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Molecular Metabolism

Laure Monteillet, Monika Gjorgjieva, Marine Silva, Vincent Verzieux, Linda Imikirene, Adeline Duchampt, Hervé Guillou, Gilles Mithieux, Fabienne Rajas
OBJECTIVE: Ectopic lipid accumulation in the liver and kidneys is a hallmark of metabolic diseases leading to non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). Moreover, recent data have highlighted a strong correlation between NAFLD and CKD incidences. In this study, we use two mouse models of hepatic steatosis or CKD, each initiated independently of the other upon the suppression of glucose production specifically in the liver or kidneys, to elucidate the mechanisms underlying the development of CKD in the context of NAFLD-like pathology...
August 1, 2018: Molecular Metabolism
Lawrence J Billing, Christopher A Smith, Pierre Larraufie, Deborah A Goldspink, Sam Galvin, Richard G Kay, Jonathan D Howe, Ryan Walker, Mihai Pruna, Leslie Glass, Ramona Pais, Fiona M Gribble, Frank Reimann
OBJECTIVE: Insulin-like peptide-5 (INSL5) is an orexigenic gut hormone found in a subset of colonic and rectal enteroendocrine L-cells together with the anorexigenic hormones glucagon-like peptide-1 (GLP-1) and peptideYY (PYY). Unlike GLP-1 and PYY, INSL5 levels are elevated by calorie restriction, raising questions about how these hormones respond to different stimuli when they arise from the same cell type. The aim of the current study was to identify whether and how INSL5, GLP-1 and PYY are co-secreted or differentially secreted from colonic L-cells...
July 30, 2018: Molecular Metabolism
Alexander W Fischer, Kirstin Albers, Lucia M Krott, Britta Hoffzimmer, Markus Heine, Hartwig Schmale, Ludger Scheja, Philip L S M Gordts, Joerg Heeren
OBJECTIVE: Insulin resistance is associated with impaired receptor dependent hepatic uptake of triglyceride-rich lipoproteins (TRL), promoting hypertriglyceridemia and atherosclerosis. Next to low-density lipoprotein (LDL) receptor (LDLR) and syndecan-1, the LDLR-related protein 1 (LRP1) stimulated by insulin action contributes to the rapid clearance of TRL in the postprandial state. Here, we investigated the hypothesis that the adaptor protein phosphotyrosine interacting domain-containing protein 1 (PID1) regulates LRP1 function, thereby controlling hepatic endocytosis of postprandial lipoproteins...
July 30, 2018: Molecular Metabolism
Umesh D Wankhade, Ji-Hyeon Lee, Pradeep K Dagur, Hariom Yadav, Michael Shen, Weiping Chen, Ashok B Kulkarni, J Philip McCoy, Toren Finkel, Aaron M Cypess, Sushil G Rane
OBJECTIVE: Beige/brite adipose tissue displays morphological characteristics and beneficial metabolic traits of brown adipose tissue. Previously, we showed that TGF-β signaling regulates the browning of white adipose tissue. Here, we inquired whether TGF-β signals regulated presumptive beige progenitors in white fat and investigated the TGF-β regulated mechanisms involved in beige adipogenesis. METHODS: We deleted TGF-β receptor 1 (TβRI) in adipose tissue (TβRIAdKO mice) and, using flow-cytometry based assays, identified and isolated presumptive beige progenitors located in the stromal vascular cells of white fat...
July 27, 2018: Molecular Metabolism
Nathan Denton, Katherine E Pinnick, Fredrik Karpe
OBJECTIVE: The composition of the extracellular matrix (ECM) impacts adipocyte function and might determine adipose tissue (AT) function and distribution. Cartilage oligomeric matrix protein (COMP), a matricellular protein usually studied in bone and cartilage, is highly differentially expressed between subcutaneous abdominal and gluteal AT. This study aimed to explore COMP's role in human subcutaneous abdominal and gluteal AT and preadipocyte biology. METHODS: COMP mRNA levels were measured in whole AT and immortalised preadipocytes via quantitative (q)-PCR...
July 27, 2018: Molecular Metabolism
James G Cash, Eddy Konaniah, Narasimha Hegde, David G Kuhel, Miki Watanabe, Lindsey Romick-Rosendale, David Y Hui
OBJECTIVE: Obesity and obesity-related metabolic disorders are major health problems worldwide. The most effective obesity intervention is bariatric surgery. This study tested the hypothesis that bariatric surgery alters phospholipid metabolism in the gastrointestinal tract to favor a metabolically healthy gut microbiota profile and therapeutic intervention of phospholipid metabolism in the gastrointestinal may have similar metabolic benefits. METHODS: The first study compared plasma levels of the bioactive lipid metabolites lysophospholipid and trimethylamine N-oxide (TMAO) as well as gut microbiota profile in high fat/carbohydrate (HFHC) diet-fed C57BL/6 mice with or without vertical sleeve gastrectomy (VSG) and in Pla2g1b-/- mice with group 1B phospholipase A2 gene inactivation...
July 26, 2018: Molecular Metabolism
Evan P Taddeo, Linsey Stiles, Samuel Sereda, Eleni Ritou, Dane M Wolf, Muhamad Abdullah, Zachary Swanson, Josh Wilhelm, Melena Bellin, Patrick McDonald, Kacey Caradonna, Andrew Neilson, Marc Liesa, Orian S Shirihai
OBJECTIVE: Islets from the same pancreas show remarkable variability in glucose sensitivity. While mitochondrial respiration is essential for glucose-stimulated insulin secretion, little is known regarding heterogeneity in mitochondrial function at the individual islet level. This is due in part to a lack of high-throughput and non-invasive methods for detecting single islet function. METHODS: We have developed a novel non-invasive, high-throughput methodology capable of assessing mitochondrial respiration in large-sized individual islets using the XF96 analyzer (Agilent Technologies)...
July 25, 2018: Molecular Metabolism
Janne R Hingst, Lea Bruhn, Mads B Hansen, Marie F Rosschou, Jesper B Birk, Joachim Fentz, Marc Foretz, Benoit Viollet, Kei Sakamoto, Nils J Færgeman, Jesper F Havelund, Benjamin L Parker, David E James, Bente Kiens, Erik A Richter, Jørgen Jensen, Jørgen F P Wojtaszewski
OBJECTIVE: A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in prior exercised muscle. Our objective was to illuminate molecular mechanisms underlying this phenomenon in skeletal muscle of man. METHODS: We studied the temporal regulation of glycogen supercompensation in human skeletal muscle during a 5 day recovery period following a single bout of exercise. Nine healthy men depleted (day 1), normalized (day 2) and supercompensated (day 5) muscle glycogen in one leg while the contralateral leg served as a resting control...
July 25, 2018: Molecular Metabolism
Lisa Suwandhi, Simone Hausmann, Alexander Braun, Tim Gruber, Silke S Heinzmann, Eric J C Gálvez, Achim Buck, Beata Legutko, Andreas Israel, Annette Feuchtinger, Elizabeth Haythorne, Harald Staiger, Martin Heni, Hans-Ulrich Häring, Philippe Schmitt-Kopplin, Axel Walch, Cristina García Cáceres, Matthias H Tschöp, Guy A Rutter, Till Strowig, Martin Elsner, Siegfried Ussar
OBJECTIVE: The metabolic role of d-serine, a non-proteinogenic NMDA receptor co-agonist, is poorly understood. Conversely, inhibition of pancreatic NMDA receptors as well as loss of the d-serine producing enzyme serine racemase have been shown to modulate insulin secretion. Thus, we aim to study the impact of chronic and acute d-serine supplementation on insulin secretion and other parameters of glucose homeostasis. METHODS: We apply MALDI FT-ICR mass spectrometry imaging, NMR based metabolomics, 16s rRNA gene sequencing of gut microbiota in combination with a detailed physiological characterization to unravel the metabolic action of d-serine in mice acutely and chronically treated with 1% d-serine in drinking water in combination with either chow or high fat diet feeding...
July 25, 2018: Molecular Metabolism
David G Lassiter, Rasmus J O Sjögren, Brendan M Gabriel, Anna Krook, Juleen R Zierath
OBJECTIVE: We sought to identify AMPK-regulated genes via bioinformatic analysis of microarray data generated from skeletal muscle of animal models with genetically altered AMPK activity. We hypothesized that such genes would play a role in metabolism. Ganglioside-induced differentiation-associated protein 1 (GDAP1), a gene which plays a role in mitochondrial fission and peroxisomal function in neuronal cells but whose function in skeletal muscle is undescribed, was identified and further validated...
July 25, 2018: Molecular Metabolism
Simone Renner, Andreas Blutke, Britta Dobenecker, Georg Dhom, Timo D Müller, Brian Finan, Christoffer Clemmensen, Maren Bernau, Istvan Novak, Birgit Rathkolb, Steffanie Senf, Susanne Zöls, Mirjam Roth, Anna Götz, Susanna M Hofmann, Martin Hrabĕ de Angelis, Rüdiger Wanke, Ellen Kienzle, Armin M Scholz, Richard DiMarchi, Mathias Ritzmann, Matthias H Tschöp, Eckhard Wolf
OBJECTIVE: The worldwide prevalence of obesity has increased to 10% in men and 15% in women and is associated with severe comorbidities such as diabetes, cancer, and cardiovascular disease. Animal models of obesity are central to experimental studies of disease mechanisms and therapeutic strategies. Diet-induced obesity (DIO) models in rodents have provided important insights into the pathophysiology of obesity and, in most instances, are the first in line for exploratory pharmacology studies...
June 28, 2018: Molecular Metabolism
Adilson Guilherme, David J Pedersen, Felipe Henriques, Alexander H Bedard, Elizabeth Henchey, Mark Kelly, Donald A Morgan, Kamal Rahmouni, Michael P Czech
OBJECTIVE: Crosstalk between adipocytes and local neurons may be an important regulatory mechanism to control energy homeostasis. We previously reported that perturbation of adipocyte de novo lipogenesis (DNL) by deletion of fatty acid synthase (FASN) expands sympathetic neurons within white adipose tissue (WAT) and stimulates the appearance of "beige" adipocytes. Here we tested whether WAT DNL activity can also influence neuronal regulation and thermogenesis in brown adipose tissue (BAT)...
June 27, 2018: Molecular Metabolism
Tomas Jelenik, Matthias Dille, Sabrina Müller-Lühlhoff, Dhiraj G Kabra, Zhou Zhou, Christian Binsch, Sonja Hartwig, Stefan Lehr, Alexandra Chadt, Eva M J Peters, Johannes Kruse, Michael Roden, Hadi Al-Hasani, Tamara R Castañeda
OBJECTIVE: Post-traumatic stress disorder (PTSD) increases type 2 diabetes risk, yet the underlying mechanisms are unclear. We investigated how early-life exposure to chronic stress affects long-term insulin sensitivity. METHODS: C57Bl/6J mice were exposed to chronic variable stress for 15 days (Cvs) and then recovered for three months without stress (Cvs3m). RESULTS: Cvs mice showed markedly increased plasma corticosterone and hepatic insulin resistance...
June 20, 2018: Molecular Metabolism
Keizo Kaneko, Maud Soty, Carine Zitoun, Adeline Duchampt, Marine Silva, Erwann Philippe, Amandine Gautier-Stein, Fabienne Rajas, Gilles Mithieux
OBJECTIVE: The respective contributions to endogenous glucose production (EGP) of the liver, kidney and intestine vary during fasting. We previously reported that the deficiency in either hepatic or intestinal gluconeogenesis modulates the repartition of EGP via glucagon secretion (humoral factor) and gut-brain-liver axis (neural factor), respectively. Considering renal gluconeogenesis reportedly accounted for approximately 50% of EGP during fasting, we examined whether a reduction in renal gluconeogenesis could promote alterations in the repartition of EGP in this situation...
June 18, 2018: Molecular Metabolism
Victoria H Cruz, Emily N Arner, Katherine W Wynne, Philipp E Scherer, Rolf A Brekken
OBJECTIVE: TANK Binding Kinase 1 (TBK1) has been implicated in the regulation of metabolism through studies with the drug amlexanox, an inhibitor of the IκB kinase (IKK)-related kinases. Amlexanox induced weight loss, reduced fatty liver and insulin resistance in high fat diet (HFD) fed mice and has now progressed into clinical testing for the treatment and prevention of obesity and type 2 diabetes. However, since amlexanox is a dual IKKε/TBK1 inhibitor, the specific metabolic contribution of TBK1 is not clear...
June 11, 2018: Molecular Metabolism
Anita Patel, Bernardo Yusta, Dianne Matthews, Maureen J Charron, Randy J Seeley, Daniel J Drucker
OBJECTIVE: Therapeutic interventions that improve glucose homeostasis such as attenuation of glucagon receptor (Gcgr) signaling and bariatric surgery share common metabolic features conserved in mice and humans. These include increased circulating levels of bile acids (BA) and the proglucagon-derived peptides (PGDPs), GLP-1 and GLP-2. Whether BA acting through TGR5 (Gpbar1) increases PGDP levels in these scenarios has not been examined. Furthermore, although the importance of GLP-1 action has been interrogated in Gcgr-/- mice and after bariatric surgery, whether GLP-2 contributes to the metabolic benefits of these interventions is not known...
June 9, 2018: Molecular Metabolism
Xu-Yun Zhao, Siming Li, Jennifer L DelProposto, Tongyu Liu, Lin Mi, Cara Porsche, Xiaoling Peng, Carey N Lumeng, Jiandie D Lin
OBJECTIVE: Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of adipocyte differentiation and gene expression. However, their significance in adipose tissue metabolism and physiology has not been demonstrated in vivo. We previously identified Blnc1 as a conserved lncRNA regulator of brown and beige adipocyte differentiation. In this study, we investigated the physiological role of Blnc1 in thermogenesis, adipose remodeling and systemic metabolism. METHODS: We generated fat-specific Blnc1 transgenic and conditional knockout mouse strains and investigated how adipocyte Blnc1 levels are causally linked to key aspects of metabolic health following diet-induced obesity...
June 8, 2018: Molecular Metabolism
Ying Cao, Huanhuan Wang, Qi Wang, Xiangli Han, Wenwen Zeng
OBJECTIVE: The vascular system is central to sustaining tissue survival and homeostasis. Blood vessels are densely present in adipose tissues and exert essential roles in their metabolism. However, conventional immunohistochemistry methods have intrinsic limitations in examining the 3D vascular network in adipose tissues as well as other organs in general. METHODS: We established a 3D volume fluorescence-imaging technique to visualize the vasculatures in mouse adipose tissues by combining the optimized steps of whole-mount immunolabeling, tissue optical clearing, and lightsheet volume fluorescence-imaging...
June 7, 2018: Molecular Metabolism
Flaminia Fanelli, Marco Mezzullo, Andrea Repaci, Ilaria Belluomo, Daniela Ibarra Gasparini, Guido Di Dalmazi, Marianna Mastroroberto, Valentina Vicennati, Alessandra Gambineri, Antonio Maria Morselli-Labate, Renato Pasquali, Uberto Pagotto
OBJECTIVE: N-acylethanolamines play different roles in energy balance; anandamide (AEA) stimulates energy intake and storage, N-palmitoylethanolamide (PEA) counters inflammation, and N-oleoylethanolamide (OEA) mediates anorectic signals and lipid oxidation. Inconsistencies in the association of plasma N-acylethanolamines with human obesity and cardiometabolic risk have emerged among previous studies, possibly caused by heterogeneous cohorts and designs, and by unstandardized N-acylethanolamine measurements...
June 6, 2018: Molecular Metabolism
Susan J Burke, Heidi M Batdorf, David H Burk, Thomas M Martin, Tamra Mendoza, Krisztian Stadler, Wateen Alami, Michael D Karlstad, Matthew J Robson, Randy D Blakely, Randall L Mynatt, J Jason Collier
OBJECTIVE: Pancreatic tissue, and islets in particular, are enriched in expression of the interleukin-1 receptor type I (IL-1R). Because of this enrichment, islet β-cells are exquisitely sensitive to the IL-1R ligands IL-1α and IL-1β, suggesting that signaling through this pathway regulates health and function of islet β-cells. METHODS: Herein, we report a targeted deletion of IL-1R in pancreatic tissue (IL-1RPdx1-/- ) in C57BL/6J mice and in db/db mice on the C57 genetic background...
June 6, 2018: Molecular Metabolism
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