title: ACE gene titration in mice uncovers a new mechanism for ACE on the control of body weight.
abstract: Mice harboring 1, 2, or 3 copies of the angiotensin-converting enzyme (ACE) gene were used to evaluate the quantitative role of the ACE locus on obesity. Three-copy mice fed with a high-fat diet had lower body weight and peri-epididymal adipose tissue than did 1- and 2-copy mice (P < 0.05). On regular diet, 3-copy mice had to eat more to maintain the same body weight; on a high-fat diet, they ate the same but weighed less than 1- and 2-copy mice (P < 0.05), indicating a higher metabolic rate in 3-copy mice that was not affected by ANG II AT(1) blocker treatment. A catalytically inactive form of thimet oligopeptidase (EC 3.4.24.15; EP24.15) was used to isolate ACE substrates from adipose tissue. Liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) identified 162 peptide peaks; 16 peptides were present in both groups (1- and 3-copy mice fed with a high-fat diet), whereas 58 of the 72 unique peptides were found only in the 3-copy mice. Peptide size distribution was shifted to lower molecular weight in 3-copy mice. Two of the identified peptides, LVVYPWTQRY and VVYPWTQRY, which are ACE substrates, inhibited in vitro protein kinase C phosphorylation in a concentration-dependent manner. In addition, neurolysin (EC 3.4.24.16; EP24.16) activity was lower in fat tissue from 3- vs. 1-copy mice (P < 0.05). Taken together, these results provide evidence that ACE is associated with body weight and peri-epididymal fat accumulation. This response may involve the generation of oligopeptides that inhibit the activity of EP24.16 and other oligopeptidases within the adipose tissue.
authors.affiliation: Heart Institute (InCor) and Department of Medicine-LIM13, University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: A S
authors.initials: AS
authors.lastname: Heimann
authors.forename: M H
authors.initials: MH
authors.lastname: Favarato
authors.forename: F C
authors.initials: FC
authors.lastname: Gozzo
authors.forename: V
authors.initials: V
authors.lastname: Rioli
authors.forename: F R
authors.initials: FR
authors.lastname: Carreño
authors.forename: M N
authors.initials: MN
authors.lastname: Eberlin
authors.forename: E S
authors.initials: ES
authors.lastname: Ferro
authors.forename: J H
authors.initials: JH
authors.lastname: Krege
authors.forename: J E
authors.initials: JE
authors.lastname: Krieger
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D001835:Body Weight; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D015233:Models, Statistical; D009842:Oligopeptides / Q000737:chemistry; D010447:Peptide Hydrolases / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D012307:Risk Factors; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D009842:Oligopeptides; D010455:Peptides; D011493:Protein Kinase C; D010447:Peptide Hydrolases; C028759:oligopeptidase; D007703:Peptidyl-Dipeptidase A; D008666:Metalloendopeptidases; C022510:thimet oligopeptidase