Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice
Lauren T Robertson, J Humberto Treviño-Villarreal, Pedro Mejia, Yohann Grondin, Eylul Harputlugil, Christopher Hine, Dorathy Vargas, Hanqiao Zheng, C Keith Ozaki, Bruce S Kristal, Stephen J Simpson, James R Mitchell, Lauren T Robertson, J Humberto Treviño-Villarreal, Pedro Mejia, Yohann Grondin, Eylul Harputlugil, Christopher Hine, Dorathy Vargas, Hanqiao Zheng, C Keith Ozaki, Bruce S Kristal, Stephen J Simpson, James R Mitchell
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.
Objectives: 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.
Keywords: AMPK; GCN2; amino acid sensing; calorie restriction; dietary restriction; geometric framework; ischemia reperfusion injury; leptin; mTOR; protein restriction.
Conflict of interest statement
Author disclosures: LT Robertson, JH Treviño-Villarreal, P Mejia, Y Grondin, E Harputlugil, C Hine, D Vargas, H Zheng, CK Ozaki, BS Kristal, SJ Simpson, and JR Mitchell, no conflicts of interest.
© 2015 American Society for Nutrition.
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Source: PubMed