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Molecular Metabolism

Judith Korner, Gary W Cline, Mark Slifstein, Pasquale Barba, Gina R Rayat, Gerardo Febres, Rudolph L Leibel, Antonella Maffei, Paul E Harris
OBJECTIVE: We hypothesized that DA and L-DOPA derived from nutritional tyrosine and the resultant observed postprandial plasma excursions of L-DOPA and DA might affect glucose tolerance via their ability to be taken-up by beta cells and inhibit glucose-stimulated β-cell insulin secretion. METHODS: To investigate a possible circuit between meal-stimulated 3,4-dihydroxy-L-phenylalanine (L-DOPA) and dopamine (DA) production in the GI tract and pancreatic β-cells, we: 1) mapped GI mucosal expression of tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase (AADC); 2) measured L-DOPA and DA content of GI mucosal tissues following meal challenges with different L-tyrosine (TYR) content, 3) determined whether meal TYR content impacts plasma insulin and glucose excursions; and 4) characterized postprandial plasma excursions of L-DOPA and DA in response to meal tyrosine content in rodents and a population of bariatric surgery patients...
February 27, 2019: Molecular Metabolism
Yoshitake Cho, Shizuko Tachibana, Bethany C Hazen, James J Moresco, John R Yates, Bernard Kok, Enrique Saez, Robert S Ross, Aaron P Russell, Anastasia Kralli
OBJECTIVE: Endurance exercise training remodels skeletal muscle, leading to increased mitochondrial content and oxidative capacity. How exercise entrains skeletal muscle signaling pathways to induce adaptive responses remains unclear. In past studies, we identified Perm1 (PGC-1 and ERR induced regulator, muscle 1) as an exercise-induced gene and showed that Perm1 overexpression elicits similar muscle adaptations as endurance exercise training. The mechanism of action and the role of Perm1 in exercise-induced responses are not known...
February 27, 2019: Molecular Metabolism
Huimin Yang, Tingting Xie, Dengren Li, Xianhong Du, Tixiao Wang, Chunyang Li, Xiaojia Song, Leiqi Xu, Fan Yi, Xiaohong Liang, Lifen Gao, Xiangdong Yang, Chunhong Ma
OBJECTIVE: Macrophage-mediated inflammation plays a significant role in the development and progression of diabetic nephropathy (DN). However, the underlying mechanisms remain unclear. Studies suggest that T cell immunoglobulin domain and mucin domain-3 (Tim-3) has complicated roles in regulating macrophage activation, but its roles in the progression of DN are still completely unknown. METHODS: We downregulated Tim-3 expression in kidney (intrarenal injection of Tim-3 shRNA expressing lentivirus or global Tim-3 knockout mice) and induced DN by streptozotocin (STZ)...
February 26, 2019: Molecular Metabolism
Curtis C Hughey, Freyja D James, Zhizhang Wang, Mickael Goelzer, David H Wasserman
OBJECTIVE: The loss of liver glycine N-methyltransferase (GNMT) promotes liver steatosis and the transition to hepatocellular carcinoma (HCC). Previous work showed endogenous glucose production is reduced in GNMT-null mice with gluconeogenic precursors being used in alternative biosynthetic pathways that utilize methyl donors and are linked to tumorigenesis. This metabolic programming occurs before the appearance of HCC in GNMT-null mice. The metabolic physiology that sustains liver tumor formation in GNMT-null mice is unknown...
February 25, 2019: Molecular Metabolism
Bernardo Stutz, Carole Nasrallah, Mariana Nigro, Daniel Curry, Zhong-Wu Liu, Xiao-Bing Gao, John D Elsworth, Liat Mintz, Tamas L Horvath
OBJECTIVE: Dopamine neurons in the Substantia nigra (SN) play crucial roles in control of voluntary movement. Extensive degeneration of this neuronal population is the cause of Parkinson's disease (PD). Many factors have been linked to SN DA neuronal survival, including neuronal pacemaker activity (responsible for maintaining basal firing and DA tone) and mitochondrial function. Dln-101, a naturally occurring splice variant of the human ghrelin gene, targets the ghrelin receptor (GHSR) present in the SN DA cells...
February 21, 2019: Molecular Metabolism
Haixia Xu, Xiao Du, Geng Liu, Shuang Huang, Wenya Du, Sailan Zou, Dongmei Tang, Chen Fan, Yongmei Xie, Yuquan Wei, Yan Tian, Xianghui Fu
OBJECTIVE: The mixed lineage kinase domain like (MLKL) protein, receptor interacting protein (RIPK) 1, and RIPK3 are key regulators of necroptosis, a highly pro-inflammatory mode of cell death that has been implicated in various pathological processes and human diseases. However, the role of these necroptotic regulators in diabetes remains unknown. Here we sought to delineate the role of MLKL in insulin resistance and type 2 diabetes (T2D). METHODS: We first analyzed the expression of key necroptotic regulators in obese/diabetic mouse models...
February 20, 2019: Molecular Metabolism
Joan Sanchez-Gurmaches, Camila Martinez Calejman, Su Myung Jung, Huawei Li, David A Guertin
OBJECTIVE: Understanding the signaling mechanisms that control brown adipose tissue (BAT) development is relevant to understanding energy homeostasis and obesity. The AKT kinases are insulin effectors with critical in vivo functions in adipocytes; however, their role in adipocyte development remains poorly understood. The goal of this study was to investigate AKT function in BAT development. METHODS: We conditionally deleted Akt1 and Akt2 either individually or together with Myf5-Cre, which targets early mesenchymal precursors that give rise to brown adipocytes...
February 20, 2019: Molecular Metabolism
Camille Allard, Fabrice Bonnet, Beibei Xu, Laurel Coons, Diana Albarado, Cristal Hill, Guy Fagherazzi, Kenneth S Korach, Ellis R Levin, John Lefante, Christopher Morrison, Franck Mauvais-Jarvis
OBJECTIVE: The endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure...
February 14, 2019: Molecular Metabolism
Ritesh Kumar Baboota, Abhijit Babaji Shinde, Katleen Lemaire, Marc Fransen, Stefan Vinckier, Paul P Van Veldhoven, Frans Schuit, Myriam Baes
OBJECTIVES: Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic β-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to β-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and β-cell restricted manner (Rip-Pex5-/- mice). METHODS: After tamoxifen-induced recombination of the Pex5 gene at the age of 6 weeks, mice were fed either normal chow or a high-fat diet for 12 weeks and were subsequently phenotyped...
February 8, 2019: Molecular Metabolism
Ayla V Orang, Janni Petersen, Ross A McKinnon, Michael Z Michael
BACKGROUND: Cancer cells possess a common metabolic phenotype, rewiring their metabolic pathways from mitochondrial oxidative phosphorylation to aerobic glycolysis and anabolic circuits, to support the energetic and biosynthetic requirements of continuous proliferation and migration. While, over the past decade, molecular and cellular studies have clearly highlighted the association of oncogenes and tumor suppressors with cancer-associated glycolysis, more recent attention has focused on the role of microRNAs (miRNAs) in mediating this metabolic shift...
February 6, 2019: Molecular Metabolism
Xinxin Ke, Alesia Walker, Sven-Bastiaan Haange, Ilias Lagkouvardos, Yuwen Liu, Philippe Schmitt-Kopplin, Martin von Bergen, Nico Jehmlich, Xin He, Thomas Clavel, Peter C K Cheung
OBJECTIVE: The gut microbiota is an important influencing factor of metabolic health. Although dietary interventions with probiotics, prebiotics, and synbiotics can be effective means to regulate obesity and associated comorbidities, the underlying shifts in gut microbial communities, especially at the functional level, have not been characterized in great details. In this study, we sought to investigate the effects of synbiotics on the regulation of gut microbiota and the alleviation of high-fat diet (HFD)-induced metabolic disorders in mice...
February 5, 2019: Molecular Metabolism
Jacqueline L Beaudry, Kiran Deep Kaur, Elodie M Varin, Laurie L Baggio, Xiemin Cao, Erin E Mulvihill, Jennifer H Stern, Jonathan E Campbell, Phillip E Scherer, Daniel J Drucker
OBJECTIVE: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined. METHODS: We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1-/- and Fgf21-/- mice...
February 5, 2019: Molecular Metabolism
Daniel Lindén, Andrea Ahnmark, Piero Pingitore, Ester Ciociola, Ingela Ahlstedt, Anne-Christine Andréasson, Kavitha Sasidharan, Katja Madeyski-Bengtson, Magdalena Zurek, Rosellina M Mancina, Anna Lindblom, Mikael Bjursell, Gerhard Böttcher, Marcus Ståhlman, Mohammad Bohlooly-Y, William G Haynes, Björn Carlsson, Mark Graham, Richard Lee, Sue Murray, Luca Valenti, Sanjay Bhanot, Peter Åkerblad, Stefano Romeo
OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD...
February 5, 2019: Molecular Metabolism
Muhannad Abu-Remaileh, Monther Abu-Remaileh, Rania Akkawi, Ibrahim Knani, Shiran Udi, Micheal E Pacold, Joseph Tam, Rami I Aqeilan
OBJECTIVE: WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism. METHODS: We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis. RESULTS: Several WWOX variants were found to be strongly associated with MetS disorders...
January 31, 2019: Molecular Metabolism
Michal Grzybek, Alessandra Palladini, Vasileia I Alexaki, Michal A Surma, Kai Simons, Triantafyllos Chavakis, Christian Klose, Ünal Coskun
OBJECTIVE: Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, the quantification of the AT lipidome is particularly challenging due to the predominance of triacylglycerides, which elicit high ion suppression of the remaining lipid classes...
January 30, 2019: Molecular Metabolism
Marine Tournissac, Philippe Bourassa, Ruben D Martinez-Cano, Tra-My Vu, Sébastien S Hébert, Emmanuel Planel, Frédéric Calon
OBJECTIVE: Old age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans...
January 26, 2019: Molecular Metabolism
Alfred K Ramirez, Simon Dankel, Weikang Cai, Masaji Sakaguchi, Simon Kasif, C Ronald Kahn
OBJECTIVE: Accumulation of visceral white adipose tissue (WAT) associates with insulin resistance, adipose tissue inflammation, and metabolic syndrome, whereas accumulation of subcutaneous WAT may be protective. We aimed to identify molecular mechanisms that might provide mechanistic insights underlying the phenotypic differences in these tissues. Membrane Metallo-Endopeptidase (MME/Neprislyin) is an extracellular, membrane-bound protease enriched in subcutaneous WAT that can target degradation of a variety of peptides, including insulin, IL6, and β-amyloids...
January 25, 2019: Molecular Metabolism
Lishu Yue, Wenjun Zhao, Dongmei Wang, Meiyao Meng, Ying Zheng, Yu Li, Jin Qiu, Jian Yu, Yang Yan, Peng Lu, Youmin Sun, Jie Fu, Jiqiu Wang, Qiang Zhang, Lingyan Xu, Xinran Ma
OBJECTIVE: Obesity is a complex chronic disease of high prevalence worldwide. Multiple factors play integral roles in obesity development, with rising interest focusing on the contribution of environmental pollutants frequent in modern society. Silver nanoparticles (AgNPs) are widely used for bactericidal purpose in various applications in daily life. However, their potential toxicity and contribution to the obesity epidemic are not clear. METHODS: Beige adipocytes are newly discovered adipocytes characterized by high thermogenic and energy dissipating capacity upon activation and the "browning" process...
January 24, 2019: Molecular Metabolism
Warren Pan, Margaret B Allison, Paul Sabatini, Alan Rupp, Jessica Adams, Christa Patterson, Justin C Jones, David P Olson, Martin G Myers
OBJECTIVES: Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression. METHODS: Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3LepRb KO mice), revealing the STAT3-dependent transcriptional targets of leptin...
January 24, 2019: Molecular Metabolism
Rodolphe Dusaulcy, Sandra Handgraaf, Florian Visentin, Christian Vesin, Jacques Philippe, Yvan Gosmain
OBJECTIVE: Diabetes is a complex disease implicating several organs and cell types. Within the islets, dysregulation occurs in both alpha- and beta-cells, leading to defects of insulin secretion and increased glucagon secretion. Dysregulation of alpha-cells is associated with transcriptome changes. We hypothesized that microRNAs (miRNAs) which are negative regulators of mRNA stability and translation could be involved in alpha-cell alterations or adaptations during type 2 diabetes. METHODS: miRNA microarray analyses were performed on pure alpha- and beta-cells from high-fat diet fed obese hyperglycemic mice and low-fat diet fed controls...
January 18, 2019: Molecular Metabolism
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