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Molecular Metabolism

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https://www.readbyqxmd.com/read/28271037/cholinergic-neurons-in-the-dorsomedial-hypothalamus-regulate-food-intake
#1
Jae Hoon Jeong, Dong Kun Lee, Young-Hwan Jo
OBJECTIVE: Central cholinergic neural circuits play a role in the regulation of feeding behavior. The dorsomedial hypothalamus (DMH) is considered the appetite-stimulating center and contains cholinergic neurons. Here, we study the role of DMH cholinergic neurons in the control of food intake. METHODS: To selectively stimulate DMH cholinergic neurons, we expressed stimulatory designer receptors exclusively activated by designer drugs (DREADDs) and channelrhodopsins in DMH cholinergic neurons by injection of adeno-associated virus (AAV) vectors into the DMH of choline acetyltransferase (ChAT)-IRES-Cre mice...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271036/functional-and-clinical-relevance-of-novel-and-known-pcsk1-variants-for-childhood-obesity-and-glucose-metabolism
#2
Dennis Löffler, Susanne Behrendt, John W M Creemers, Jürgen Klammt, Gabriela Aust, Juraj Stanik, Wieland Kiess, Peter Kovacs, Antje Körner
OBJECTIVE: Variants in Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1) may be causative for obesity as suggested by monogenic cases and association studies. Here we assessed the functional relevance in experimental studies and the clinical relevance through detailed metabolic phenotyping of newly identified and known PCSK1 variants in children. RESULTS: In 52 obese children selected for elevated proinsulin levels and/or impaired glucose tolerance, we found eight known variants and two novel heterozygous variants (c...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271035/attenuated-secretion-of-glucose-dependent-insulinotropic-polypeptide-gip-does-not-alleviate-hyperphagic-obesity-and-insulin-resistance-in-ob-ob-mice
#3
Satoko Shimazu-Kuwahara, Norio Harada, Shunsuke Yamane, Erina Joo, Akiko Sankoda, Timothy J Kieffer, Nobuya Inagaki
OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lep(ob/ob)) mice. METHODS: We crossbred GIP-GFP knock-in homozygous mice (GIP(gfp/gfp)) that have complete GIP knockout, and mice heterozygous for the ob mutation (Lep(ob/+)) mice to generate Lep(ob/+)/GIP(+/+), Lep(ob/ob)/GIP(+/+), and Lep(ob/ob)/GIP(gfp/gfp) mice...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271034/divergent-effects-of-a-designer-natriuretic-peptide-cd-np-in-the-regulation-of-adipose-tissue-and-metabolism
#4
Anja Glöde, Jennifer Naumann, Thorsten Gnad, Valentina Cannone, Ana Kilic, John C Burnett, Alexander Pfeifer
OBJECTIVE: Obesity is defined as an abnormal increase in white adipose tissue (WAT) and is a major risk factor for type 2 diabetes and cardiovascular disease. Brown adipose tissue (BAT) dissipates energy and correlates with leanness. Natriuretic peptides have been shown to be beneficial for brown adipocyte differentiation and browning of WAT. METHODS: Here, we investigated the effects of an optimized designer natriuretic peptide (CD-NP) on murine adipose tissues in vitro and in vivo...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271033/inducible-overexpression-of-adiponectin-receptors-highlight-the-roles-of-adiponectin-induced-ceramidase-signaling-in-lipid-and-glucose-homeostasis
#5
William L Holland, Jonathan Y Xia, Joshua A Johnson, Kai Sun, Mackenzie J Pearson, Ankit X Sharma, Ezekiel Quittner-Strom, Trevor S Tippetts, Ruth Gordillo, Philipp E Scherer
OBJECTIVE: Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling. METHODS: Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271032/bezafibrate-ameliorates-diabetes-via-reduced-steatosis-and-improved-hepatic-insulin-sensitivity-in-diabetic-tallyho-mice
#6
Andras Franko, Susanne Neschen, Jan Rozman, Birgit Rathkolb, Michaela Aichler, Annette Feuchtinger, Laura Brachthäuser, Frauke Neff, Marketa Kovarova, Eckhard Wolf, Helmut Fuchs, Hans-Ulrich Häring, Andreas Peter, Martin Hrabě de Angelis
OBJECTIVE: Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. METHODS: TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271031/enteroendocrine-derived-glucagon-like-peptide-2-controls-intestinal-amino-acid-transport
#7
Jennifer Lee, Jacqueline Koehler, Bernardo Yusta, Jasmine Bahrami, Dianne Matthews, Mahroukh Rafii, Paul B Pencharz, Daniel J Drucker
OBJECTIVE: Glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 from gut endocrine cells, and both peptides act as growth factors to expand the surface area of the mucosal epithelium. Notably, GLP-2 also enhances glucose and lipid transport in enterocytes; however, its actions on control of amino acid (AA) transport remain unclear. Here we examined the mechanisms linking gain and loss of GLP-2 receptor (GLP-2R) signaling to control of intestinal amino acid absorption in mice. METHODS: Absorption, transport, and clearance of essential AAs, specifically lysine, were measured in vivo by Liquid Chromatography triple quadrupole Mass Spectrometry (LC-MS/MS) and ex vivo with Ussing chambers using intestinal preparations from Glp2r(+/+) and Glp2r(-/-) mice...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271030/high-fidelity-glucagon-creer-mouse-line-generated-by-crispr-cas9-assisted-gene-targeting
#8
Amanda M Ackermann, Jia Zhang, Aryel Heller, Anna Briker, Klaus H Kaestner
OBJECTIVE: α-cells are the second most prominent cell type in pancreatic islets and are responsible for producing glucagon to increase plasma glucose levels in times of fasting. α-cell dysfunction and inappropriate glucagon secretion occur in both type 1 and type 2 diabetes. Thus, there is growing interest in studying both normal function and pathophysiology of α-cells. However, tools to target gene ablation or activation specifically of α-cells have been limited, compared to those available for β-cells...
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28271029/adiponectin-serenades-ceramidase-to-improve-metabolism
#9
Saskia Reibe-Pal, Mark A Febbraio
No abstract text is available yet for this article.
March 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180064/dipeptidyl-peptidase-4-inhibitor-treatment-induces-a-greater-increase-in-plasma-levels-of-bioactive-gip-than-glp-1-in-non-diabetic-subjects
#10
Tsuyoshi Yanagimachi, Yukihiro Fujita, Yasutaka Takeda, Jun Honjo, Hidemitsu Sakagami, Hiroya Kitsunai, Yumi Takiyama, Atsuko Abiko, Yuichi Makino, Timothy J Kieffer, Masakazu Haneda
OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) possess multiple bioactive isoforms that are rendered non-insulinotropic by the enzyme dipeptidyl peptidase-4 (DPP-4). Recently, some ELISA kits have been developed to specifically measure "active" GIP and GLP-1, but it is unclear if these kits can accurately quantify all bioactive forms. Therefore, it remains uncertain to what extent treatment with a DPP-4 inhibitor boosts levels of biologically active GIP and GLP-1...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180063/carnitine-acetyltransferase-crat-expression-in-macrophages-is-dispensable-for-nutrient-stress-sensing-and-inflammation
#11
Emily L Goldberg, Vishwa Deep Dixit
OBJECTIVE: Fatty acid oxidation in macrophages is thought to regulate inflammatory status and insulin-sensitivity. An important unanswered question in this field is whether carnitine acetyl-transferase (CrAT) that regulates fatty acid oxidation and mitochondrial acetyl-CoA balance is required to integrate nutrient stress sensing to inflammatory response in macrophages. METHODS: Mice with myeloid lineage-specific Crat deletion were subjected to several metabolic stressors, including high-fat diet-induced obesity, fasting, and LPS-induced endotoxemia...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180062/blocking-inos-and-endoplasmic-reticulum-stress-synergistically-improves-insulin-resistance-in-mice
#12
Tamires M Zanotto, Paula G F Quaresma, Dioze Guadagnini, Lais Weissmann, Andressa C Santos, Juliana F Vecina, Kelly Calisto, Andrey Santos, Patrícia O Prada, Mario J A Saad
OBJECTIVE: Recent data show that iNOS has an essential role in ER stress in obesity. However, whether iNOS is sufficient to account for obesity-induced ER stress and Unfolded Protein Response (UPR) has not yet been investigated. In the present study, we used iNOS knockout mice to investigate whether high-fat diet (HFD) can still induce residual ER stress-associated insulin resistance. METHODS: For this purpose, we used the intraperitoneal glucose tolerance test (GTT), euglycemic-hyperinsulinemic clamp, western blotting and qPCR in liver, muscle, and adipose tissue of iNOS KO and control mice on HFD...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180061/kinase-suppressor-of-ras-2-ksr2-expression-in-the-brain-regulates-energy-balance-and-glucose-homeostasis
#13
Lili Guo, Diane L Costanzo-Garvey, Deandra R Smith, Beth K Neilsen, Richard G MacDonald, Robert E Lewis
OBJECTIVE: Kinase Suppressor of Ras 2 (KSR2) is a molecular scaffold coordinating Raf/MEK/ERK signaling that is expressed at high levels in the brain. KSR2 disruption in humans and mice causes obesity and insulin resistance. Understanding the anatomical location and mechanism of KSR2 function should lead to a better understanding of physiological regulation over energy balance. METHODS: Mice bearing floxed alleles of KSR2 (KSR2(fl/fl)) were crossed with mice expressing the Cre recombinase expressed by the Nestin promoter (Nes-Cre) to produce Nes-CreKSR2(fl/fl) mice...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180060/gprc6a-jack-of-all-metabolism-or-master-of-none
#14
REVIEW
Min Pi, Satoru Kenneth Nishimoto, L Darryl Quarles
BACKGROUND: GPRC6A, a widely expressed G-protein coupled receptor, is proposed to be a master regulator of complex endocrine networks and metabolic processes. GPRC6A is activated by multiple ligands, including osteocalcin (Ocn), testosterone (T), basic amino acids, and various cations. SCOPE OF REVIEW: We review the controversy surrounding GPRC6A functions. In mice, GPRC6A is proposed to integrate metabolic functions through the coordinated secretion of hormones, including insulin, GLP-1, T, and IL-6, and direct effects of this receptor to control glucose and fat metabolism in the liver, skeletal muscle, and fat...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180059/jnk-at-the-crossroad-of-obesity-insulin-resistance-and-cell-stress-response
#15
REVIEW
Giovanni Solinas, Barbara Becattini
BACKGROUND: The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity...
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28180058/leptin-deficient-mice-are-not-hypothermic-they-are-anapyrexic
#16
Alexander W Fischer, Barbara Cannon, Jan Nedergaard
No abstract text is available yet for this article.
February 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28123946/endospanin1-affects-oppositely-body-weight-regulation-and-glucose-homeostasis-by-differentially-regulating-central-leptin-signaling
#17
Virginie Vauthier, Clara Roujeau, Patty Chen, Chamsy Sarkis, Stéphanie Migrenne, Toru Hosoi, Koichiro Ozawa, Yves Rouillé, Marc Foretz, Jacques Mallet, Jean-Marie Launay, Christophe Magnan, Ralf Jockers, Julie Dam
The hypothalamic arcuate nucleus (ARC) is a major integration center for energy and glucose homeostasis that responds to leptin. Resistance to leptin in the ARC is an important component of the development of obesity and type 2 diabetes. Recently, we showed that Endospanin1 (Endo1) is a negative regulator of the leptin receptor (OBR) that interacts with OBR and retains the receptor inside the cell, leading to a decreased activation of the anorectic STAT3 pathway. Endo1 is up-regulated in the ARC of high fat diet (HFD)-fed mice, and its silencing in the ARC of lean and obese mice prevents and reverses the development of obesity...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28123945/the-neuropeptide-tlqp-21-opposes-obesity-via%C3%A2-c3ar1-mediated-enhancement-of-adrenergic-induced-lipolysis
#18
Cheryl Cero, Maria Razzoli, Ruijun Han, Bhavani Shankar Sahu, Jessica Patricelli, ZengKui Guo, Nathan A Zaidman, John M Miles, Scott M O'Grady, Alessandro Bartolomucci
OBJECTIVES: Obesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity-associated diseases...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28123944/celastrol-ameliorates-liver-metabolic-damage-caused-by-a-high-fat-diet-through-sirt1
#19
Yinliang Zhang, Chao Geng, Xiaoyan Liu, Meixia Li, Mingyue Gao, Xiaojun Liu, Fude Fang, Yongsheng Chang
OBJECTIVE: Celastrol was recently identified as a potential novel treatment for obesity. However, the effect of Celastrol on nonalcoholic fatty liver disease (NAFLD) remains elusive. The aim of this study is to evaluate the role of Celastrol in NAFLD. METHODS: Functional studies were performed using wild-type C57BL/6J (WT) mice and liver specific Sirt1-deficient (LKO) mice. The molecular mechanism was explored in primary mouse liver and primary hepatocytes. RESULTS: When WT mice receiving a high-fat diet (HFD) were treated with Celastrol, reductions in body weight, subcutaneous and visceral fat content, and liver lipid droplet formation were observed, along with reduced hepatic intracellular triglyceride and serum triglyceride, free fatty acid, and ALT concentrations...
January 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/28123943/systemic-insulin-sensitivity-is-regulated-by-gps2-inhibition-of-akt-ubiquitination-and-activation-in-adipose-tissue
#20
Carly T Cederquist, Claudia Lentucci, Camila Martinez-Calejman, Vanessa Hayashi, Joseph Orofino, David Guertin, Susan K Fried, Mi-Jeong Lee, M Dafne Cardamone, Valentina Perissi
OBJECTIVE: Insulin signaling plays a unique role in the regulation of energy homeostasis and the impairment of insulin action is associated with altered lipid metabolism, obesity, and Type 2 Diabetes. The main aim of this study was to provide further insight into the regulatory mechanisms governing the insulin signaling pathway by investigating the role of non-proteolytic ubiquitination in insulin-mediated activation of AKT. METHODS: The molecular mechanism of AKT regulation through ubiquitination is first dissected in vitro in 3T3-L1 preadipocytes and then validated in vivo using mice with adipo-specific deletion of GPS2, an endogenous inhibitor of Ubc13 activity (GPS2-AKO mice)...
January 2017: Molecular Metabolism
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