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Javier R Jaldin-Fincati, Martin Pavarotti, Scott Frendo-Cumbo, Philip J Bilan, Amira Klip
Glucose transport is rate limiting for dietary glucose utilization by muscle and fat. The glucose transporter GLUT4 is dynamically sorted and retained intracellularly and redistributes to the plasma membrane (PM) by insulin-regulated vesicular traffic, or 'GLUT4 translocation'. Here we emphasize recent findings in GLUT4 translocation research. The application of total internal reflection fluorescence microscopy (TIRFM) has increased our understanding of insulin-regulated events beneath the PM, such as vesicle tethering and membrane fusion...
June 8, 2017: Trends in Endocrinology and Metabolism: TEM
Sabina Paglialunga, Genevieve Simnett, Holly Robson, Monica Hoang, Renjitha Pillai, Alicia M Arkell, Jeremy A Simpson, Arend Bonen, Mark Huising, Jamie W Joseph, Graham P Holloway
Tre-2/USP6, BUB2, cdc16 domain family, member 1 (TBC1D1), a Rab-GTPase activating protein, is a paralogue of AS160, and has been implicated in the canonical insulin-signaling cascade in peripheral tissues. More recently, TBC1D1 was identified in rat and human pancreatic islets; however, the islet function of TBC1D1 remains not fully understood. We examined the role of TBC1D1 in glucose homeostasis and insulin secretion utilizing a rat knockout (KO) model. Chow-fed TBC1D1 KO rats had improved insulin action but impaired glucose-tolerance tests (GTT) and a lower insulin response during an intraperitoneal GTT compared with wild-type (WT) rats...
January 31, 2017: Applied Physiology, Nutrition, and Metabolism, Physiologie Appliquée, Nutrition et Métabolisme
Yan-Na Chen, Xin Gu, X Edward Zhou, Weidong Wang, Dandan Cheng, Yinghua Ge, Fei Ye, H Eric Xu, Zhengbing Lv
TBC1D15 belongs to the TBC (Tre-2/Bub2/Cdc16) domain family and functions as a GTPase-activating protein (GAP) for Rab GTPases. So far, the structure of TBC1D15 or the TBC1D15·Rab complex has not been determined, thus, its catalytic mechanism on Rab GTPases is still unclear. In this study, we solved the crystal structures of the Shark and Sus TBC1D15 GAP domains, to 2.8 Å and 2.5 Å resolution, respectively. Shark-TBC1D15 and Sus-TBC1D15 belong to the same subfamily of TBC domain-containing proteins, and their GAP-domain structures are highly similar...
April 2017: Protein Science: a Publication of the Protein Society
Jianping Jiang, Yahui Gao, Yali Hou, Wenhui Li, Shengli Zhang, Qin Zhang, Dongxiao Sun
The use of whole-genome resequencing to obtain more information on genetic variation could produce a range of benefits for the dairy cattle industry, especially with regard to increasing milk production and improving milk composition. In this study, we sequenced the genomes of eight Holstein bulls from four half- or full-sib families, with high and low estimated breeding values (EBVs) of milk protein percentage and fat percentage at an average effective depth of 10×, using Illumina sequencing. Over 0.9 million nonredundant short insertions and deletions (indels) [1-49 base pairs (bp)] were obtained...
2016: PloS One
Qiaoli Chen, Bingxian Xie, Sangsang Zhu, Ping Rong, Yang Sheng, Serge Ducommun, Liang Chen, Chao Quan, Min Li, Kei Sakamoto, Carol MacKintosh, Shuai Chen, Hong Yu Wang
AIMS/HYPOTHESIS: TBC1D1 (tre-2/USP6, BUB2, cdc16 domain family member 1) is a Rab GTPase-activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser(231), which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesised that TBC1D1-Ser(231) phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis...
February 2017: Diabetologia
Kohei Kido, Satoru Ato, Takumi Yokokawa, Yuhei Makanae, Koji Sato, Satoshi Fujita
Acute aerobic exercise (AE) is a major physiological stimulus for skeletal muscle glucose uptake through activation of 5' AMP-activated protein kinase (AMPK). However, the regulation of glucose uptake by acute resistance exercise (RE) remains unclear. To investigate the intracellular regulation of glucose uptake after acute RE versus acute AE, male Sprague-Dawley rats were divided into three groups: RE, AE, or nonexercise control. After fasting for 12 h overnight, the right gastrocnemius muscle in the RE group was exercised at maximum isometric contraction via percutaneous electrical stimulation (3 × 10 sec, 5 sets)...
August 2016: Physiological Reports
(no author information available yet)
[This corrects the article DOI: 10.1371/journal.pone.0157027.].
2016: PloS One
Cathrine Laustrup Møller, Rasmus Kjøbsted, Pablo J Enriori, Thomas Elbenhardt Jensen, Cecilia Garcia-Rudaz, Sara A Litwak, Kirsten Raun, Jørgen Wojtaszewski, Birgitte Schjellerup Wulff, Michael A Cowley
The melanocortin system includes five G-protein coupled receptors (family A) defined as MC1R-MC5R, which are stimulated by endogenous agonists derived from proopiomelanocortin (POMC). The melanocortin system has been intensely studied for its central actions in body weight and energy expenditure regulation, which are mainly mediated by MC4R. The pituitary gland is the source of various POMC-derived hormones released to the circulation, which raises the possibility that there may be actions of the melanocortins on peripheral energy homeostasis...
2016: PloS One
Liang Chen, Qiaoli Chen, Bingxian Xie, Chao Quan, Yang Sheng, Sangsang Zhu, Ping Rong, Shuilian Zhou, Kei Sakamoto, Carol MacKintosh, Hong Yu Wang, Shuai Chen
Tre-2/USP6, BUB2, cdc16 domain family member 1 (the TBC domain is the GTPase activating protein domain) (TBC1D1) is a Rab GTPase activating protein that is phosphorylated on Ser(231) by the AMP-activated protein kinase (AMPK) in response to intracellular energy stress. However, the in vivo role and importance of this phosphorylation event remains unknown. To address this question, we generated a mouse model harboring a TBC1D1(Ser231Ala) knockin (KI) mutation and found that the KI mice developed obesity on a normal chow diet...
June 28, 2016: Proceedings of the National Academy of Sciences of the United States of America
J Dokas, A Chadt, H-G Joost, H Al-Hasani
BACKGROUND: Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined...
August 2016: International Journal of Obesity: Journal of the International Association for the Study of Obesity
Anna-Lena Volckmar, Chung Ting Han, Carolin Pütter, Stefan Haas, Carla I G Vogel, Nadja Knoll, Christoph Struve, Maria Göbel, Katharina Haas, Nikolas Herrfurth, Ivonne Jarick, Harald Grallert, Annette Schürmann, Hadi Al-Hasani, Johannes Hebebrand, Sascha Sauer, Anke Hinney
INTRODUCTION: Genes involved in body weight regulation that were previously investigated in genome-wide association studies (GWAS) and in animal models were target-enriched followed by massive parallel next generation sequencing. METHODS: We enriched and re-sequenced continuous genomic regions comprising FTO, MC4R, TMEM18, SDCCAG8, TKNS, MSRA and TBC1D1 in a screening sample of 196 extremely obese children and adolescents with age and sex specific body mass index (BMI) ≥ 99th percentile and 176 lean adults (BMI ≤ 15th percentile)...
2016: PloS One
Rasmus Kjøbsted, Andreas J T Pedersen, Janne R Hingst, Rugivan Sabaratnam, Jesper B Birk, Jonas M Kristensen, Kurt Højlund, Jørgen F P Wojtaszewski
Current evidence on exercise-mediated AMPK regulation in skeletal muscle of patients with type 2 diabetes (T2D) is inconclusive. This may relate to inadequate segregation of trimeric complexes in the investigation of AMPK activity. We examined the regulation of AMPK and downstream targets ACC-β, TBC1D1, and TBC1D4 in muscle biopsy specimens obtained from 13 overweight/obese patients with T2D and 14 weight-matched male control subjects before, immediately after, and 3 h after exercise. Exercise increased AMPK α2β2γ3 activity and phosphorylation of ACCβ Ser(221), TBC1D1 Ser(237)/Thr(596), and TBC1D4 Ser(704) Conversely, exercise decreased AMPK α1β2γ1 activity and TBC1D4 Ser(318)/Thr(642) phosphorylation...
May 2016: Diabetes
Haiyan Wang, Edward B Arias, Gregory D Cartee
Skeletal muscle insulin resistance is associated with many common age-related diseases, but moderate calorie restriction (CR) can substantially elevate glucose uptake by insulin-stimulated skeletal muscle from both young and old rats. The current study evaluated the isolated epitrochlearis muscle from ∼24.5-mo-old rats that were either fed ad libitum (AL) or subjected to CR (consuming ∼65% of ad libitum, AL, intake beginning at ∼22.5 mo old). Some muscles were also incubated with MK-2206, a potent and selective Akt inhibitor...
March 1, 2016: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
M Sokolowski, J Wasserman, D Wasserman
The risk for suicidal behavior (SB) is elevated in schizophrenia (SCZ), bipolar disorder (BPD) and major depressive disorder (MDD), but also occurs in subjects without psychiatric diagnoses. Genome-wide association studies (GWAS) on SB may help to understand this risk, but have been hampered by low power due to limited sample sizes, weakly ascertained SB or a reliance on single-nucleotide protein (SNP)-by-SNP analyses. Here, we tried to mitigate such issues with polygenic risk score (PRS) association tests combined with hypothesis-driven strategies using a family-based sample of 660 trios with a well-ascertained suicide attempt (SA) outcome in the offspring (Genetic Investigation of Suicide and SA, GISS)...
October 2016: Molecular Psychiatry
Kang Liu, Fan Mei, Yapu Wang, Na Xiao, Lele Yang, Yilei Wang, Jia Li, Fang Huang, Junping Kou, Baolin Liu, Lian-Wen Qi
SCOPE: Quercetin is a dietary flavonoid whose role in the regulation of the activity of insulin remains controversial. Our study aimed to investigate how quercetin and its major metabolite quercetin-3-glucuronide (Q-3-G) regulate insulin-mediated glucose disposal in skeletal muscle under normal and inflammatory conditions. METHODS AND RESULTS: Under normal conditions, quercetin impaired glucose and insulin tolerance and attenuated insulin-mediated phosphorylation of Akt substrate of 160 kDa (AS160) and TBC1D1 without affecting Akt activity in male Institute of Cancer Research (ICR) mice...
March 2016: Molecular Nutrition & Food Research
Stefan R Hargett, Natalie N Walker, Susanna R Keller
The related Rab GTPase-activating proteins (Rab GAPs) AS160 and Tbc1d1 regulate the trafficking of the glucose transporter GLUT4 that controls glucose uptake in muscle and fat cells and glucose homeostasis. AS160- and Tbc1d1-deficient mice exhibit different adipocyte- and skeletal muscle-specific defects in glucose uptake, GLUT4 expression and trafficking, and glucose homeostasis. A recent study analyzed male mice with simultaneous deletion of AS160 and Tbc1d1 (AS160(-/-)/Tbc1d1(-/-) mice). Herein, we describe abnormalities in male and female AS160(-/-)/Tbc1d1(-/-) mice on another strain background...
February 15, 2016: American Journal of Physiology. Endocrinology and Metabolism
Anne Kosfeld, Martin Kreuzer, Christoph Daniel, Frank Brand, Anne-Kathrin Schäfer, Alexandra Chadt, Anna-Carina Weiss, Vera Riehmer, Cécile Jeanpierre, Michael Klintschar, Jan Hinrich Bräsen, Kerstin Amann, Lars Pape, Andreas Kispert, Hadi Al-Hasani, Dieter Haffner, Ruthild G Weber
Congenital anomalies of the kidneys and urinary tract (CAKUT) are genetically highly heterogeneous leaving most cases unclear after mutational analysis of the around 30 causative genes known so far. Assuming that phenotypes frequently showing dominant inheritance, such as CAKUT, can be caused by de novo mutations, de novo analysis of whole-exome sequencing data was done on two patient-parent-trios to identify novel CAKUT genes. In one case, we detected a heterozygous de novo frameshift variant in TBC1D1 encoding a Rab-GTPase-activating protein regulating glucose transporter GLUT4 translocation...
January 2016: Human Genetics
Haiyan Wang, Naveen Sharma, Edward B Arias, Gregory D Cartee
Exercise and calorie restriction (CR) can each improve insulin sensitivity in older individuals, but benefits of combining these treatments on skeletal muscle insulin signaling and glucose uptake are poorly understood, especially in predominantly slow-twitch muscles (eg, soleus). Accordingly, our purpose was to determine independent and combined effects of prior acute exercise and CR (beginning at 14 weeks old) on insulin signaling and glucose uptake in insulin-stimulated soleus muscles of 30-month-old rats...
March 2016: Journals of Gerontology. Series A, Biological Sciences and Medical Sciences
Y D Peng, H Y Xu, F Ye, X Lan, X Peng, A Rustempašić, H D Yin, X L Zhao, Y P Liu, Q Zhu, Y Wang
The objective of this study was to investigate the effects of sex and slaughter age of chickens on fatty acid composition and TBC1D1 gene expression in 4 different tissues: breast muscle, thigh muscle, abdominal fat, and subcutaneous fat. Sixty Erlang mountainous chickens (hybrid SD02 x SD03) were raised under the same conditions and slaughtered at 8, 10, and 13 weeks of age. The results showed that the sex of the animal significantly affected the content of arachidic acid (C20:0), sinapic (C22:1), linoleic (C18:2n-6), eicosapentaenoic (C20:5n-3), and docosahexaenoic acids (C22:6n-3), whereas other fatty acid contents were not affected...
2015: Genetics and Molecular Research: GMR
Anja Reyer, Nancy Schindler, Daniela Ohde, Christina Walz, Martin Kunze, Armin Tuchscherer, Elisa Wirthgen, Julia Brenmoehl, Andreas Hoeflich
Recent studies suggest that insulin-like growth factor-binding protein-2 (IGFBP-2) affects both growth and metabolism. Whereas negative growth effects are primarily due to negative interference with IGF-I, the mechanisms for metabolic interference of IGFBP-2 are less clear. As we demonstrate, overexpression of IGFBP-2 in transgenic mice is correlated with a decelerated clearance of blood glucose after oral administration. IGFBP-2 carries an integrin-binding domain (RGD motif), which has been shown to also mediate IGF-independent effects...
August 15, 2015: American Journal of Physiology. Endocrinology and Metabolism
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