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Cell Metabolism

Li-Hao Huang, Bernd H Zinselmeyer, Chih-Hao Chang, Brian T Saunders, Andrew Elvington, Osamu Baba, Thomas J Broekelmann, Lina Qi, Joseph S Rueve, Melody A Swartz, Brian S Kim, Robert P Mecham, Helge Wiig, Michael J Thomas, Mary G Sorci-Thomas, Gwendalyn J Randolph
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries...
November 5, 2018: Cell Metabolism
Lillian J Eichner, Sonja N Brun, Sébastien Herzig, Nathan P Young, Stephanie D Curtis, David B Shackelford, Maxim N Shokhirev, Mathias Leblanc, Liliana I Vera, Amanda Hutchins, Debbie S Ross, Reuben J Shaw, Robert U Svensson
AMPK, a conserved sensor of low cellular energy, can either repress or promote tumor growth depending on the context. However, no studies have examined AMPK function in autochthonous genetic mouse models of epithelial cancer. Here, we examine the role of AMPK in murine KrasG12D -mediated non-small-cell lung cancer (NSCLC), a cancer type in humans that harbors frequent inactivating mutations in the LKB1 tumor suppressor-the predominant upstream activating kinase of AMPK and 12 related kinases. Unlike LKB1 deletion, AMPK deletion in KrasG12D lung tumors did not accelerate lung tumor growth...
November 5, 2018: Cell Metabolism
Jakob G Knudsen, Alexander Hamilton, Reshma Ramracheya, Andrei I Tarasov, Melissa Brereton, Elizabeth Haythorne, Margarita V Chibalina, Peter Spégel, Hindrik Mulder, Quan Zhang, Frances M Ashcroft, Julie Adam, Patrik Rorsman
Diabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion...
November 1, 2018: Cell Metabolism
Elodie M Varin, Erin E Mulvihill, Jacqueline L Beaudry, Gemma Pujadas, Shai Fuchs, Jean-François Tanti, Sofia Fazio, Kirandeep Kaur, Xiemin Cao, Laurie L Baggio, Dianne Matthews, Jonathan E Campbell, Daniel J Drucker
Dipeptidyl peptidase-4 (DPP-4) controls glucose homeostasis through enzymatic termination of incretin action. We report that plasma DPP-4 activity correlates with body weight and fat mass, but not glucose control, in mice. Genetic disruption of adipocyte Dpp4 expression reduced plasma DPP-4 activity in older mice but did not perturb incretin levels or glucose homeostasis. Knockdown of hepatocyte Dpp4 completely abrogated the obesity-associated increase in plasma DPP-4 activity, reduced liver cytokine expression, and partially attenuated inflammation in adipose tissue without changes in incretin levels or glucose homeostasis...
October 26, 2018: Cell Metabolism
Selin Neseliler, Wen Hu, Kevin Larcher, Maria Zacchia, Mahsa Dadar, Stephanie G Scala, Marie Lamarche, Yashar Zeighami, Stephen C Stotland, Maurice Larocque, Errol B Marliss, Alain Dagher
Insufficient responses to hypocaloric diets have been attributed to hormonal adaptations that override self-control of food intake. We tested this hypothesis by measuring circulating energy-balance hormones and brain functional magnetic resonance imaging reactivity to food cues in 24 overweight/obese participants before, and 1 and 3 months after starting a calorie restriction diet. Increased activity and functional connectivity in prefrontal regions at month 1 correlated with weight loss at months 1 and 3...
October 15, 2018: Cell Metabolism
Alessandro Scopelliti, Christin Bauer, Yachuan Yu, Tong Zhang, Björn Kruspig, Daniel J Murphy, Marcos Vidal, Oliver D K Maddocks, Julia B Cordero
The control of systemic metabolic homeostasis involves complex inter-tissue programs that coordinate energy production, storage, and consumption, to maintain organismal fitness upon environmental challenges. The mechanisms driving such programs are largely unknown. Here, we show that enteroendocrine cells in the adult Drosophila intestine respond to nutrients by secreting the hormone Bursicon α, which signals via its neuronal receptor DLgr2. Bursicon α/DLgr2 regulate energy metabolism through a neuronal relay leading to the restriction of glucagon-like, adipokinetic hormone (AKH) production by the corpora cardiaca and subsequent modulation of AKH receptor signaling within the adipose tissue...
October 15, 2018: Cell Metabolism
Benjamin D Weger, Cédric Gobet, Jake Yeung, Eva Martin, Sonia Jimenez, Bertrand Betrisey, Francis Foata, Bernard Berger, Aurélie Balvay, Anne Foussier, Aline Charpagne, Brigitte Boizet-Bonhoure, Chieh Jason Chou, Felix Naef, Frédéric Gachon
The circadian clock and associated feeding rhythms have a profound impact on metabolism and the gut microbiome. To what extent microbiota reciprocally affect daily rhythms of physiology in the host remains elusive. Here, we analyzed transcriptome and metabolome profiles of male and female germ-free mice. While mRNA expression of circadian clock genes revealed subtle changes in liver, intestine, and white adipose tissue, germ-free mice showed considerably altered expression of genes associated with rhythmic physiology...
October 15, 2018: Cell Metabolism
Lingyun Li, Xia Liu, Katherine L Sanders, James L Edwards, Jian Ye, Fusheng Si, Aiqin Gao, Lan Huang, Eddy C Hsueh, David A Ford, Daniel F Hoft, Guangyong Peng
Regulatory T (Treg) cells induce an immunosuppressive microenvironment that is a major obstacle for successful tumor immunotherapy. Dissecting the regulatory mechanisms between energy metabolism and functionality in Treg cells will provide insight toward developing novel immunotherapies against cancer. Here we report that human naturally occurring and tumor-associated Treg cells exhibit distinct metabolic profiles with selectivity for glucose metabolism compared with effector T cells. Treg-mediated accelerated glucose consumption induces cellular senescence and suppression of responder T cells through cross-talk...
October 13, 2018: Cell Metabolism
Saul Soberanes, Alexander V Misharin, Amit Jairaman, Luisa Morales-Nebreda, Alexandra C McQuattie-Pimentel, Takugo Cho, Robert B Hamanaka, Angelo Y Meliton, Paul A Reyfman, James M Walter, Ching-I Chen, Monica Chi, Stephen Chiu, Francisco J Gonzalez-Gonzalez, Matthew Antalek, Hiam Abdala-Valencia, Sergio E Chiarella, Kaitlyn A Sun, Parker S Woods, Andrew J Ghio, Manu Jain, Harris Perlman, Karen M Ridge, Richard I Morimoto, Jacob I Sznajder, William E Balch, Sangeeta M Bhorade, Ankit Bharat, Murali Prakriya, Navdeep S Chandel, Gökhan M Mutlu, G R Scott Budinger
Urban particulate matter air pollution induces the release of pro-inflammatory cytokines including interleukin-6 (IL-6) from alveolar macrophages, resulting in an increase in thrombosis. Here, we report that metformin provides protection in this murine model. Treatment of mice with metformin or exposure of murine or human alveolar macrophages to metformin prevented the particulate matter-induced generation of complex III mitochondrial reactive oxygen species, which were necessary for the opening of calcium release-activated channels (CRAC) and release of IL-6...
October 11, 2018: Cell Metabolism
Elizabeth T Cirulli, Lining Guo, Christine Leon Swisher, Naisha Shah, Lei Huang, Lori A Napier, Ewen F Kirkness, Tim D Spector, C Thomas Caskey, Bernard Thorens, J Craig Venter, Amalio Telenti
Obesity is a heterogeneous phenotype that is crudely measured by body mass index (BMI). There is a need for a more precise yet portable method of phenotyping and categorizing risk in large numbers of people with obesity to advance clinical care and drug development. Here, we used non-targeted metabolomics and whole-genome sequencing to identify metabolic and genetic signatures of obesity. We find that obesity results in profound perturbation of the metabolome; nearly a third of the assayed metabolites associated with changes in BMI...
October 8, 2018: Cell Metabolism
Amanda E Brandon, Bing M Liao, Barbara Diakanastasis, Benjamin L Parker, Katy Raddatz, Sophie A McManus, Liam O'Reilly, Erica Kimber, A Gabrielle van der Kraan, Dale Hancock, Darren C Henstridge, Peter J Meikle, Gregory J Cooney, David E James, Saskia Reibe, Mark A Febbraio, Trevor J Biden, Carsten Schmitz-Peiffer
Protein kinase C epsilon (PKCɛ) activation in the liver is proposed to inhibit insulin action through phosphorylation of the insulin receptor. Here, however, we demonstrated that global, but not liver-specific, deletion of PKCɛ in mice protected against diet-induced glucose intolerance and insulin resistance. Furthermore, PKCɛ-dependent alterations in insulin receptor phosphorylation were not detected. Adipose-tissue-specific knockout mice did exhibit improved glucose tolerance, but phosphoproteomics revealed no PKCɛ-dependent effect on the activation of insulin signaling pathways...
October 8, 2018: Cell Metabolism
Claudiane Guay, Janine K Kruit, Sophie Rome, Véronique Menoud, Niels L Mulder, Angelika Jurdzinski, Francesca Mancarella, Guido Sebastiani, Alena Donda, Bryan J Gonzalez, Camilla Jandus, Karim Bouzakri, Michel Pinget, Christian Boitard, Pedro Romero, Francesco Dotta, Romano Regazzi
Type 1 diabetes is an autoimmune disease initiated by the invasion of pancreatic islets by immune cells that selectively kill the β cells. We found that rodent and human T lymphocytes release exosomes containing the microRNAs (miRNAs) miR-142-3p, miR-142-5p, and miR-155, which can be transferred in active form to β cells favoring apoptosis. Inactivation of these miRNAs in recipient β cells prevents exosome-mediated apoptosis and protects non-obese diabetic (NOD) mice from diabetes development. Islets from protected NOD mice display higher insulin levels, lower insulitis scores, and reduced inflammation...
October 5, 2018: Cell Metabolism
Alessandra Misto, Gustavo Provensi, Valentina Vozella, Maria Beatrice Passani, Daniele Piomelli
The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). Here, we present evidence that mast cells contribute to the control of fasting-induced ketogenesis via a paracrine mechanism that involves secretion of histamine into the hepatic portal circulation, stimulation of liver H1 receptors, and local biosynthesis of the high-affinity PPAR-α agonist, oleoylethanolamide (OEA)...
October 4, 2018: Cell Metabolism
Jorge Domínguez-Andrés, Boris Novakovic, Yang Li, Brendon P Scicluna, Mark S Gresnigt, Rob J W Arts, Marije Oosting, Simone J C F M Moorlag, Laszlo A Groh, Jelle Zwaag, Rebecca M Koch, Rob Ter Horst, Leo A B Joosten, Cisca Wijmenga, Alessandro Michelucci, Tom van der Poll, Matthijs Kox, Peter Pickkers, Vinod Kumar, Henk Stunnenberg, Mihai G Netea
Sepsis involves simultaneous hyperactivation of the immune system and immune paralysis, leading to both organ dysfunction and increased susceptibility to secondary infections. Acute activation of myeloid cells induced itaconate synthesis, which subsequently mediated innate immune tolerance in human monocytes. In contrast, induction of trained immunity by β-glucan counteracted tolerance induced in a model of human endotoxemia by inhibiting the expression of immune-responsive gene 1 (IRG1), the enzyme that controls itaconate synthesis...
October 1, 2018: Cell Metabolism
Ben C King, Klaudia Kulak, Ulrika Krus, Rebecca Rosberg, Ewelina Golec, Katarzyna Wozniak, Maria F Gomez, Enming Zhang, David J O'Connell, Erik Renström, Anna M Blom
We show here that human pancreatic islets highly express C3, which is both secreted and present in the cytosol. Within isolated human islets, C3 expression correlates with type 2 diabetes (T2D) donor status, HbA1c, and inflammation. Islet C3 expression is also upregulated in several rodent diabetes models. C3 interacts with ATG16L1, which is essential for autophagy. Autophagy relieves cellular stresses faced by β cells during T2D and maintains cellular homeostasis. C3 knockout in clonal β cells impaired autophagy and led to increased apoptosis after exposure of cells to palmitic acid and IAPP...
October 1, 2018: Cell Metabolism
Enming Zhang, Israa Mohammed Al-Amily, Sarheed Mohammed, Cheng Luan, Olof Asplund, Meftun Ahmed, Yingying Ye, Danya Ben-Hail, Arvind Soni, Neelanjan Vishnu, Pradeep Bompada, Yang De Marinis, Leif Groop, Varda Shoshan-Barmatz, Erik Renström, Claes B Wollheim, Albert Salehi
Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP-conducting mitochondrial outer membrane voltage-dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This is caused by a glucotoxicity-induced transcriptional program, triggered during years of prediabetes with suboptimal blood glucose control. Metformin counteracts VDAC1 induction. VDAC1 overexpression causes its mistargeting to the plasma membrane of the insulin-secreting β cells with loss of the crucial metabolic coupling factor ATP...
October 1, 2018: Cell Metabolism
Thomas Bertero, William M Oldham, Eloise M Grasset, Isabelle Bourget, Etienne Boulter, Sabrina Pisano, Paul Hofman, Floriant Bellvert, Guerrino Meneguzzi, Dmitry V Bulavin, Soline Estrach, Chloe C Feral, Stephen Y Chan, Alexandre Bozec, Cedric Gaggioli
Dysregulation of extracellular matrix (ECM) deposition and cellular metabolism promotes tumor aggressiveness by sustaining the activity of key growth, invasion, and survival pathways. Yet mechanisms by which biophysical properties of ECM relate to metabolic processes and tumor progression remain undefined. In both cancer cells and carcinoma-associated fibroblasts (CAFs), we found that ECM stiffening mechanoactivates glycolysis and glutamine metabolism and thus coordinates non-essential amino acid flux within the tumor niche...
September 28, 2018: Cell Metabolism
Sahar Ashrafzadeh, Osama Hamdy
The growing burden of diabetes is fueled by obesity-inducing lifestyle behaviors including high-calorie diets and lack of physical activity. Challenges in access to diabetes specialists and educators, low adherence to medications, and inadequate motivational support for proper disease self-management contribute to poor glycemic control in patients with diabetes. Simultaneously, high patient volumes and low reimbursement rates limit physicians' time spent on lifestyle behavior counseling. These barriers to efficient diabetes care lead to high rates of diabetes-related complications, driving healthcare costs up and reducing the quality of patients' lives...
September 20, 2018: Cell Metabolism
Anne-Marie Lundsgaard, Jacob B Holm, Kim A Sjøberg, Kirstine N Bojsen-Møller, Lene S Myrmel, Even Fjære, Benjamin A H Jensen, Trine S Nicolaisen, Janne R Hingst, Sine L Hansen, Sophia Doll, Philip E Geyer, Atul S Desmukh, Jens J Holst, Lise Madsen, Karsten Kristiansen, Jørgen F P Wojtaszewski, Erik A Richter, Bente Kiens
Prolonged intervention studies investigating molecular metabolism are necessary for a deeper understanding of dietary effects on health. Here we provide mechanistic information about metabolic adaptation to fat-rich diets. Healthy, slightly overweight men ingested saturated or polyunsaturated fat-rich diets for 6 weeks during weight maintenance. Hyperinsulinemic clamps combined with leg balance technique revealed unchanged peripheral insulin sensitivity, independent of fatty acid type. Both diets increased fat oxidation potential in muscle...
September 20, 2018: Cell Metabolism
Vasilis Ntziachristos, Miguel A Pleitez, Silvio Aime, Kevin M Brindle
Due to the implication of altered metabolism in a large spectrum of tissue function and disease, assessment of metabolic processes becomes essential in managing health. In this regard, imaging can play a critical role in allowing observation of biochemical and physiological processes. Nuclear imaging methods, in particular positron emission tomography, have been widely employed for imaging metabolism but are mainly limited by the use of ionizing radiation and the sensing of only one parameter at each scanning session...
September 19, 2018: Cell Metabolism
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