Neurolysin knockout mice generation and initial phenotype characterization

J Biol Chem. 2014 May 30;289(22):15426-40. doi: 10.1074/jbc.M113.539148. Epub 2014 Apr 9.

Abstract

The oligopeptidase neurolysin (EC 3.4.24.16; Nln) was first identified in rat brain synaptic membranes and shown to ubiquitously participate in the catabolism of bioactive peptides such as neurotensin and bradykinin. Recently, it was suggested that Nln reduction could improve insulin sensitivity. Here, we have shown that Nln KO mice have increased glucose tolerance, insulin sensitivity, and gluconeogenesis. KO mice have increased liver mRNA for several genes related to gluconeogenesis. Isotopic label semiquantitative peptidomic analysis suggests an increase in specific intracellular peptides in gastrocnemius and epididymal adipose tissue, which likely is involved with the increased glucose tolerance and insulin sensitivity in the KO mice. These results suggest the exciting new possibility that Nln is a key enzyme for energy metabolism and could be a novel therapeutic target to improve glucose uptake and insulin sensitivity.

Keywords: Gluconeogenesis; Glucose Metabolism; Insulin; Intracellular Peptides; Oligopeptidase; Peptidases; Peptides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / physiology
  • Animals
  • Blood Glucose / metabolism
  • Blood Pressure / physiology
  • Genotype
  • Gluconeogenesis / genetics
  • Gluconeogenesis / physiology*
  • Glucose Intolerance / enzymology*
  • Glucose Intolerance / genetics
  • Insulin Resistance / genetics
  • Insulin Resistance / physiology*
  • Liver / physiology
  • Metalloendopeptidases / genetics*
  • Metalloendopeptidases / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle Fibers, Fast-Twitch / physiology
  • Muscle, Skeletal / physiology
  • Phenotype
  • Physical Conditioning, Animal / physiology
  • Pyruvic Acid / metabolism

Substances

  • Blood Glucose
  • Pyruvic Acid
  • Metalloendopeptidases
  • neurolysin