title: ACE2 deficiency shifts energy metabolism towards glucose utilization.
abstract: BACKGROUND
  This study aimed at investigating the effects of genetic angiotensin-converting enzyme (ACE) 2 deficiency on glucose homeostasis in the pancreas and skeletal muscle and their reversibility following ACE inhibition.
  
  
  METHODS
  ACE2-knockout and C57bl6J mice were placed on a standard diet (SD) or a high-fat diet (HFD) for 12 weeks. An additional group of ACE2-knockout mice was fed a SD and treated with the ACE inhibitor, perindopril (2 mg kg(-1)day(-1)). Glucose and insulin tolerance tests, indirect calorimetry measurements and EchoMRI were performed. Non-esterfied 'free' fatty acid oxidation rate in skeletal muscle was calculated by measuring the palmitate oxidation rate. β-cell mass was determined by immunostaining. Insulin, collectrin, glucose transporter protein, and peroxisome proliferator-activated receptor-γ expression were analysed by RT-PCR. Markers of mithocondrial biogenesis/content were also evaluated.
  
  
  RESULTS
  ACE2-knockout mice showed a β-cell defect associated with low insulin and collectrin levels and reduced compensatory hypertrophy in response to a HFD, which were not reversed by perindopril. On the other hand, ACE2 deficiency shifted energy metabolism towards glucose utilization, as it increased the respiratory exchange ratio, reduced palmitate oxidation and PCG-1α expression in the skeletal muscle, where it up-regulated glucose transport proteins. Treatment of ACE2-knockout mice with perindopril reversed the skeletal muscle changes, suggesting that these were dependent on Angiotensin II (Ang II).
  
  
  CONCLUSIONS
  ACE2-knockout mice display a β-cell defect, which does not seem to be dependent on Ang II but may reflect the collectrin-like action of ACE2. This defect seemed to be compensated by the fact that ACE2-knockout mice shifted their energy consumption towards glucose utilisation via Ang II.
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia; Department of Internal Medicine, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: stella.bernardi@aots.sanita.fvg.it.
authors.forename: Stella
authors.initials: S
authors.lastname: Bernardi
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: chris.tikellis@bakeridi.edu.au.
authors.forename: Christos
authors.initials: C
authors.lastname: Tikellis
authors.affiliation: Diabetes Centre "ASS 1 Triestina", Trieste, Italy. Electronic address: riccardocandido@yahoo.it.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Candido
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: desi.tsorotes@bakeridi.edu.au.
authors.forename: Despina
authors.initials: D
authors.lastname: Tsorotes
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: raelene.pickering@bakeridi.edu.au.
authors.forename: Raelene J
authors.initials: RJ
authors.lastname: Pickering
authors.affiliation: Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: fbossi@units.it.
authors.forename: Fleur
authors.initials: F
authors.lastname: Bossi
authors.affiliation: Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: r.carretta@fmc.units.it.
authors.forename: Renzo
authors.initials: R
authors.lastname: Carretta
authors.affiliation: Department of Medical Surgical and Health Sciences, Cattinara University Hospital, Strada di Fiume 447, Trieste, Italy. Electronic address: b.fabris@fmc.units.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Fabris
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: mark.cooper@bakeridi.edu.au.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Baker IDI Heart and Diabetes Institute, 75 Commercial Road 3004 VIC, Melbourne, Australia. Electronic address: merlin.thomas@bakeridi.edu.au.
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
mesh_terms: D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001823:Body Composition / Q000235:genetics; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics*; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency* / Q000235:genetics; D020913:Perindopril / Q000627:therapeutic use
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007328:Insulin; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D005947:Glucose; D020913:Perindopril
keywords: Angiotensin-converting enzyme 2; Collectrin; High-fat diet; Pancreas; Skeletal muscle