ACE2 deficiency shifts energy metabolism towards glucose utilization

Stella Bernardi, Christos Tikellis, Riccardo Candido, Despina Tsorotes, Raelene J. Pickering, Fleur Bossi, Renzo Carretta, Bruno Fabris, Mark E. Cooper, Merlin C. Thomas

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

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. Procedures: 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. Main Findings: 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). Principal 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.

Original languageEnglish
Pages (from-to)406-415
Number of pages10
JournalMetabolism: Clinical and Experimental
Volume64
Issue number3
DOIs
Publication statusPublished - 1 Mar 2015
Externally publishedYes

Keywords

  • Angiotensin-converting enzyme 2
  • Collectrin
  • High-fat diet
  • Pancreas
  • Skeletal muscle

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