA mathematical model of the impact of insulin secretion dynamics on selective hepatic insulin resistance
Dysregulation of insulin secretion dynamics plays a role in diabetes development. Here, the authors build a mathematical model of hepatic insulin signaling and propose a sequential model of post-meal control of glucose and lipids, according to which delayed aPKC suppression would contribute to selective hepatic insulin resistance.
- Gang Zhao
- , Dagmar Wirth
- & Michael Meyer-Hermann
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| Open AccessHeterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance
Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
- Kashyap A. Patel
- , Jarno Kettunen
- & Michael N. Weedon
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| Open AccessMKK6 controls T3-mediated browning of white adipose tissue
Brown and beige adipose tissues dissipate heat via uncoupling protein 1 (UCP1). Here the authors show that the stress activated kinase MKK6 acts as a repressor of UCP1 expression, suggesting that its inhibition promotes adipose tissue browning and increases organismal energy expenditure.
- Nuria Matesanz
- , Edgar Bernardo
- & Guadalupe Sabio
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Article
| Open AccessNon-invasive assessment of hepatic mitochondrial metabolism by positional isotopomer NMR tracer analysis (PINTA)
Liver mitochondrial metabolism plays an important role for glucose and lipid homeostasis and its alterations contribute to metabolic disorders, including fatty liver and diabetes. Here Perry et al. develop a method for the measurement of hepatic fluxes by using lactate and glucose tracers in combination with NMR spectroscopy.
- Rachel J. Perry
- , Liang Peng
- & Gerald I. Shulman
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| Open AccessInsights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas
Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.
- Huan Wang
- , Aaron Bender
- & Andrew F. Stewart
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Article
| Open AccessGCN5L1 modulates cross-talk between mitochondria and cell signaling to regulate FoxO1 stability and gluconeogenesis
Hepatic gluconeogenesis is tightly regulated at transcriptional level and is essential for survival during prolonged fasting. Here Wang et al. show that the mitochondrial enriched GCN5-like 1 protein controls hepatic glucose production by regulating FoxO1 protein levels via proteasome-dependent degradation and, in turn, gluconeogenic gene expression.
- Lingdi Wang
- , Iain Scott
- & Michael N. Sack
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Article
| Open AccessFas cell surface death receptor controls hepatic lipid metabolism by regulating mitochondrial function
Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.
- Flurin Item
- , Stephan Wueest
- & Daniel Konrad
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| Open AccessTanycytes control the hormonal output of the hypothalamic-pituitary-thyroid axis
The hypothalamic-pituitary-thyroid (HPT) axis regulates a wide range of physiological processes. Here the authors show that hypothalamic tanycytes play a role in the homeostatic regulation of the HPT axis; activation of TRH signaling in tanycytes elevates their intracellular Ca2+ via Gαq/11 pathway, ultimately resulting in reduced TRH release into the pituitary vessels.
- Helge Müller-Fielitz
- , Marcus Stahr
- & Markus Schwaninger
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| Open AccessRetinol saturase coordinates liver metabolism by regulating ChREBP activity
Fatty liver is one of the major features of metabolic syndrome and its development is associated with deregulation of systemic lipid and glucose homeostasis. Here Heidenreich et al. show that retinol saturase is implicated in hepatic lipid metabolism by regulating the activity of the transcription factor ChREBP.
- Steffi Heidenreich
- , Nicole Witte
- & Michael Schupp
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| Open AccessRETRACTED ARTICLE:Endocrine disruptors induce perturbations in endoplasmic reticulum and mitochondria of human pluripotent stem cell derivatives
Harmful chemicals that disrupt the endocrine system and hormone regulation have been associated with obesity. Here the authors apply a human pluripotent stem cell-based platform to study the effects of such compounds on developing gut endocrine and neuroendocrine systems.
- Uthra Rajamani
- , Andrew R. Gross
- & Dhruv Sareen
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Article
| Open AccessEndotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Elevated plasma LPS levels have been associated with insulin resistance. Here Cao et al. show that LPS induces ER stress and P300 activity via the XBP1/IRE1 pathway. P300 acetylates IRS1/2 and inhibits its binding with the insulin receptor. The consequent impairment of insulin signaling can be rescued by pharmacological inhibition of P300.
- Jia Cao
- , Jinghua Peng
- & Ling He
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Article
| Open AccessHDAC3 is a molecular brake of the metabolic switch supporting white adipose tissue browning
Histone deacetylases, such as HDAC3, have been shown to alter cellular metabolism in various tissues. Here the authors show that HDAC3 regulates WAT metabolism by activating a futile cycle of fatty acid synthesis and oxidation, which supports WAT browning.
- Alessandra Ferrari
- , Raffaella Longo
- & Maurizio Crestani
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| Open AccessCentral insulin modulates food valuation via mesolimbic pathways
The influence of insulin on food preference and the corresponding underlying neural circuits are unknown in humans. Here, the authors show that increasing insulin changes food preference by modulating mesolimbic neural circuits, and that this pattern is changed in insulin-resistant individuals.
- Lena J. Tiedemann
- , Sebastian M. Schmid
- & Stefanie Brassen
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| Open AccessAdipocyte adaptive immunity mediates diet-induced adipose inflammation and insulin resistance by decreasing adipose Treg cells
Obesity is associated with inflammation in adipose tissue, characterized by a shift in local T cell subsets. Here the authors show that loss of MHCII expression on adipocytes increases levels of immunosuppressive regulatory T cells in adipose tissue, which enhances insulin sensitivity.
- Tuo Deng
- , Joey Liu
- & Willa A. Hsueh
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| Open AccessLoss of mTORC1 signalling impairs β-cell homeostasis and insulin processing
Deregulation of mTORC1 pathway has been associated with several human diseases including diabetes, neurodegeneration and cancer. Here Blandino-Rosanoet al. show that mTORC1 signalling controls insulin secretion and β-cell maintenance by regulation of β-cell proliferation, apoptosis and autophagy and insulin processing.
- Manuel Blandino-Rosano
- , Rebecca Barbaresso
- & Ernesto Bernal-Mizrachi
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| Open AccessRaptor regulates functional maturation of murine beta cells
mTORC1 regulates beta cell survival, function and adaptation to physiologic and pathological stimuli. Here Niet al. demonstrate that that deficiency of Raptor, a component of mTORC1 complex, impairs insulin secretion and glucose tolerance in mice by affecting maturation of beta cells during the postnatal period.
- Qicheng Ni
- , Yanyun Gu
- & Qidi Wang
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| Open AccessSox5 regulates beta-cell phenotype and is reduced in type 2 diabetes
Type 2 diabetes (T2D) is a heterogeneous disorder characterized by insulin resistance and impaired insulin secretion. Here Axelssonet al. show that Sox5, which is reduced in diabetes, regulates a set of differentially expressed genes in T2D and its genetic and pharmacological induction improves insulin secretion by diabetic islets.
- A. S. Axelsson
- , T. Mahdi
- & A. H. Rosengren
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Article
| Open AccessThe genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing
Papillary thyroid carcinomas are often found with coincidental benign thyroid nodules. Here, the authors provide genomic evidence that papillary thyroid carcinomas and coincidental benign thyroid nodules originate and evolve independently.
- Lei Ye
- , Xiaoyi Zhou
- & Weiqing Wang
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Article
| Open AccessSuccinate and its G-protein-coupled receptor stimulates osteoclastogenesis
Bone loss is common in patients with diabetes, but the underlying molecular and cellular mechanisms are unclear. Here the authors show high succinate levels in mice with type 2 diabetes and that succinate can signal through succinate receptor 1 on osteoclasts to induce bone resorption.
- Yuqi Guo
- , Chengzhi Xie
- & Xin Li
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| Open AccessImpact of fat mass and distribution on lipid turnover in human adipose tissue
Lipid turnover in tissues can be calculated from ratios of different carbon isotopes. Here the authors use this approach to study lipid turnover in two distinct adipose tissue depots and find that, in obese individuals, visceral fat is more lipolytic than subcutaneous fat.
- Kirsty L. Spalding
- , Samuel Bernard
- & Peter Arner
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Article
| Open AccessTNFα drives mitochondrial stress in POMC neurons in obesity
Long-term consumption of a calorie-rich diet persistently activates brain microglia. Here, the authors show that microglial activity in mouse brains oscillates daily in conjunction with feeding, and that TNFα, secreted by activated microglia, induces mitochondrial stress in satiety-promoting POMC neurons.
- Chun-Xia Yi
- , Marc Walter
- & Matthias H. Tschöp
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| Open AccessHepatic p63 regulates steatosis via IKKβ/ER stress
p53 regulates lipid metabolism and fatty acid oxidation, and its inactivation promotes diet-induced liver steatosis. Here Porteiroet al. show that p53 deficiency leads to compensatory p63 upregulation, which, in turn, triggers endoplasmic reticulum stress through IKKβ activation, fatty acid synthesis and lipid accumulation.
- Begoña Porteiro
- , Marcos F. Fondevila
- & Ruben Nogueiras
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| Open AccessSteviol glycosides enhance pancreatic beta-cell function and taste sensation by potentiation of TRPM5 channel activity
Steviol glycosides are sweet-tasting compounds isolated from a South American shrub and are increasingly used as sweeteners in foods and beverages. Philippaertet al. demonstrate that steviol glycosides potentiate Ca2+-dependent TRPM5 activity and promote glucose-induced insulin secretion and glucose tolerance.
- Koenraad Philippaert
- , Andy Pironet
- & Rudi Vennekens
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| Open AccessFluorene-9-bisphenol is anti-oestrogenic and may cause adverse pregnancy outcomes in mice
Bisphenol A is used in the production of many plastic products, but has adverse health effects and is therefore being replaced. Here the authors show that its substitute, fluorene-9-bisphenol, is released from commercial plastic bottles into drinking water, and has anti-oestrogenic effects in mice.
- Zhaobin Zhang
- , Ying Hu
- & Jianying Hu
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| Open AccessFAK signalling controls insulin sensitivity through regulation of adipocyte survival
The kinase FAK is important for integrin signalling and promotes cell survival. Here, the authors demonstrate FAK regulates adipocyte survival, and is particularly important for maintaining insulin sensitivity during adipose tissue expansion in the context of a calorie-rich diet.
- Cynthia T. Luk
- , Sally Yu Shi
- & Minna Woo
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| Open AccessA-FABP mediates adaptive thermogenesis by promoting intracellular activation of thyroid hormones in brown adipocytes
The protein A-FABP is secreted from adipocytes and known to regulate glucose and lipid metabolism. Here the authors show A-FABP enhances thermogenesis by promoting the conversion of thyroxine T4 to the bioactive form, T3, in brown adipocytes, and by enhancing fatty acid uptake of brown fat.
- Lingling Shu
- , Ruby L. C. Hoo
- & Aimin Xu
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| Open AccessA TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice
Tolerance is required to prevent rejection of intrahepatic islet allografts as a potential treatment for type 1 diabetes. Here the authors show that IL-22 produced by NK1.1+cells in the liver of streptozotocin T1D model mice can drive tolerance to allografted islets.
- Deepak Tripathi
- , Sambasivan Venkatasubramanian
- & Ramakrishna Vankayalapati
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Article
| Open AccessTaotie neurons regulate appetite in Drosophila
Feeding control requires the integration and coordination of motivational, sensory and motor circuits in the brain. Here, the authors discover a set of neurons that regulate feeding inDrosophilaby promoting insulin release, and whose activity reflects physiological hunger and satiety states of flies.
- Yin Peng Zhan
- , Li Liu
- & Yan Zhu
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| Open AccessThe GCN5-CITED2-PKA signalling module controls hepatic glucose metabolism through a cAMP-induced substrate switch
GCN5 inhibits hepatic gluconeogenesis through acetylation of PGC-1α. Here the authors show that GCN5 also activates hepatic gluconeogenesis by acetylating histone H3K9, and that the affinity of GCN5 for its different substrates is regulated via phosphorylation at S275 by PKA in a CITED2-dependent manner.
- Mashito Sakai
- , Tomoko Tujimura-Hayakawa
- & Michihiro Matsumoto
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| Open AccessHyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
Patients with diabetes often have delayed wound healing, associated with excessive inflammation. Here the authors report that REG3A inhibits TLR3-driven inflammation in skin wounds, and show that REG3A is reduced in models of diabetes, which exacerbates inflammation in diabetic wounds.
- Yelin Wu
- , Yanchun Quan
- & Yuping Lai
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| Open AccessControl of diabetic hyperglycaemia and insulin resistance through TSC22D4
TSC22D4 regulates hepatic lipoprotein production, but has so far mainly been studied in the context of cancer cachexia. Here, the authors show TSC22D4 inhibition improves insulin sensitivity in several mouse models of diabetes, which they attribute at least in part to the induction of secreted LCN13.
- Bilgen Ekim Üstünel
- , Kilian Friedrich
- & Stephan Herzig
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| Open AccessSIKs control osteocyte responses to parathyroid hormone
Parathyroid hormone (PTH) is an endogenous hormone and osteoporosis therapeutic that suppresses sclerostin activity. Here the authors develop SIK inhibitors as potential therapeutic tools and use them to show that PTH-cAMP signalling in osteocytes inhibits SIK2 from driving Hdac4/5 nuclear shuttling to suppress sclerostin.
- Marc N. Wein
- , Yanke Liang
- & Henry M. Kronenberg
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| Open AccessInsulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing
The TOR and insulin/IGF signalling (IIS) network are central responses to wound healing. Here the authors develop a technique of live imaging of laser-induced epidermal wounds to flies and show that TOR and IIS are independently required for wound healing, which may have implications for diabetic wound healing and its treatment.
- Parisa Kakanj
- , Bernard Moussian
- & Maria Leptin
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Article
| Open AccessLoss of immune tolerance to IL-2 in type 1 diabetes
Type 1 diabetes is driven by T-cell autoimmunity to pancreatic islet cells. Here the authors show that autoreactive anti-IL-2 T and B cells are present in type 1 diabetes patients, and that anti-IL-2 antibodies precede diabetes onset in mice, suggesting their potential as a diagnostic marker.
- Louis Pérol
- , John M. Lindner
- & Eliane Piaggio
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| Open AccessDivergent effects of central melanocortin signalling on fat and sucrose preference in humans
Hypothalamic melanocortin-4-receptors (MC4R) regulate food preference in rodents, but their role in humans is unclear. Here, the authors perform food preference and liking tests in humans with MC4R mutations and find that they prefer fatty food more, but sweet food less, than people without MC4R mutations.
- Agatha A. van der Klaauw
- , Julia M. Keogh
- & I. Sadaf Farooqi
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Article
| Open AccessGDF11 decreases bone mass by stimulating osteoclastogenesis and inhibiting osteoblast differentiation
GDF11 is related to myostatin yet has no known role in postnatal bone turnover. Here the authors show that recombinant GDF11 injection causes bone loss and impairs healing by driving osteoclastogenesis while inhibiting osteoblast differentiation, plus they show that anti-GDF11 Ab can inhibit bone loss in ovariectomy and ageing mouse models.
- Weiqing Liu
- , Liyan Zhou
- & Quan Yuan
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Article
| Open AccessHuman islets contain four distinct subtypes of β cells
Dysfunction or loss of insulin-secreting β cells in the pancreas is a hallmark of diabetes. Here, Dorrell et al.identify four subpopulations of β cells in humans, which differ in gene expression and insulin secretion kinetics, and the abundance of which is altered in patients with type 2 diabetes.
- Craig Dorrell
- , Jonathan Schug
- & Markus Grompe
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| Open AccessMouse strains to study cold-inducible beige progenitors and beige adipocyte formation and function
Beige adipocytes are formed in response to cold and thought to contribute to organismal energy homeostasis. Here, the authors study a range of conditional and inducible RFP-expressing Cre mouse strains and find that SMA-based lines are the most useful for mapping beige adipocyte progenitor cells.
- Daniel C. Berry
- , Yuwei Jiang
- & Jonathan M. Graff
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| Open AccessPostnatal β-cell maturation is associated with islet-specific microRNA changes induced by nutrient shifts at weaning
Pancreatic β-cells are less responsive to changes in glucose concentration in newborn than in adult rats. Here, the authors show that functional β-cell maturation is associated with changes in miRNA expression induced by nutritional shifts at the suckling-to-weaning transition.
- Cécile Jacovetti
- , Scot J. Matkovich
- & Romano Regazzi
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Oestrogen signalling in white adipose progenitor cells inhibits differentiation into brown adipose and smooth muscle cells
Oestrogen has various metabolic and physiological effects. Here the authors show that oestrogen receptor alpha signalling determines lineage commitment of murine adipose progenitor cells, regulating their differentiation into white adipocytes, beige adipocytes or smooth muscle cells.
- Kfir Lapid
- , Ajin Lim
- & Jonathan M. Graff
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Steroid hormone signalling links reproduction to lifespan in dietary-restricted Caenorhabditis elegans
Dietary restriction increases the lifespan of many species, but often at the cost of reduced fertility. Here, Thondamal et al. show that the dietary restriction-mediated increase in lifespan in Caenorhabditis elegansdepends on the production of a steroid hormone and its inhibition of germline plasticity.
- Manjunatha Thondamal
- , Michael Witting
- & Hugo Aguilaniu
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Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration
The age-related decline in the regenerative capacity of muscle can be reversed in mice by exposure to young circulation. Elabd et al.identify the hormone, oxytocin, as a potential mediator of this effect, showing that its plasma levels decline with age and that administration of oxytocin to aged mice improves muscle regeneration.
- Christian Elabd
- , Wendy Cousin
- & Irina M. Conboy
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| Open AccessMolecular mechanics of mineralized collagen fibrils in bone
Bone is a natural composite of collagen and hydroxyapatite but, surprising, little is known about its characteristics at the molecular scale. Nair et al. conduct molecular-scale simulations of mineralized collagen networks to better understand how bone achieves superior mechanical properties to its constituents.
- Arun K. Nair
- , Alfonso Gautieri
- & Markus J. Buehler
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| Open AccessNeuronal influence on peripheral circadian oscillators in pupal Drosophila prothoracic glands
In the fruit flyDrosophila, changes in expression of circadian clock genes are believed to control eclosion. Morioka and colleagues show that transcriptional oscillations of the clock gene, period, in prothoracic gland cells are amplified by photic inputs from the central nervous system.
- Eri Morioka
- , Akira Matsumoto
- & Masayuki Ikeda