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Molecular Metabolism

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https://www.readbyqxmd.com/read/28702332/dysregulation-of-a-novel-mir-23b-27b-p53-axis-impairs-muscle-stem-cell-differentiation-of-humans-with-type-2-diabetes
#1
Tora I Henriksen, Peter K Davidsen, Maria Pedersen, Heidi S Schultz, Ninna S Hansen, Therese J Larsen, Allan Vaag, Bente K Pedersen, Søren Nielsen, Camilla Scheele
OBJECTIVE: MicroRNAs (miRNAs) are increasingly recognized as fine-tuning regulators of metabolism, and are dysregulated in several disease conditions. With their capacity to rapidly change gene expression, miRNAs are also important regulators of development and cell differentiation. In the current study, we describe an impaired myogenic capacity of muscle stem cells isolated from humans with type 2 diabetes (T2DM) and assess whether this phenotype is regulated by miRNAs. METHODS: We measured global miRNA expression during in vitro differentiation of muscle stem cells derived from T2DM patients and healthy controls...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702331/uncoupling-protein-2-regulates-daily-rhythms-of-insulin-secretion-capacity-in-min6-cells-and-isolated-islets-from-male-mice
#2
Nivedita Seshadri, Michael E Jonasson, Kristin L Hunt, Bo Xiang, Steven Cooper, Michael B Wheeler, Vernon W Dolinsky, Christine A Doucette
OBJECTIVE: Upregulation of uncoupling protein 2 (UCP2) is associated with impaired glucose-stimulated insulin secretion (GSIS), which is thought to be an important contributor to pathological β cell failure in obesity and type 2 diabetes (T2D); however, the physiological function of UCP2 in the β cell remains undefined. It has been suggested, but not yet tested, that UCP2 plays a physiological role in β cells by coordinating insulin secretion capacity with anticipated fluctuating nutrient supply, such that upregulation of UCP2 in the inactive/fasted state inhibits GSIS as a mechanism to prevent hypoglycemia...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702330/neonatal-glp1r-activation-limits-adult-adiposity-by-durably-altering-hypothalamic-architecture
#3
Andrea V Rozo, Daniella A Babu, PoMan A Suen, David N Groff, Randy J Seeley, Rebecca A Simmons, Patrick Seale, Rexford S Ahima, Doris A Stoffers
OBJECTIVE: Adult obesity risk is influenced by alterations to fetal and neonatal environments. Modifying neonatal gut or neurohormone signaling pathways can have negative metabolic consequences in adulthood. Here we characterize the effect of neonatal activation of glucagon like peptide-1 (GLP-1) receptor (GLP1R) signaling on adult adiposity and metabolism. METHODS: Wild type C57BL/6 mice were injected with 1 nmol/kg Exendin-4 (Ex-4), a GLP1R agonist, for 6 consecutive days after birth...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702329/metformin-causes-a-futile-intestinal-hepatic-cycle-which-increases-energy-expenditure-and-slows-down-development-of-a-type-2-diabetes-like-state
#4
Philipp Schommers, Anna Thurau, Insa Bultmann-Mellin, Maria Guschlbauer, Andreas R Klatt, Jan Rozman, Martin Klingenspor, Martin Hrabe de Angelis, Jens Alber, Dirk Gründemann, Anja Sterner-Kock, Rudolf J Wiesner
OBJECTIVE: Metformin, the first line drug for treatment of type 2 diabetes, suppresses hepatic gluconeogenesis and reduces body weight in patients, the latter by an unknown mechanism. METHODS: Mice on a high fat diet were continuously fed metformin in a therapeutically relevant dose, mimicking a retarded formulation. RESULTS: Feeding metformin in pharmacologically relevant doses to mice on a high fat diet normalized HbA1c levels and ameliorated glucose tolerance, as expected, but also considerably slowed down weight gain...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702328/ask1-map3k5-is-transcriptionally-upregulated-by-e2f1-in-adipose-tissue-in-obesity-molecularly-defining-a-human-dys-metabolic-obese-phenotype
#5
Yulia Haim, Matthias Blüher, Daniel Konrad, Nir Goldstein, Nora Klöting, Ilana Harman-Boehm, Boris Kirshtein, Doron Ginsberg, Tanya Tarnovscki, Yftach Gepner, Iris Shai, Assaf Rudich
OBJECTIVE: Obesity variably disrupts human health, but molecular-based patients' health-risk stratification is limited. Adipose tissue (AT) stresses may link obesity with metabolic dysfunction, but how they signal in humans remains poorly-characterized. We hypothesized that a transcriptional AT stress-signaling cascade involving E2F1 and ASK1 (MAP3K5) molecularly defines high-risk obese subtype. METHODS: ASK1 expression in human AT biopsies was determined by real-time PCR analysis, and chromatin immunoprecipitation (ChIP) adopted to AT explants was used to evaluate the binding of E2F1 to the ASK1 promoter...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702327/loss-of-adamts5-enhances-brown-adipose-tissue-mass-and-promotes-browning-of-white-adipose-tissue-via-creb-signaling
#6
Dries Bauters, Mathias Cobbaut, Lotte Geys, Johan Van Lint, Bianca Hemmeryckx, H Roger Lijnen
OBJECTIVE: A potential strategy to treat obesity - and the associated metabolic consequences - is to increase energy expenditure. This could be achieved by stimulating thermogenesis through activation of brown adipose tissue (BAT) and/or the induction of browning of white adipose tissue (WAT). Over the last years, it has become clear that several metalloproteinases play an important role in adipocyte biology. Here, we investigated the potential role of ADAMTS5. METHODS: Mice deficient in ADAMTS5 (Adamts5(-/-)) and wild-type (Adamts5(+/+)) littermates were kept on a standard of Western-type diet for 15 weeks...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702326/rev-erb-co-regulates-muscle-regeneration-via-tethered-interaction-with-the-nf-y-cistrome
#7
Ryan D Welch, Chun Guo, Monideepa Sengupta, Katherine J Carpenter, Natalie A Stephens, Stacy A Arnett, Marvin J Meyers, Lauren M Sparks, Steven R Smith, Jinsong Zhang, Thomas P Burris, Colin A Flaveny
OBJECTIVE: The loss of skeletal muscle mass and strength are a central feature of traumatic injury and degenerative myopathies. Unfortunately, pharmacological interventions typically fail to stem the long-term decline in quality of life. Reduced Rev-Erb-mediated gene suppression in cultured C2C12 myoblasts has been shown to stimulate myoblast differentiation. Yet the mechanisms that allow Rev-Erb to pleiotropically inhibit muscle differentiation are not well understood. In this study, we sought to elucidate the role of Rev-Erb in the regulation of muscle differentiation and regeneration in vivo...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702325/the-human-digestive-tract-has-proteases-capable-of-gluten-hydrolysis
#8
Sergio Gutiérrez, Jenifer Pérez-Andrés, Honorina Martínez-Blanco, Miguel Angel Ferrero, Luis Vaquero, Santiago Vivas, Javier Casqueiro, Leandro B Rodríguez-Aparicio
OBJECTIVE: To identify, purify, and characterize the proteins responsible for glutenase activity in the feces of healthy subjects and patients with celiac disease (CD). METHODS: Sixteen subjects were included in this study; 8 were healthy with no known food intolerances, and 8 were treated CD patients on a gluten-free diet. Fecal samples were homogenized, and precipitated proteins were purified by chromatography. Glutenase activity was evaluated by bioassays, zymography, and high-performance liquid chromatography with immunogenic 33-mer, 19-mer, and 13-mer gliadin peptides...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702324/the-endogenous-preproglucagon-system-is-not-essential-for-gut-growth-homeostasis-in-mice
#9
Pernille Wismann, Pernille Barkholt, Thomas Secher, Niels Vrang, Henrik B Hansen, Palle Bekker Jeppesen, Laurie L Baggio, Jacqueline A Koehler, Daniel J Drucker, Darleen A Sandoval, Jacob Jelsing
OBJECTIVE: The prevalence of obesity and related co-morbidities is reaching pandemic proportions. Today, the most effective obesity treatments are glucagon-like peptide 1 (GLP-1) analogs and bariatric surgery. Interestingly, both intervention paradigms have been associated with adaptive growth responses in the gut; however, intestinotrophic mechanisms associated with or secondary to medical or surgical obesity therapies are poorly understood. Therefore, the objective of this study was to assess the local basal endogenous and pharmacological intestinotrophic effects of glucagon-like peptides and bariatric surgery in mice...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702323/aav-mediated-pancreatic-overexpression-of-igf1-counteracts-progression-to-autoimmune-diabetes-in-mice
#10
Cristina Mallol, Estefania Casana, Veronica Jimenez, Alba Casellas, Virginia Haurigot, Claudia Jambrina, Victor Sacristan, Meritxell Morró, Judith Agudo, Laia Vilà, Fatima Bosch
OBJECTIVE: Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702322/mitochondrial-transcription-factor-b2-is-essential-for-mitochondrial-and-cellular-function-in-pancreatic-%C3%AE-cells
#11
Lisa M Nicholas, Bérengère Valtat, Anya Medina, Lotta Andersson, Mia Abels, Inês G Mollet, Deepak Jain, Lena Eliasson, Nils Wierup, Malin Fex, Hindrik Mulder
OBJECTIVE: Insulin release from pancreatic β-cells is controlled by plasma glucose levels via mitochondrial fuel metabolism. Therefore, insulin secretion is critically dependent on mitochondrial DNA (mtDNA) and the genes it encodes. Mitochondrial transcription factor B2 (TFB2M) controls transcription of mitochondrial-encoded genes. However, its precise role in mitochondrial metabolism in pancreatic β-cells and, consequently, in insulin secretion remains unknown. METHODS: To elucidate the role of TFB2M in mitochondrial function and insulin secretion in vitro and in vivo, mice with a β-cell specific homozygous or heterozygous knockout of Tfb2m and rat clonal insulin-producing cells in which the gene was silenced were examined with an array of metabolic and functional assays...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702321/a-high-content-small-molecule-screen-identifies-novel-inducers-of-definitive-endoderm
#12
Alexander Korostylev, Pallavi U Mahaddalkar, Oliver Keminer, Kamyar Hadian, Kenji Schorpp, Philip Gribbon, Heiko Lickert
OBJECTIVES: Human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) can generate any given cell type in the human body. One challenge for cell-replacement therapy is the efficient differentiation and expansion of large quantities of progenitor cells from pluripotent stem cells produced under good manufacturing practice (GMP). FOXA2 and SOX17 double positive definitive endoderm (DE) progenitor cells can give rise to all endoderm-derived cell types in the thymus, thyroid, lung, pancreas, liver, and gastrointestinal tract...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702320/parental-obesity-leads-to-metabolic-changes-in-the-f2-generation-in-drosophila
#13
Rebecca A S Palu, Sophia A Praggastis, Carl S Thummel
OBJECTIVE: A significant portion of the heritable risk for complex metabolic disorders cannot be attributed to classic Mendelian genetic factors. At least some of this missing heritability is thought to be due to the epigenetic influence of parental and grandparental metabolic state on offspring health. Previous work suggests that this transgenerational phenomenon is evolutionarily conserved in Drosophila. These studies, however, have all depended on dietary paradigms to alter parental metabolic state, which can have inconsistent heritable effects on the metabolism of offspring...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28702319/grandpaternal-induced-transgenerational-dietary-reprogramming-of-the-unfolded-protein-response-in-skeletal-muscle
#14
Petter S Alm, Thais de Castro Barbosa, Romain Barrès, Anna Krook, Juleen R Zierath
OBJECTIVE: Parental nutrition and lifestyle impact the metabolic phenotype of the offspring. We have reported that grandpaternal chronic high-fat diet (HFD) transgenerationally impairs glucose metabolism in subsequent generations. Here we determined whether grandpaternal diet transgenerationally impacts the transcriptome and lipidome in skeletal muscle. Our aim was to identify tissue-specific pathways involved in transgenerational inheritance of environmental-induced phenotypes. METHODS: F0 male Sprague-Dawley rats were fed a HFD or chow for 12 weeks before breeding with chow-fed females to generate the F1 generation...
July 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580291/%C3%AE-3-adrenergically-induced-glucose-uptake-in-brown-adipose-tissue-is-independent-of-ucp1-presence-or-activity-mediation-through-the-mtor-pathway
#15
Jessica M Olsen, Robert I Csikasz, Nodi Dehvari, Li Lu, Anna Sandström, Anette I Öberg, Jan Nedergaard, Sharon Stone-Elander, Tore Bengtsson
OBJECTIVE: Today, the presence and activity of brown adipose tissue (BAT) in adult humans is generally equated with the induced accumulation of [2-(18)F]2-fluoro-2-deoxy-d-glucose ([(18)F]FDG) in adipose tissues, as investigated by positron emission tomography (PET) scanning. In reality, PET-FDG is currently the only method available for in vivo quantification of BAT activity in adult humans. The underlying assumption is that the glucose uptake reflects the thermogenic activity of the tissue...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580290/fgf21-resistance-is-not-mediated-by-downregulation-of-beta-klotho-expression-in-white-adipose-tissue
#16
Kathleen R Markan, Meghan C Naber, Sarah M Small, Lila Peltekian, Rachel L Kessler, Matthew J Potthoff
OBJECTIVE: Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates metabolic homeostasis. Previous work has suggested that impairment of FGF21 signaling in adipose tissue may occur through downregulation of the obligate FGF21 co-receptor, β-klotho, which leads to "FGF21 resistance" during the onset of diet-induced obesity. Here, we sought to determine whether maintenance of β-klotho expression in adipose tissue prevents FGF21 resistance and whether other mechanisms also contribute to FGF21 resistance in vivo...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580289/endocannabinoid-dependent-disinhibition-of-orexinergic-neurons-electrophysiological-evidence-in-leptin-knockout-obese-mice
#17
Thorsten Michael Becker, Morgana Favero, Vincenzo Di Marzo, Luigia Cristino, Giuseppe Busetto
OBJECTIVES: In the ob/ob mouse model of obesity, chronic absence of leptin causes a significant increase of orexin (OX) production by hypothalamic neurons and excessive food intake. The altered OX level is linked to a dramatic increase of the inhibitory innervation of OX producing neurons (OX neurons) and the over expression of the endocannabinoid 2-arachidonoylglycerol (2-AG) by OX neurons of ob/ob mice. Little is known about the function of the excitatory synapses of OX neurons in ob/ob mice, and their modulation by 2-AG...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580288/restoration-of-lepr-in-%C3%AE-cells-of-lepr-null-mice-does-not-prevent-hyperinsulinemia-and-hyperglycemia
#18
Anna M D'souza, Timothy J Kieffer
OBJECTIVE: The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre-loxP to disrupt the leptin receptor gene (Lepr) in β cells, but variable results were obtained. Furthermore, recombination of Lepr was observed in the hypothalamus or exocrine pancreas, in addition to the β cells, and Lepr in non-β cells may have compensated for the loss of Lepr in β cells, thus making it difficult to assess the direct effects of Lepr in β cells...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580287/insulin-controls-food-intake-and-energy-balance-via-npy-neurons
#19
Kim Loh, Lei Zhang, Amanda Brandon, Qiaoping Wang, Denovan Begg, Yue Qi, Melissa Fu, Rishikesh Kulkarni, Jonathan Teo, Paul Baldock, Jens C Brüning, Gregory Cooney, Greg Neely, Herbert Herzog
OBJECTIVES: Insulin signaling in the brain has been implicated in the control of satiety, glucose homeostasis and energy balance. However, insulin signaling is dispensable in energy homeostasis controlling AgRP or POMC neurons and it is unclear which other neurons regulate these effects. Here we describe an ancient insulin/NPY neuronal network that governs energy homeostasis across phyla. METHODS: To address the role of insulin action specifically in NPY neurons, we generated a variety of models by selectively removing insulin signaling in NPY neurons in flies and mice and testing the consequences on energy homeostasis...
June 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28580286/role-of-nutrients-and-mtor-signaling-in-the-regulation-of-pancreatic-progenitors-development
#20
Lynda Elghazi, Manuel Blandino-Rosano, Emilyn Alejandro, Corentin Cras-Méneur, Ernesto Bernal-Mizrachi
OBJECTIVE: Poor fetal nutrition increases the risk of type 2 diabetes in the offspring at least in part by reduced embryonic β-cell growth and impaired function. However, it is not entirely clear how fetal nutrients and growth factors impact β-cells during development to alter glucose homeostasis and metabolism later in life. The current experiments aimed to test the impact of fetal nutrients and growth factors on endocrine development and how these signals acting on mTOR signaling regulate β-cell mass and glucose homeostasis...
June 2017: Molecular Metabolism
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