title: Loss of ACE2 exaggerates high-calorie diet-induced insulin resistance by reduction of GLUT4 in mice.
abstract: ACE type 2 (ACE2) functions as a negative regulator of the renin-angiotensin system by cleaving angiotensin II (AII) into angiotensin 1-7 (A1-7). This study assessed the role of endogenous ACE2 in maintaining insulin sensitivity. Twelve-week-old male ACE2 knockout (ACE2KO) mice had normal insulin sensitivities when fed a standard diet. AII infusion or a high-fat, high-sucrose (HFHS) diet impaired glucose tolerance and insulin sensitivity more severely in ACE2KO mice than in their wild-type (WT) littermates. The strain difference in glucose tolerance was not eliminated by an AII receptor type 1 (AT1) blocker but was eradicated by A1-7 or an AT1 blocker combined with the A1-7 inhibitor (A779). The expression of GLUT4 and a transcriptional factor, myocyte enhancer factor (MEF) 2A, was dramatically reduced in the skeletal muscles of the standard diet-fed ACE2KO mice. The expression of GLUT4 and MEF2A was increased by A1-7 in ACE2KO mice and decreased by A779 in WT mice. A1-7 enhanced upregulation of MEF2A and GLUT4 during differentiation of myoblast cells. In conclusion, ACE2 protects against high-calorie diet-induced insulin resistance in mice. This mechanism may involve the transcriptional regulation of GLUT4 via an A1-7-dependent pathway.
authors.affiliation: Department of Geriatric Medicine and Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Takeda
authors.forename: Koichi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Takemura
authors.forename: Hikari
authors.initials: H
authors.lastname: Takeshita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Hongyo
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kawai
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hanasaki-Yamamoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Oguro
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Takami
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tatara
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Takeya
authors.forename: Ken
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Kei
authors.initials: K
authors.lastname: Kamide
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Ohishi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D059305:Diet, High-Fat; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D002149:Energy Intake; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000502:physiology; D006706:Homeostasis; D007333:Insulin Resistance; D064326:MEF2 Transcription Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000235:genetics; D010446:Peptide Fragments / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000502:physiology*
chemical_list: D004040:Dietary Carbohydrates; D051275:Glucose Transporter Type 4; D064326:MEF2 Transcription Factors; C578036:Mef2a protein, mouse; D018006:Myogenic Regulatory Factors; D010446:Peptide Fragments; C495693:Slc2a4 protein, mouse; D000804:Angiotensin II; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; C118790:angiotensin I (1-7); D005947:Glucose