Renal nutrient loss promotes metabolic health at the expense of increased vulnerability to acute kidney injury
- 1The University of Sydney
Abstract
Obesity is a major risk factor for interrelated cardiorenal metabolic diseases including type 2 diabetes, heart failure and chronic kidney disease (1-4). Although obesity develops when energy intake chronically exceeds energy expenditure, individuals vary markedly in the amount of adiposity and metabolic dysfunction that develop in response to comparable caloric excess. Controlled overfeeding studies demonstrate several-fold variation in weight gain between individuals (5), while susceptibility to metabolic dysfunction also differs substantially between populations (6), suggesting considerable variation in how excess nutrients are partitioned. Energy balance is conventionally considered in terms of intake and expenditure, yet energy-containing nutrients can also be eliminated from the body. The kidney is uniquely positioned to regulate this third component of energy balance by determining whether filtered metabolites are reabsorbed or excreted. The metabolic benefits of SGLT2 inhibition demonstrate that reducing renal nutrient reabsorption can favourably alter systemic metabolic function (7,8), but whether naturally occurring variation in renal nutrient conservation contributes to metabolic disease susceptibility remains unknown. Here, screening eleven genetically divergent mouse strains identified BXD34 mice as strikingly resistant to diet-induced obesity, ectopic lipid accumulation and insulin resistance despite increased caloric intake. Mechanistically, this protection was associated with widespread urinary nutrient loss accompanied by coordinated suppression of renal solute transport, but came at the cost of profound susceptibility to acute kidney injury. Together, these findings identify renal nutrient conservation as an underappreciated determinant of whole-body metabolism and reveal a renometabolic trade-off in which protection from obesity is achieved at the expense of renal resilience.
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BibTeX
@misc{cutler2026renal,
title = {{Renal nutrient loss promotes metabolic health at the expense of increased vulnerability to acute kidney injury}},
author = {H. B. Cutler and A. Diaz Vegas and O. K. Fuller and K. C. Cooke and S. W. Masson and S. Madsen and J. Stöckli and S. Ashitani and K. Igarashi and T. Soga and L. Gao and F. Torta and D. E. James},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.24.754002},
url = {https://www.biorxiv.org/content/10.64898/2026.09.24.754002v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Renal nutrient loss promotes metabolic health at the expense of increased vulnerability to acute kidney injury
AU - H. B. Cutler
AU - A. Diaz Vegas
AU - O. K. Fuller
AU - K. C. Cooke
AU - S. W. Masson
AU - S. Madsen
AU - J. Stöckli
AU - S. Ashitani
AU - K. Igarashi
AU - T. Soga
AU - L. Gao
AU - F. Torta
AU - D. E. James
PY - 2026
DA - 2026/09/24
PB - bioRxiv
DO - 10.64898/2026.09.24.754002
UR - https://www.biorxiv.org/content/10.64898/2026.09.24.754002v1
AB - Obesity is a major risk factor for interrelated cardiorenal metabolic diseases including type 2 diabetes, heart failure and chronic kidney disease (1-4). Although obesity develops when energy intake chronically exceeds energy expenditure, individuals vary markedly in the amount of adiposity and metabolic dysfunction that develop in response to comparable caloric excess. Controlled overfeeding studies demonstrate several-fold variation in weight gain between individuals (5), while susceptibility to metabolic dysfunction also differs substantially between populations (6), suggesting considerable variation in how excess nutrients are partitioned. Energy balance is conventionally considered in terms of intake and expenditure, yet energy-containing nutrients can also be eliminated from the body. The kidney is uniquely positioned to regulate this third component of energy balance by determining whether filtered metabolites are reabsorbed or excreted. The metabolic benefits of SGLT2 inhibition demonstrate that reducing renal nutrient reabsorption can favourably alter systemic metabolic function (7,8), but whether naturally occurring variation in renal nutrient conservation contributes to metabolic disease susceptibility remains unknown. Here, screening eleven genetically divergent mouse strains identified BXD34 mice as strikingly resistant to diet-induced obesity, ectopic lipid accumulation and insulin resistance despite increased caloric intake. Mechanistically, this protection was associated with widespread urinary nutrient loss accompanied by coordinated suppression of renal solute transport, but came at the cost of profound susceptibility to acute kidney injury. Together, these findings identify renal nutrient conservation as an underappreciated determinant of whole-body metabolism and reveal a renometabolic trade-off in which protection from obesity is achieved at the expense of renal resilience.
ER -