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Molecular Metabolism

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https://www.readbyqxmd.com/read/28752056/the-munich-midy-pig-biobank-a-unique-resource-for-studying-organ-crosstalk-in-diabetes
#1
Andreas Blutke, Simone Renner, Florian Flenkenthaler, Mattias Backman, Serena Haesner, Elisabeth Kemter, Erik Ländström, Christina Braun-Reichhart, Barbara Albl, Elisabeth Streckel, Birgit Rathkolb, Cornelia Prehn, Alessandra Palladini, Michal Grzybek, Stefan Krebs, Stefan Bauersachs, Andrea Bähr, Andreas Brühschwein, Cornelia A Deeg, Erica De Monte, Michaela Dmochewitz, Caroline Eberle, Daniela Emrich, Robert Fux, Frauke Groth, Sophie Gumbert, Antonia Heitmann, Arne Hinrichs, Barbara Keßler, Mayuko Kurome, Miriam Leipig-Rudolph, Kaspar Matiasek, Hazal Öztürk, Christiane Otzdorff, Myriam Reichenbach, Horst Dieter Reichenbach, Alexandra Rieger, Birte Rieseberg, Marco Rosati, Manuel Nicolas Saucedo, Anna Schleicher, Marlon R Schneider, Kilian Simmet, Judith Steinmetz, Nicole Übel, Patrizia Zehetmaier, Andreas Jung, Jerzy Adamski, Ünal Coskun, Martin Hrabě de Angelis, Christian Simmet, Mathias Ritzmann, Andrea Meyer-Lindenberg, Helmut Blum, Georg J Arnold, Thomas Fröhlich, Rüdiger Wanke, Eckhard Wolf
OBJECTIVE: The prevalence of diabetes mellitus and associated complications is steadily increasing. As a resource for studying systemic consequences of chronic insulin insufficiency and hyperglycemia, we established a comprehensive biobank of long-term diabetic INS(C94Y) transgenic pigs, a model of mutant INS gene-induced diabetes of youth (MIDY), and of wild-type (WT) littermates. METHODS: Female MIDY pigs (n = 4) were maintained with suboptimal insulin treatment for 2 years, together with female WT littermates (n = 5)...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752055/maternal-obesity-programs-increased-leptin-gene-expression-in-rat-male-offspring-via-epigenetic-modifications-in-a-depot-specific-manner
#2
Simon Lecoutre, Frederik Oger, Charlène Pourpe, Laura Butruille, Lucie Marousez, Anne Dickes-Coopman, Christine Laborie, Céline Guinez, Jean Lesage, Didier Vieau, Claudine Junien, Delphine Eberlé, Anne Gabory, Jérôme Eeckhoute, Christophe Breton
OBJECTIVE: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752054/serotonergic-modulation-of-the-activity-of-glp-1-producing-neurons-in-the-nucleus-of-the-solitary-tract-in-mouse
#3
Marie K Holt, Ida J Llewellyn-Smith, Frank Reimann, Fiona M Gribble, Stefan Trapp
OBJECTIVE: Glucagon-like peptide-1 (GLP-1) and 5-HT are potent regulators of food intake within the brain. GLP-1 is expressed by preproglucagon (PPG) neurons in the nucleus tractus solitarius (NTS). We have previously shown that PPG neurons innervate 5-HT neurons in the ventral brainstem. Here, we investigate whether PPG neurons receive serotonergic input and respond to 5-HT. METHODS: We employed immunohistochemistry to reveal serotonergic innervation of PPG neurons...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752053/dietary-sugars-not-lipids-drive-hypothalamic-inflammation
#4
Yuanqing Gao, Maximilian Bielohuby, Thomas Fleming, Gernot F Grabner, Ewout Foppen, Wagner Bernhard, Mara Guzmán-Ruiz, Clarita Layritz, Beata Legutko, Erwin Zinser, Cristina García-Cáceres, Ruud M Buijs, Stephen C Woods, Andries Kalsbeek, Randy J Seeley, Peter P Nawroth, Martin Bidlingmaier, Matthias H Tschöp, Chun-Xia Yi
OBJECTIVE: The hypothalamus of hypercaloric diet-induced obese animals is featured by a significant increase of microglial reactivity and its associated cytokine production. However, the role of dietary components, in particular fat and carbohydrate, with respect to the hypothalamic inflammatory response and the consequent impact on hypothalamic control of energy homeostasis is yet not clear. METHODS: We dissected the different effects of high-carbohydrate high-fat (HCHF) diets and low-carbohydrate high-fat (LCHF) diets on hypothalamic inflammatory responses in neurons and non-neuronal cells and tested the hypothesis that HCHF diets induce hypothalamic inflammation via advanced glycation end-products (AGEs) using mice lacking advanced glycation end-products (AGEs) receptor (RAGE) and/or the activated leukocyte cell-adhesion molecule (ALCAM)...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752052/the-role-of-ghrelin-responsive-mediobasal-hypothalamic-neurons-in-mediating-feeding-responses-to-fasting
#5
Bharath K Mani, Sherri Osborne-Lawrence, Mathieu Mequinion, Sydney Lawrence, Laurent Gautron, Zane B Andrews, Jeffrey M Zigman
OBJECTIVE: Ghrelin is a stomach-derived hormone that affects food intake and regulates blood glucose. The best-characterized actions of ghrelin are mediated by its binding to and activation of the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Adequate examination of the identity, function, and relevance of specific subsets of GHSR-expressing neurons has been hampered by the absence of a suitable Cre recombinase (Cre)-expressing mouse line with which to manipulate gene expression in a targeted fashion within GHSR-expressing neurons...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752051/repletion-of-branched-chain-amino-acids-reverses-mtorc1-signaling-but-not-improved-metabolism-during-dietary-protein-dilution
#6
Adriano Maida, Jessica S K Chan, Kim A Sjøberg, Annika Zota, Dieter Schmoll, Bente Kiens, Stephan Herzig, Adam J Rose
OBJECTIVE: Dietary protein dilution (PD) has been associated with metabolic advantages such as improved glucose homeostasis and increased energy expenditure. This phenotype involves liver-induced release of FGF21 in response to amino acid insufficiency; however, it has remained unclear whether dietary dilution of specific amino acids (AAs) is also required. Circulating branched chain amino acids (BCAAs) are sensitive to protein intake, elevated in the serum of obese humans and mice and thought to promote insulin resistance...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752050/nrg4-promotes-fuel-oxidation-and-a-healthy-adipokine-profile-to-ameliorate-diet-induced-metabolic-disorders
#7
Zhimin Chen, Guo-Xiao Wang, Sara L Ma, Dae Young Jung, Hyekyung Ha, Tariq Altamimi, Xu-Yun Zhao, Liang Guo, Peng Zhang, Chun-Rui Hu, Ji-Xin Cheng, Gary D Lopaschuk, Jason K Kim, Jiandie D Lin
OBJECTIVE: Brown and white adipose tissue exerts pleiotropic effects on systemic energy metabolism in part by releasing endocrine factors. Neuregulin 4 (Nrg4) was recently identified as a brown fat-enriched secreted factor that ameliorates diet-induced metabolic disorders, including insulin resistance and hepatic steatosis. However, the physiological mechanisms through which Nrg4 regulates energy balance and glucose and lipid metabolism remain incompletely understood. The aims of the current study were: i) to investigate the regulation of adipose Nrg4 expression during obesity and the physiological signals involved, ii) to elucidate the mechanisms underlying Nrg4 regulation of energy balance and glucose and lipid metabolism, and iii) to explore whether Nrg4 regulates adipose tissue secretome gene expression and adipokine secretion...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752049/beta-adrenergic-receptors-are-critical-for-weight-loss-but-not-for-other-metabolic-adaptations-to-the-consumption-of-a-ketogenic-diet-in-male-mice
#8
Nicholas Douris, Bhavna N Desai, Ffolliott M Fisher, Theodore Cisu, Alan J Fowler, Eleen Zarebidaki, Ngoc Ly T Nguyen, Donald A Morgan, Timothy J Bartness, Kamal Rahmouni, Jeffrey S Flier, Eleftheria Maratos-Flier
OBJECTIVE: We have previously shown that the consumption of a low-carbohydrate ketogenic diet (KD) by mice leads to a distinct physiologic state associated with weight loss, increased metabolic rate, and improved insulin sensitivity [1]. Furthermore, we identified fibroblast growth factor 21 (FGF21) as a necessary mediator of the changes, as mice lacking FGF21 fed KD gain rather than lose weight [2]. FGF21 activates the sympathetic nervous system (SNS) [3], which is a key regulator of metabolic rate...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752048/myeloid-protein-tyrosine-phosphatase-1b-ptp1b-deficiency-protects-against-atherosclerotic-plaque-formation-in-the-apoe-mouse-model-of-atherosclerosis-with-alterations-in-il10-ampk%C3%AE-pathway
#9
D Thompson, N Morrice, L Grant, S Le Sommer, K Ziegler, P Whitfield, N Mody, H M Wilson, M Delibegović
OBJECTIVE: Cardiovascular disease (CVD) is the most prevalent cause of mortality among patients with Type 1 or Type 2 diabetes, due to accelerated atherosclerosis. Recent evidence suggests a strong link between atherosclerosis and insulin resistance due to impaired insulin receptor (IR) signaling. Moreover, inflammatory cells, in particular macrophages, play a key role in pathogenesis of atherosclerosis and insulin resistance in humans. We hypothesized that inhibiting the activity of protein tyrosine phosphatase 1B (PTP1B), the major negative regulator of the IR, specifically in macrophages, would have beneficial anti-inflammatory effects and lead to protection against atherosclerosis and CVD...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752047/amyloid-formation-disrupts-the-balance-between-interleukin-1%C3%AE-and-interleukin-1-receptor-antagonist-in-human-islets
#10
Queenie Hui, Ali Asadi, Yoo Jin Park, Timothy J Kieffer, Ziliang Ao, Garth L Warnock, Lucy Marzban
OBJECTIVES: β-cell dysfunction and apoptosis associated with islet inflammation play a key role in the pathogenesis of type 2 diabetes (T2D). Growing evidence suggests that islet amyloid, formed by aggregation of human islet amyloid polypeptide (hIAPP), contributes to islet inflammation and β-cell death in T2D. We recently showed the role of interleukin-1β (IL-1β)/Fas/caspase-8 apoptotic pathway in amyloid-induced β-cell death. In this study, we used human islets in culture as an ex vivo model of amyloid formation to: (1) investigate the effects of amyloid on islet levels of the natural IL-1 receptor antagonist (IL-1Ra); (2) examine if modulating the IL-1β/IL-1Ra balance can prevent amyloid-induced β-cell Fas upregulation and apoptosis...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752046/nicotinamide-riboside-kinases-display-redundancy-in-mediating-nicotinamide-mononucleotide-and-nicotinamide-riboside-metabolism-in-skeletal-muscle-cells
#11
Rachel S Fletcher, Joanna Ratajczak, Craig L Doig, Lucy A Oakey, Rebecca Callingham, Gabriella Da Silva Xavier, Antje Garten, Yasir S Elhassan, Philip Redpath, Marie E Migaud, Andrew Philp, Charles Brenner, Carles Canto, Gareth G Lavery
OBJECTIVE: Augmenting nicotinamide adenine dinucleotide (NAD(+)) availability may protect skeletal muscle from age-related metabolic decline. Dietary supplementation of NAD(+) precursors nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) appear efficacious in elevating muscle NAD(+). Here we sought to identify the pathways skeletal muscle cells utilize to synthesize NAD(+) from NMN and NR and provide insight into mechanisms of muscle metabolic homeostasis. METHODS: We exploited expression profiling of muscle NAD(+) biosynthetic pathways, single and double nicotinamide riboside kinase 1/2 (NRK1/2) loss-of-function mice, and pharmacological inhibition of muscle NAD(+) recycling to evaluate NMN and NR utilization...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752045/angiopoietin-like-4-directs-uptake-of-dietary-fat-away-from-adipose-during-fasting
#12
Emily M Cushing, Xun Chi, Kelli L Sylvers, Shwetha K Shetty, Matthew J Potthoff, Brandon S J Davies
OBJECTIVE: Angiopoietin-like 4 (ANGPTL4) is a fasting-induced inhibitor of lipoprotein lipase (LPL) and a regulator of plasma triglyceride metabolism. Here, we examined the kinetics of Angptl4 induction and tested the hypothesis that ANGPTL4 functions physiologically to reduce triglyceride delivery to adipose tissue during nutrient deprivation. METHODS: Gene expression, LPL activity, and triglyceride uptake were examined in fasted and fed wild-type and Angptl4(-/-) mice...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752044/ca-2-associated-triphasic-ph-changes-in-mitochondria-during-brown-adipocyte-activation
#13
Yanyan Hou, Tetsuya Kitaguchi, Rókus Kriszt, Yu-Hua Tseng, Michael Raghunath, Madoka Suzuki
OBJECTIVE: Brown adipocytes (BAs) are endowed with a high metabolic capacity for energy expenditure due to their high mitochondria content. While mitochondrial pH is dynamically regulated in response to stimulation and, in return, affects various metabolic processes, how mitochondrial pH is regulated during adrenergic stimulation-induced thermogenesis is unknown. We aimed to reveal the spatial and temporal dynamics of mitochondrial pH in stimulated BAs and the mechanisms behind the dynamic pH changes...
August 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28752043/adipocyte-lipid-synthesis-coupled-to-neuronal-control-of-thermogenic-programming
#14
Adilson Guilherme, David J Pedersen, Elizabeth Henchey, Felipe S Henriques, Laura V Danai, Yuefei Shen, Batuhan Yenilmez, DaeYoung Jung, Jason K Kim, Irfan J Lodhi, Clay F Semenkovich, Michael P Czech
BACKGROUND: The de novo biosynthesis of fatty acids (DNL) through fatty acid synthase (FASN) in adipocytes is exquisitely regulated by nutrients, hormones, fasting, and obesity in mice and humans. However, the functions of DNL in adipocyte biology and in the regulation of systemic glucose homeostasis are not fully understood. METHODS & RESULTS: Here we show adipocyte DNL controls crosstalk to localized sympathetic neurons that mediate expansion of beige/brite adipocytes within inguinal white adipose tissue (iWAT)...
August 2017: Molecular Metabolism
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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