title: Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice.
abstract: BACKGROUND
  Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood.
  
  
  OBJECTIVE
  We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects.
  
  
  METHODS
  Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2-dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period.
  
  
  RESULTS
  CR-mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI.
  
  
  CONCLUSIONS
  In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression.
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Robertson
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: J Humberto
authors.initials: JH
authors.lastname: Treviño-Villarreal
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Pedro
authors.initials: P
authors.lastname: Mejia
authors.affiliation: Environmental Health, Harvard School of Public Health, Boston, MA;
authors.forename: Yohann
authors.initials: Y
authors.lastname: Grondin
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Eylul
authors.initials: E
authors.lastname: Harputlugil
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Hine
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Dorathy
authors.initials: D
authors.lastname: Vargas
authors.affiliation: Departments of Genetics and Complex Diseases and.
authors.forename: Hanqiao
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Departments of Surgery and.
authors.forename: C Keith
authors.initials: CK
authors.lastname: Ozaki
authors.affiliation: Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Kristal
authors.affiliation: Charles Perkins Centre, University of Sydney, Sydney, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Simpson
authors.affiliation: Departments of Genetics and Complex Diseases and jmitchel@hsph.harvard.edu.
authors.forename: James R
authors.initials: JR
authors.lastname: Mitchell
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D000818:Animals; D019540:Area Under Curve; D031204:Caloric Restriction; D004044:Dietary Proteins / Q000008:administration & dosage*; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control*; D014508:Urea / Q000097:blood
chemical_list: D004044:Dietary Proteins; D020738:Leptin; D014508:Urea; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: AMPK; GCN2; amino acid sensing; calorie restriction; dietary restriction; geometric framework; ischemia reperfusion injury; leptin; mTOR; protein restriction