title: TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling.
abstract: OBJECTIVE
  Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal.
  
  
  METHODS
  We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts.
  
  
  RESULTS
  Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted.
  
  
  CONCLUSIONS
  Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Nigel
authors.initials: N
authors.lastname: Beaton
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Rudigier
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Moest
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Müller
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Nadja
authors.initials: N
authors.lastname: Mrosek
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Eva
authors.initials: E
authors.lastname: Röder
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Rudofsky
authors.affiliation: Institute of Laboratory Animal Science, Vetmeduni, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Ukropec
authors.affiliation: Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia ; Institute of Pathophysiology, School of Medicine, Comenius University, Bratislava, Slovakia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ukropcova
authors.affiliation: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach a.d. Riss, Germany ; Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH&CoKG, Biberach a.d. Riss, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Augustin
authors.affiliation: CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH&Co. KG, Biberach a.d. Riss, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Neubauer
authors.affiliation: Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
keywords: Glucose uptake; Insulin resistance; Obesity; Type 2 diabetes