title: Adipocyte-Specific Enhancement of Angiotensin II Type 1 Receptor-Associated Protein Ameliorates Diet-Induced Visceral Obesity and Insulin Resistance.
abstract: BACKGROUND
  The renin-angiotensin system has a pivotal role in the pathophysiology of visceral obesity. Angiotensin II type 1 receptor (AT1R) is a major player in the signal transduction of the renin-angiotensin system, and the overactivation of this signaling contributes to the progression of visceral obesity. We have shown that the AT1R-associated protein (ATRAP) promotes AT1R internalization from the cell surface into cytoplasm along with the suppression of overactivation of tissue AT1R signaling. In this study, we examined whether the enhancement of adipose ATRAP expression could efficiently prevent diet-induced visceral obesity and insulin resistance.
  
  
  RESULTS
  We generated adipocyte-specific ATRAP transgenic mice using a 5.4-kb adiponectin promoter, and transgenic mice and littermate control mice were fed either a low- or high-fat diet for 10 weeks. Although the physiological phenotypes of the transgenic and control mice fed a low-fat diet were comparable, the transgenic mice exhibited significant protection against high-fat diet-induced adiposity, adipocyte hypertrophy, and insulin resistance concomitant with an attenuation of adipose inflammation, macrophage infiltration, and adipokine dysregulation. In addition, when mice were fed a high-fat diet, the adipose expression of glucose transporter type 4 was significantly elevated and the level of adipose phospho-p38 mitogen-activated protein kinase was significantly attenuated in the transgenic mice compared with control mice.
  
  
  CONCLUSIONS
  Results presented in this study suggested that the enhancement in adipose ATRAP plays a protective role against the development of diet-induced visceral obesity and insulin resistance through improvement of adipose inflammation and function via the suppression of overactivation of adipose AT1R signaling. Consequently, adipose tissue ATRAP is suggested to be an effective therapeutic target for the treatment of visceral obesity.
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan tamukou@med.yokohama-cu.ac.jp azushima@yokohama-cu.ac.jp.|Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.
authors.forename: Kengo
authors.initials: K
authors.lastname: Azushima
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Ohki
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kazushi
authors.initials: K
authors.lastname: Uneda
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Sona
authors.initials: S
authors.lastname: Haku
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Ryu
authors.initials: R
authors.lastname: Kobayashi
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Haruhara
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kinguchi
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Akinobu
authors.initials: A
authors.lastname: Maeda
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
authors.affiliation: Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan tamukou@med.yokohama-cu.ac.jp azushima@yokohama-cu.ac.jp.
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D017667:Adipocytes / Q000276:immunology / Q000378:metabolism*; D054392:Adipokines / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D007249:Inflammation; D007333:Insulin Resistance / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D056128:Obesity, Abdominal / Q000235:genetics* / Q000276:immunology; D010750:Phosphoproteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D054392:Adipokines; C119712:Agtrap protein, mouse; D010750:Phosphoproteins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: adipocyte; insulin resistance; obesity; receptor; renin–angiotensin system