A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Adriano Maida, … , Stephan Herzig, Adam J. Rose
Adriano Maida, … , Stephan Herzig, Adam J. Rose
Published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):e85946. https://doi.org/10.1172/JCI85946.
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Research Article Metabolism

A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution

Abstract

Dietary protein intake is linked to an increased incidence of type 2 diabetes (T2D). Although dietary protein dilution (DPD) can slow the progression of some aging-related disorders, whether this strategy affects the development and risk for obesity-associated metabolic disease such as T2D is unclear. Here, we determined that DPD in mice and humans increases serum markers of metabolic health. In lean mice, DPD promoted metabolic inefficiency by increasing carbohydrate and fat oxidation. In nutritional and polygenic murine models of obesity, DPD prevented and curtailed the development of impaired glucose homeostasis independently of obesity and food intake. DPD-mediated metabolic inefficiency and improvement of glucose homeostasis were independent of uncoupling protein 1 (UCP1), but required expression of liver-derived fibroblast growth factor 21 (FGF21) in both lean and obese mice. FGF21 expression and secretion as well as the associated metabolic remodeling induced by DPD also required induction of liver-integrated stress response–driven nuclear protein 1 (NUPR1). Insufficiency of select nonessential amino acids (NEAAs) was necessary and adequate for NUPR1 and subsequent FGF21 induction and secretion in hepatocytes in vitro and in vivo. Taken together, these data indicate that DPD promotes improved glucose homeostasis through an NEAA insufficiency–induced liver NUPR1/FGF21 axis.

Authors

Adriano Maida, Annika Zota, Kim A. Sjøberg, Jonas Schumacher, Tjeerd P. Sijmonsma, Anja Pfenninger, Marie M. Christensen, Thomas Gantert, Jessica Fuhrmeister, Ulrike Rothermel, Dieter Schmoll, Mathias Heikenwälder, Juan L. Iovanna, Kerstin Stemmer, Bente Kiens, Stephan Herzig, Adam J. Rose

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Figure 6

The integrated stress response mediates liver FGF21 induction and associated metabolic remodeling with dietary protein dilution via nuclear protein 1.

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The integrated stress response mediates liver FGF21 induction and associ...
(A) Serum FGF21 levels following overnight fasting and refeeding in mice on control (CD) or protein-diluted (PD) diets for 3 weeks. n = 5/group. (B) Liver phospho-Ser51-eukaryotic initiation factor 2α (p-S51-eIF2α) levels in overnight fasted and then 6-hour-refed mice following a 2-week adaptation to the respective diets. n = 6/group. Representative images shown are from the same samples blotted on different membranes on separate occasions. (C) Liver mRNA levels of fibroblast growth factor 21 (Fgf21), nuclear protein 1 (Nupr1), growth arrest and DNA damage–induced 45 beta (Gadd45b), tribbles homologue 3 (Trb3), asparagine synthetase (Asns), and sestrin 2 (Sesn2) of mice treated as in A. (D) Liver mRNA levels of Nupr1, Gadd45b, Trb3, Asns, Sesn2, and Fgf21 of mice adapted to CD or PD for 2 weeks, overnight fasted, and then refed and administered integrated stress response inhibitor (ISRIB) or vehicle. n = 5/group. (E) Serum FGF21 levels from mice treated as in D. (F) Serum FGF21 levels from whole-body nuclear protein 1 knockout (Nupr1–/–) and Nupr1+/+ mice adapted to low-fat CD or PD and subjected to overnight fasting and refeeding. n =5 or 6/group. (G) Liver NUPR1 protein expression in CD- or PD-fed mice given adenoviruses overexpressing negative control (NC) or Nupr1-selective shRNAs in the liver using a similar experimental design as in Supplemental Figure 5P. n = 5 or 6/group. (H) Liver mRNA expression of Nupr1, Gadd45b, Trb3, Asns, and Sesn2 in mice treated as in G. (I) Serum FGF21 levels of mice treated as in G. (J) Feed efficiency of mice treated as in G. (K) Fasting insulin sensitivity index [ISI(f)] of mice treated as in G. Data are presented as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 for differences between diets. #P < 0.05, ##P < 0.01, and ###P < 0.001 for differences between genotype/virus. Statistical tests used were 2-way repeated measures ANOVA with Holm-Sidak post-hoc test (A), unpaired t test (B and C), and 2-way ANOVA with Holm-Sidak post-hoc test (D–K). See also Supplemental Figure 6.