Effect of a long-term high-protein diet on survival, obesity development, and gut microbiota in mice

Pia Kiilerich, Lene Secher Myrmel, Even Fjære, Qin Hao, Floor Hugenholtz, Si Brask Sonne, Muriel Derrien, Lone Møller Pedersen, Rasmus K. Petersen, Alicja Mortensen, Tine Rask Licht, Maria Unni Rømer, Ulla Birgitte Vogel, Linn Jeanette Waagbø, Natasa Giallourou, Qiang Feng, Liang Xiao, Chuan Liu, Bjørn Liaset, Michiel KleerebezemJun Wang, Lise Madsen, Karsten Kristiansen

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Female C57BL/6J mice were fed a regular low-fat diet or high-fat diets combined with either high or low protein-to-sucrose ratios during their entire lifespan to examine the long-term effects on obesity development, gut microbiota, and survival. Intake of a high-fat diet with a low protein/sucrose ratio precipitated obesity and reduced survival relative to mice fed a low-fat diet. By contrast, intake of a high-fat diet with a high protein/sucrose ratio attenuated lifelong weight gain and adipose tissue expansion, and survival was not significantly altered relative to low-fat-fed mice. Our findings support the notion that reduced survival in response to high-fat/high-sucrose feeding is linked to obesity development. Digital gene expression analyses, further validated by qPCR, demonstrated that the protein/sucrose ratio modulated global gene expression over time in liver and adipose tissue, affecting pathways related to metabolism and inflammation. Analysis of fecal bacterial DNA using the Mouse Intestinal Tract Chip revealed significant changes in the composition of the gut microbiota in relation to host age and dietary fat content, but not the protein/sucrose ratio. Accordingly, dietary fat rather than the protein/sucrose ratio or adiposity is a major driver shaping the gut microbiota, whereas the effect of a high-fat diet on survival is dependent on the protein/sucrose ratio.
Original languageEnglish
Article numberE886-99
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Issue number11
Number of pages14
Publication statusPublished - 2016


  • gut microbiota
  • high-fat diet
  • high-protein diet
  • obesity
  • survival

Cite this

Kiilerich, P., Myrmel, L. S., Fjære, E., Hao, Q., Hugenholtz, F., Sonne, S. B., Derrien, M., Pedersen, L. M., Petersen, R. K., Mortensen, A., Licht, T. R., Rømer, M. U., Vogel, U. B., Waagbø, L. J., Giallourou, N., Feng, Q., Xiao, L., Liu, C., Liaset, B., ... Kristiansen, K. (2016). Effect of a long-term high-protein diet on survival, obesity development, and gut microbiota in mice. American Journal of Physiology: Endocrinology and Metabolism, 310(11), [E886-99]. https://doi.org/10.1152/ajpendo.00363.2015