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Molecular Metabolism

Mohamad-Reza Aghanoori, Darrell R Smith, Shiva Shariati-Ievari, Andrew Ajisebutu, Annee Nguyen, Fiona Desmond, Carlos H A Jesus, Xiajun Zhou, Nigel A Calcutt, Michel Aliani, Paul Fernyhough
OBJECTIVE: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN...
November 28, 2018: Molecular Metabolism
Lorena López-Ferreras, Kim Eerola, Devesh Mishra, Olesya T Shevchouk, Jennifer E Richard, Fredrik H Nilsson, Matthew R Hayes, Karolina P Skibicka
OBJECTIVE: The supramammillary nucleus (SuM) is nestled between the lateral hypothalamus (LH) and the ventral tegmental area (VTA). This neuroanatomical position is consistent with a potential role of this nucleus to regulate ingestive and motivated behavior. Here neuroanatomical, molecular, and behavior approaches are utilized to determine whether SuM contributes to ingestive and food-motivated behavior control. METHODS: Through the application of anterograde and retrograde neural tract tracing with novel designer viral vectors, the current findings show that SuM neurons densely innervate the LH in a sex dimorphic fashion...
November 27, 2018: Molecular Metabolism
Michaela Keuper, Lucia Berti, Bernhard Raedle, Stephan Sachs, Anja Böhm, Louise Fritsche, Andreas Fritsche, Hans-Ulrich Häring, Martin Hrabě de Angelis, Martin Jastroch, Susanna M Hofmann, Harald Staiger
BACKGROUND/OBJECTIVES: Although the prevalence of obesity and its associated metabolic disorders is increasing in both sexes, the clinical phenotype differs between men and women, highlighting the need for individual treatment options. Mitochondrial dysfunction in various tissues, including white adipose tissue (WAT), has been accepted as a key factor for obesity-associated comorbidities such as diabetes. Given higher expression of mitochondria-related genes in the WAT of women, we hypothesized that gender differences in the bioenergetic profile of white (pre-) adipocytes from obese (age- and BMI-matched) donors must exist...
November 26, 2018: Molecular Metabolism
Benjamin P Tooke, Hui Yu, Jessica M Adams, Graham L Jones, Talisha Sutton-Kennedy, Lakshmi Mundada, Nathan R Qi, Malcolm J Low, Kavaljit H Chhabra
OBJECTIVE: Life-threatening hypoglycemia is a major limiting factor in the management of diabetes. While it is known that counterregulatory responses to hypoglycemia are impaired in diabetes, molecular mechanisms underlying the reduced responses remain unclear. Given the established roles of the hypothalamic proopiomelanocortin (POMC)/melanocortin 4 receptor (MC4R) circuit in regulating sympathetic nervous system (SNS) activity and the SNS in stimulating counterregulatory responses to hypoglycemia, we hypothesized that hypothalamic POMC as well as MC4R, a receptor for POMC derived melanocyte stimulating hormones, is required for normal hypoglycemia counterregulation...
November 20, 2018: Molecular Metabolism
Yury O Nunez Lopez, Ravi Retnakaran, Bernard Zinman, Richard E Pratley, Attila A Seyhan
OBJECTIVE: Short-term intensive insulin therapy (IIT) early in the course of type 2 diabetes acutely improves beta-cell function with long-lasting effects on glycemic control. However, conventional measures cannot determine which patients are better suited for IIT, and little is known about the molecular mechanisms determining response. Therefore, this study aimed to develop a model that could accurately predict the response to IIT and provide insight into molecular mechanisms driving such response in humans...
November 16, 2018: Molecular Metabolism
Leonidas S Lundell, Julie Massart, Ali Altıntaş, Anna Krook, Juleen R Zierath
OBJECTIVE: Forkhead box class O (FOXO) transcription factors regulate whole body energy metabolism, skeletal muscle mass, and substrate switching. FOXO1 and FOXO3 are highly abundant transcription factors, but their precise role in skeletal muscle metabolism has not been fully elucidated. METHODS: To elucidate the role of FOXO in skeletal muscle, dominant negative (dn) constructs for FOXO1 (FOXO1dn) or FOXO3 (FOXO3dn) were transfected by electroporation into mouse tibialis anterior muscle and glucose uptake, signal transduction, and gene expression profiles were assessed after an oral glucose tolerance test...
November 16, 2018: Molecular Metabolism
Julia C Wilmanns, Raghav Pandey, Olivia Hon, Anjana Chandran, Jan M Schilling, Elvira Forte, Qizhu Wu, Gael Cagnone, Preeti Bais, Vivek Philip, David Coleman, Heidi Kocalis, Stuart K Archer, James T Pearson, Mirana Ramialison, Joerg Heineke, Hemal H Patel, Nadia A Rosenthal, Milena B Furtado, Mauro W Costa
OBJECTIVE: Congenital heart disease (CHD) is the most frequent birth defect worldwide. The number of adult patients with CHD, now referred to as ACHD, is increasing with improved surgical and treatment interventions. However the mechanisms whereby ACHD predisposes patients to heart dysfunction are still unclear. ACHD is strongly associated with metabolic syndrome, but how ACHD interacts with poor modern lifestyle choices and other comorbidities, such as hypertension, obesity, and diabetes, is mostly unknown...
November 15, 2018: Molecular Metabolism
Min-Yu Chung, Ji-Hye Song, Jinhyuk Lee, Eun Ju Shin, Jae Ho Park, Seung-Hyun Lee, Jin-Taek Hwang, Hyo-Kyoung Choi
OBJECTIVE: We examined the potential of tannic acid (TA) as a novel histone acetyltransferase inhibitor (HATi) and demonstrated that TA prevents non-alcoholic fatty liver disease (NAFLD) by inhibiting HAT activity. METHODS: The anti-HAT activity of TA was examined using HAT activity assays. An in vitro NAFLD model was generated by treating HepG2 cells with oleic and palmitic acids. Male C57BL/6J mice were fed a control diet (CD) or Western diet (WD) with or without supplementation with either 1% or 3% TA (w/w) for 12 weeks...
November 10, 2018: Molecular Metabolism
Brandon L Panaro, Andrew L Coppage, Jacqueline L Beaudry, Elodie M Varin, Kirandeep Kaur, Jack H Lai, Wengen Wu, Yuxin Liu, William W Bachovchin, Daniel J Drucker
OBJECTIVE: Fibroblast Activation Protein (FAP), an enzyme structurally related to dipeptidyl peptidase-4 (DPP-4), has garnered interest as a potential metabolic drug target due to its ability to cleave and inactivate FGF-21 as well as other peptide substrates. Here we investigated the metabolic importance of FAP for control of body weight and glucose homeostasis in regular chow-fed and high fat diet-fed mice. METHODS: FAP enzyme activity was transiently attenuated using a highly-specific inhibitor CPD60 and permanently ablated by genetic inactivation of the mouse Fap gene...
November 5, 2018: Molecular Metabolism
Olga Rudenko, Jin Shang, Alexander Munk, Jeppe P Ekberg, Natalia Petersen, Maja S Engelstoft, Kristoffer L Egerod, Siv A Hjorth, Margaret Wu, Yue Feng, Yun-Ping Zhou, Jacek Mokrosinski, Peter Thams, Frank Reimann, Fiona Gribble, Jens F Rehfeld, Jens J Holst, Jonas T Treebak, Andrew D Howard, Thue W Schwartz
OBJECTIVES: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear. METHODS AND RESULTS: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp...
November 5, 2018: Molecular Metabolism
Rosalía Rodríguez-Rodríguez, Cristina Miralpeix, Anna Fosch, Macarena Pozo, María Calderón-Domínguez, Xavier Perpinyà, Miquel Vellvehí, Miguel López, Laura Herrero, Dolors Serra, Núria Casals
OBJECTIVE: Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity. METHODS: CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated...
November 2, 2018: Molecular Metabolism
Takayoshi Suga, Osamu Kikuchi, Masaki Kobayashi, Sho Matsui, Hiromi Yokota-Hashimoto, Eri Wada, Daisuke Kohno, Tsutomu Sasaki, Kazusane Takeuchi, Satoru Kakizaki, Masanobu Yamada, Tadahiro Kitamura
OBJECTIVES: It is controversial whether sodium glucose transporter (SGLT) 2 inhibitors increase glucagon secretion via direct inhibition of SGLT2 in pancreatic α cells. The role of SGLT1 in α cells is also unclear. We aimed to elucidate these points that are important not only for basic research but also for clinical insight. METHODS: Plasma glucagon levels were assessed in the high-fat, high-sucrose diet (HFHSD) fed C57BL/6J mice treated with dapagliflozin or canagliflozin...
October 27, 2018: Molecular Metabolism
Natalie J Haywood, Thomas A Slater, Connor J Matthews, Stephen B Wheatcroft
BACKGROUND: Recent changes in nutrition and lifestyle have provoked an unprecedented increase in the prevalence of obesity and metabolic disorders. Recognition of the adverse effects on health has prompted intense efforts to understand the molecular determinants of insulin sensitivity and dysglycemia. In many respects, actions of insulin-like growth factors (IGFs) mirror those of insulin in metabolic regulation. Unlike insulin, however, the bioactivity of IGFs is regulated by a family of seven high-affinity binding proteins (IGFBPs) which confer temporospatial modulation with implications for metabolic homeostasis...
October 24, 2018: Molecular Metabolism
G Wolff, A E Taranko, I Meln, J Weinmann, T Sijmonsma, S Lerch, D Heide, A T Billeter, D Tews, D Krunic, P Fischer-Posovszky, B P Müller-Stich, S Herzig, D Grimm, M Heikenwälder, W W Kao, A Vegiopoulos
OBJECTIVE: Extracellular matrix remodeling is required for adipose expansion under increased caloric intake. In turn, inhibited expandability due to aberrant collagen deposition promotes insulin resistance and progression towards the metabolic syndrome. An emerging role for the small leucine-rich proteoglycan Lumican in metabolically driven nonalcoholic fatty liver disease sparks an interest in further understanding its role in diet-induced obesity and metabolic complications. METHODS: Whole body ablation of Lumican (Lum-/- ) gene and adeno-associated virus-mediated over-expression were used in combination with control or high fat diet to assess energy balance, glucose homeostasis as well as adipose tissue health and remodeling...
October 23, 2018: Molecular Metabolism
Irene Trinh, Oxana B Gluscencova, Gabrielle L Boulianne
OBJECTIVE: Obesity is a complex disorder involving many genetic and environmental factors that are required to maintain energy homeostasis. While studies in human populations have led to significant progress in the generation of an obesity gene map and broadened our understanding of the genetic basis of common obesity, there is still a large portion of heritability and etiology that remains unknown. Here, we have used the genetically tractable fruit fly, Drosophila melanogaster, to identify genes/pathways that function in the nervous system to regulate energy balance...
October 19, 2018: Molecular Metabolism
Sandra López-Domènech, Zaida Abad-Jiménez, Francesca Iannantuoni, Aranzazu M de Marañón, Susana Rovira-Llopis, Carlos Morillas, Celia Bañuls, Víctor Manuel Víctor, Milagros Rocha
OBJECTIVE: In obese patients undergoing caloric restriction, there are several potential mechanisms involved in the improvement of metabolic outcomes. The present study further explores whether caloric restriction can modulate endoplasmic reticulum (ER) stress and mitochondrial function, as both are known to be mechanisms underlying inflammation and insulin resistance (IR) during obesity. METHODS: A total of 64 obese patients with BMI ≥35 kg/m2 underwent a dietary program consisting of 6 weeks of a very-low-calorie diet followed by 18 weeks of low-calorie diet...
October 19, 2018: Molecular Metabolism
Joey Bou Karam, Weikang Cai, Rowaida Mohamed, Tianwen Huang, Lingqiong Meng, Erica Paige Homan, Ercument Dirice, C Ronald Kahn, Abdelfattah El Ouaamari
There is emerging evidence to support an important role for the transient receptor potential vanilloid type 1 (TRPV1) sensory innervation in glucose homeostasis. However, it remains unknown whether the glucoregulatory action of these afferent neurons is sex-biased and whether it is pancreatic β-cell-mediated. OBJECTIVE: We investigated in male and female mice whether denervation of whole-body or pancreas-projecting TRPV1 sensory neurons regulates adult functional β-cell mass and alters systemic glucose homeostasis...
December 2018: Molecular Metabolism
Tamer Coskun, Kyle W Sloop, Corina Loghin, Jorge Alsina-Fernandez, Shweta Urva, Krister B Bokvist, Xuewei Cui, Daniel A Briere, Over Cabrera, William C Roell, Uma Kuchibhotla, Julie S Moyers, Charles T Benson, Ruth E Gimeno, David A D'Alessio, Axel Haupt
OBJECTIVE: A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM). METHODS: LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice...
December 2018: Molecular Metabolism
Jérémy Amosse, Maëva Durcin, Marine Malloci, Luisa Vergori, Audrey Fleury, Frédéric Gagnadoux, Séverine Dubois, Gilles Simard, Jérôme Boursier, Olivier Hue, M Carmen Martinez, Ramaroson Andriantsitohaina, Soazig Le Lay
OBJECTIVE: Obesity-associated metabolic dysfunctions are linked to dysregulated production of adipokines. Accumulating evidence suggests a role for fat-derived extracellular vesicles (EVs) in obesity-metabolic disturbances. Since EVs convey numerous proteins we aimed to evaluate their contribution in adipokine secretion. METHODS: Plasma collected from metabolic syndrome patients were used to isolate EV subtypes, namely microvesicles (MVs) and exosomes (EXOs). Numerous soluble factor concentrations were measured successively on total, MV- and EXO-depleted plasma by multiplexed immunoassays...
December 2018: Molecular Metabolism
Giuseppe Bruschetta, Jung Dae Kim, Sabrina Diano, Li F Chan
OBJECTIVE: Melanocortin 2 receptor accessory protein 2 (MRAP2) has a critical role in energy homeostasis. Although MRAP2 has been shown to regulates a number of GPCRs involved in metabolism, the key neurons responsible for the phenotype of gross obesity in MRAP2 deficient animals are unclear. Furthermore, to date, all the murine MRAP2 models involve the prenatal deletion of MRAP2. METHODS: To target Melanocortin 4 receptor (MC4R)-expressing neurons in the hypothalamic paraventricular nucleus (PVN), we performed stereotaxic surgery using AAV to selectively overexpress MRAP2 postnatally in adult Mc4r-cre mice...
December 2018: Molecular Metabolism
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