ACE2 Deficiency Shifts Energy Metabolism Towards Glucose Utilization

Metabolism. 2015 Mar;64(3):406-15. doi: 10.1016/j.metabol.2014.11.004. Epub 2014 Nov 20.

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.

Keywords: Angiotensin-converting enzyme 2; Collectrin; High-fat diet; Pancreas; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Animals
  • Body Composition / genetics
  • Diet, High-Fat
  • Energy Metabolism / genetics*
  • Glucose / metabolism*
  • Homeostasis
  • Insulin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Skeletal / metabolism
  • Pancreas / metabolism
  • Peptidyl-Dipeptidase A / deficiency*
  • Peptidyl-Dipeptidase A / genetics
  • Perindopril / therapeutic use

Substances

  • Angiotensin-Converting Enzyme Inhibitors
  • Insulin
  • Peptidyl-Dipeptidase A
  • angiotensin converting enzyme 2
  • Glucose
  • Perindopril