title: Angiotensin receptor-binding protein ATRAP/Agtrap inhibits metabolic dysfunction with visceral obesity.
abstract: BACKGROUND
  Metabolic disorders with visceral obesity have become a major medical problem associated with the development of hypertension, type 2 diabetes, and dyslipidemia and, ultimately, life-threatening cardiovascular and renal diseases. Adipose tissue dysfunction has been proposed as the cause of visceral obesity-related metabolic disorders, moving the tissue toward a proinflammatory phenotype.
  
  
  RESULTS
  Here we first report that adipose tissues from patients and mice with metabolic disorders exhibit decreased expression of ATRAP/Agtrap, which is a specific binding modulator of the angiotensin II type 1 receptor, despite its abundant expression in adipose tissues from normal human and control mice. Subsequently, to examine a functional role of ATRAP in the pathophysiology of metabolic disorders, we produced homozygous ATRAP deficient (Agtrap(-/-)) mice, which exhibited largely normal physiological phenotype at baseline. Under dietary high fat loading, Agtrap(-/-) mice displayed systemic metabolic dysfunction, characterized by an increased accumulation of pad fat, hypertension, dyslipidemia, and insulin resistance, along with adipose tissue inflammation. Conversely, subcutaneous transplantation of donor fat pads overexpressing ATRAP derived from Agtrap transgenic mice to Agtrap(-/-) recipient mice improved the systemic metabolic dysfunction.
  
  
  CONCLUSIONS
  These results demonstrate that Agtrap(-/-) mice are an effective model of metabolic disorders with visceral obesity and constitute evidence that ATRAP plays a protective role against insulin resistance, suggesting a new therapeutic target in metabolic disorders. Identification of ATRAP as a novel receptor binding modulator of adipose tissue inflammation not only has cardiovascular significance but may have generalized implication in the regulation of tissue function.
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.forename: Kouichi
authors.initials: K
authors.lastname: Tamura
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Wakui
authors.forename: Toru
authors.initials: T
authors.lastname: Dejima
authors.forename: Masato
authors.initials: M
authors.lastname: Ohsawa
authors.forename: Kengo
authors.initials: K
authors.lastname: Azushima
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kanaoka
authors.forename: Kazushi
authors.initials: K
authors.lastname: Uneda
authors.forename: Miyuki
authors.initials: M
authors.lastname: Matsuda
authors.forename: Akio
authors.initials: A
authors.lastname: Yamashita
authors.forename: Nobuko
authors.initials: N
authors.lastname: Miyazaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yatsu
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Hirawa
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Toya
authors.forename: Satoshi
authors.initials: S
authors.lastname: Umemura
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050154:Adiposity; D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D016022:Case-Control Studies; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D006984:Hypertrophy; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000637:transplantation; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015434:Panniculitis / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D055815:Young Adult
chemical_list: C544065:AGTR1 protein, human; C449676:AGTRAP protein, human; D048868:Adaptor Proteins, Signal Transducing; C119712:Agtrap protein, mouse; D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1
keywords: adipocyte; angiotensin receptor; inflammation; insulin resistance; transplantation
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