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Molecular Metabolism

Elizabeth M Rhea, Therese S Salameh, Sarah Gray, Jingjing Niu, William A Banks, Jenny Tong
OBJECTIVE: The blood-brain barrier (BBB) regulates the entry of substrates and peptides into the brain. Ghrelin is mainly produced in the stomach but exerts its actions in the central nervous system (CNS) by crossing the BBB. Once present in the CNS, ghrelin can act in the hypothalamus to regulate food intake, in the hippocampus to regulate neurogenesis, and in the olfactory bulb to regulate food-seeking behavior. The goal of this study was to determine whether the primary signaling receptor for ghrelin, the growth hormone secretagogue receptor (GHSR), mediates the transport of ghrelin from blood to brain...
September 24, 2018: Molecular Metabolism
Yukitomo Arao, Katherine J Hamilton, Sydney L Lierz, Kenneth S Korach
OBJECTIVE: Studies using the estrogen receptor alpha (ERα) knock-out (αERKO) mice have demonstrated that ERα plays a crucial role in various estrogen-mediated metabolic regulations. ERα is a ligand dependent transcription regulator and its activity is regulated by estrogenic compounds. ERα consists of two transcriptional activation domains, AF-1 and AF-2. The activities of these domains are regulated through different mechanisms; however, the specific physiological role in metabolic regulation by these domains is still unclear...
September 20, 2018: Molecular Metabolism
Manoj K Gupta, Dario F De Jesus, Sevim Kahraman, Ivan A Valdez, Farnaz Shamsi, Lian Yi, Adam C Swensen, Yu-Hua Tseng, Wei-Jun Qian, Rohit N Kulkarni
OBJECTIVES: Insulin receptor (IR)-mediated signaling is involved in the regulation of pluripotent stem cells; however, its direct effects on regulating the maintenance of pluripotency and lineage development are not fully understood. The main objective of this study is to understand the role of IR signaling in pluripotency and lineage development. METHODS: To explore the role of IR signaling, we generated IR knock-out (IRKO) mouse induced pluripotent stem cells (miPSCs) from E14...
September 19, 2018: Molecular Metabolism
R Gerlini, L Berti, J Darr, M Lassi, S Brandmaier, L Fritsche, F Scheid, A Böhm, A Königsrainer, H Grallert, H U Häring, M Hrabě de Angelis, H Staiger, R Teperino
OBJECTIVE: Although debated, metabolic health characterizes 10-25% of obese individuals and reduces risk of developing life-threatening co-morbidities. Adipose tissue is a recognized endocrine organ important for the maintenance of whole-body metabolic health. Adipocyte transcriptional signatures of healthy and unhealthy obesity are largely unknown. METHODS: Here, we used a small cohort of highly characterized obese individuals discordant for metabolic health, characterized their adipocytes transcriptional signatures, and cross-referenced them to mouse phenotypic and human GWAs databases...
September 19, 2018: Molecular Metabolism
Dagmar Schumacher, Jakob Morgenstern, Yoko Oguchi, Nadine Volk, Stefan Kopf, Jan Benedikt Groener, Peter Paul Nawroth, Thomas Fleming, Marc Freichel
OBJECTIVES: The deficit of Glyoxalase I (Glo1) and the subsequent increase in methylglyoxal (MG) has been reported to be one the five mechanisms by which hyperglycemia causes diabetic late complications. Aldo-keto reductases (AKR) have been shown to metabolize MG; however, the relative contribution of this superfamily to the detoxification of MG in vivo, particularly within the diabetic state, remains unknown. METHODS: CRISPR/Cas9-mediated genome editing was used to generate a Glo1 knock-out (Glo1-/- ) mouse line...
September 19, 2018: Molecular Metabolism
Zoltán Péterfi, Imre Farkas, Raphael G P Denis, Erzsébet Farkas, Motokazu Uchigashima, Tamás Füzesi, Masahiko Watanabe, Ronald M Lechan, Zsolt Liposits, Serge Luquet, Csaba Fekete
OBJECTIVE: Neuropeptide Y (NPY) is one of the most potent orexigenic peptides. The hypothalamic paraventricular nucleus (PVN) is a major locus where NPY exerts its effects on energy homeostasis. We investigated how NPY exerts its effect within the PVN. METHODS: Patch clamp electrophysiology and Ca2+ imaging were used to understand the involvement of Ca2+ signaling and retrograde transmitter systems in the mediation of NPY induced effects in the PVN. Immuno-electron microscopy were performed to elucidate the subcellular localization of the elements of nitric oxide (NO) system in the parvocellular PVN...
September 18, 2018: Molecular Metabolism
Steven J Millership, Simon J Tunster, Mathew Van de Pette, Agharul I Choudhury, Elaine E Irvine, Mark Christian, Amanda G Fisher, Rosalind M John, James Scott, Dominic J Withers
OBJECTIVE: Imprinted genes are crucial for the growth and development of fetal and juvenile mammals. Altered imprinted gene dosage causes a variety of human disorders, with growth and development during these crucial early stages strongly linked with future metabolic health in adulthood. Neuronatin (Nnat) is a paternally expressed imprinted gene found in neuroendocrine systems and white adipose tissue and is regulated by the diet and leptin. Neuronatin expression is downregulated in obese children and has been associated with stochastic obesity in C57BL/6 mice...
September 15, 2018: Molecular Metabolism
Roberta S Santos, Aaron P Frank, Luciana A Fátima, Biff F Palmer, Deborah J Clegg
OBJECTIVES: Brown adipose tissue (BAT) and BAT-like adipose tissues, referred to as 'beige' adipose tissues uncouple respiration from ATP synthesis via uncoupling protein one (UCP-1). There is a sexual dimorphism with respect to beige and BAT tissues; pre-menopausal women have more BAT and are more sensitive to BAT activation than men or postmenopausal women. We hypothesized selective activation of adipose tissue estrogen receptor alpha (ERα) induces beiging of WAT through induction of lipolysis mediated by adipose tissue triglyceride lipase (ATGL)...
September 15, 2018: Molecular Metabolism
Zhenyan He, Yong Gao, Amber L Alhadeff, Carlos M Castorena, Yiru Huang, Linh Lieu, Sadia Afrin, Jia Sun, J Nicholas Betley, Hongbo Guo, Kevin W Williams
OBJECTIVE: Hypothalamic Pro-opiomelanocortin (POMC) and Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons are critical nodes of a circuit within the brain that sense key metabolic cues as well as regulate metabolism. Importantly, these neurons retain an innate ability to rapidly reorganize synaptic inputs and electrophysiological properties in response to metabolic state. While the cellular properties of these neurons have been investigated in the context of obesity, much less is known about the effects of exercise training...
September 12, 2018: Molecular Metabolism
Melanie J Mittenbühler, Hans-Georg Sprenger, Sabine Gruber, Claudia M Wunderlich, Lara Kern, Jens C Brüning, F Thomas Wunderlich
OBJECTIVE: The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options...
September 5, 2018: Molecular Metabolism
Zhencheng Li, Mette Line Rasmussen, Jingwen Li, Carlos Henriquez-Olguin, Jonas Roland Knudsen, Agnete Bjerregaard Madsen, Eva Sanchez-Quant, Maximilian Kleinert, Thomas Elbenhardt Jensen
OBJECTIVE: Chronic ad libitum low protein-high carbohydrate diet (LPHC) increases health- and life-span in mice. A periodized (p) LPHC regimen would be a more practical long-term human lifestyle intervention, but the metabolic benefits of pLPHC are not known. Also, the interactions between LPHC diet and exercise training have not been investigated. Presently, we aimed to provide proof-of-concept data in mice of the efficacy of pLPHC and to explore the potential interactions with concurrent exercise training...
August 28, 2018: Molecular Metabolism
Kathleen Smith, Elnaz Karimian Azari, Traci E LaMoia, Tania Hussain, Veronika Vargova, Katalin Karolyi, Paula P Veldhuis, Juan Pablo Arnoletti, Sebastian G de la Fuente, Richard E Pratley, Timothy F Osborne, George A Kyriazis
OBJECTIVE: Beyond the taste buds, sweet taste receptors (STRs; T1R2/T1R3) are also expressed on enteroendocrine cells, where they regulate gut peptide secretion but their regulatory function within the intestine is largely unknown. METHODS: Using T1R2-knock out (KO) mice we evaluated the role of STRs in the regulation of glucose absorption in vivo and in intact intestinal preparations ex vivo. RESULTS: STR signaling enhances the rate of intestinal glucose absorption specifically in response to the ingestion of a glucose-rich meal...
August 27, 2018: Molecular Metabolism
Peter Kirwan, Richard G Kay, Bas Brouwers, Vicente Herranz-Pérez, Magdalena Jura, Pierre Larraufie, Julie Jerber, Jason Pembroke, Theresa Bartels, Anne White, Fiona M Gribble, Frank Reimann, I Sadaf Farooqi, Stephen O'Rahilly, Florian T Merkle
OBJECTIVE: The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study was to determine which POMC-derived peptides are present in the human brain, to establish their relative concentrations, and to test if their production is dynamically regulated...
August 21, 2018: Molecular Metabolism
Mariana Schroeder, Mira Jakovcevski, Tamar Polacheck, Yonat Drori, Shifra Ben-Dor, Simone Röh, Alon Chen
OBJECTIVE: Vulnerability to eating disorders (EDs) is broadly assumed to be associated with early life stress. However, a careful examination of the literature shows that susceptibility to EDs may depend on the type, severity and timing of the stressor and the sex of the individual. We aimed at exploring the link between chronic prenatal stress and predisposition to EDs and metabolic disease. METHODS: We used a chronic variable stress protocol during gestation to explore the metabolic response of male and female offspring to food restriction (FR), activity-based anorexia (ABA), binge eating (BE) and exposure to high fat (HF) diet...
August 20, 2018: Molecular Metabolism
Belen Rivero-Gutierrez, April Haller, Jenna Holland, Emily Yates, Radha Khrisna, Kirk Habegger, Richard Dimarchi, David D'Alessio, Diego Perez-Tilve
OBJECTIVE: Mice with congenital loss of the glucagon receptor gene (Gcgr-/- mice) remain normoglycemic in insulinopenic conditions, suggesting that unopposed glucagon action is the driving force for hyperglycemia in Type-1 Diabetes Mellitus (T1DM). However, chronic loss of GCGR results in a neomorphic phenotype that includes hormonal signals with hypoglycemic activity. We combined temporally-controlled GCGR deletion with pharmacological treatments to dissect the direct contribution of GCGR signaling to glucose control in a common mouse model of T1DM...
August 20, 2018: Molecular Metabolism
Sabine Daemen, Anne Gemmink, Bram Brouwers, Ruth C R Meex, Peter R Huntjens, Gert Schaart, Esther Moonen-Kornips, Johanna Jörgensen, Joris Hoeks, Patrick Schrauwen, Matthijs K C Hesselink
OBJECTIVE: Intramyocellular lipid (IMCL) storage negatively associates with insulin resistance, albeit not in endurance-trained athletes. We investigated the putative contribution of lipid droplet (LD) morphology and subcellular localization to the so-called athlete's paradox. METHODS: We performed quantitative immunofluorescent confocal imaging of muscle biopsy sections from endurance Trained, Lean sedentary, Obese, and Type 2 diabetes (T2DM) participants (n = 8/group)...
August 18, 2018: Molecular Metabolism
Ali J Chakera, Paul S Hurst, Gill Spyer, Emmanuel O Ogunnowo-Bada, William J Marsh, Christine H Riches, Chen-Yu Yueh, S Pauliina Markkula, Jeffrey W Dalley, Roger D Cox, Ian A Macdonald, Stephanie A Amiel, Kenneth M MacLeod, Lora K Heisler, Andrew T Hattersley, Mark L Evans
OBJECTIVE: Appropriate glucose levels are essential for survival; thus, the detection and correction of low blood glucose is of paramount importance. Hypoglycemia prompts an integrated response involving reduction in insulin release and secretion of key counter-regulatory hormones glucagon and epinephrine that together promote endogenous glucose production to restore normoglycemia. However, specifically how this response is orchestrated remains to be fully clarified. The low affinity hexokinase glucokinase is found in glucose-sensing cells involved in glucose homeostasis including pancreatic β-cells and in certain brain areas...
August 13, 2018: Molecular Metabolism
Yusuke Adachi, Ana Luisa De Sousa-Coelho, Ikue Harata, Charlie Aoun, Sandra Weimer, Xu Shi, Karina N Gonzalez Herrera, Hirokazu Takahashi, Chris Doherty, Yasushi Noguchi, Laurie J Goodyear, Marcia C Haigis, Robert E Gerszten, Mary-Elizabeth Patti
OBJECTIVE: AMP activated protein kinase (AMPK) is recognized as an important nutrient sensor contributing to regulation of cellular, tissue, and systemic metabolism. We aimed to identify specific amino acids which could modulate AMPK and determine effects on cellular and systemic metabolism. METHODS: We performed an unbiased amino acid screen to identify activators of AMPK. Detailed analysis of cellular signaling and metabolism was performed in cultured hepatoma cells, and in vivo glucose metabolism and metabolomic patterns were assessed in both chow-fed mice and mice made obese by high-fat diet feeding...
August 11, 2018: Molecular Metabolism
Fanny Langlet, Marcel Tarbier, Rebecca A Haeusler, Stefania Camastra, Eleuterio Ferrannini, Marc R Friedländer, Domenico Accili
OBJECTIVES: Hepatic insulin resistance is a hallmark of type 2 diabetes and obesity. Insulin receptor signaling through AKT and FOXO has important metabolic effects that have traditionally been ascribed to regulation of gene expression. However, whether all the metabolic effects of FOXO arise from its regulation of protein-encoding mRNAs is unknown. METHODS: To address this question, we obtained expression profiles of FOXO-regulated murine hepatic microRNAs (miRNAs) during fasting and refeeding using mice lacking Foxo1, 3a, and 4 in liver (L-Foxo1,3a, 4)...
August 11, 2018: Molecular Metabolism
Bernard P Kok, Andrea Galmozzi, Nicole K Littlejohn, Verena Albert, Cristina Godio, Woojoo Kim, Sean M Kim, Jeffrey S Bland, Neile Grayson, Mingliang Fang, Wolfgang Meyerhof, Gary Siuzdak, Supriya Srinivasan, Maik Behrens, Enrique Saez
OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1)...
August 4, 2018: Molecular Metabolism
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