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 September 1, 2016; First published August 22, 2016
Citation Information: J Clin Invest. 2016;126(9):3263-3278. 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 3

Dietary protein dilution promotes improved glucose homeostasis independently of obesity.

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Dietary protein dilution promotes improved glucose homeostasis independe...
(A) Body mass accrual of C57Bl/6N mice fed either control diet (CD) containing 20% caloric energy from protein or a protein-diluted (PD) diet containing 5% caloric energy from protein, diluted by added carbohydrate, with either 10% (LF) or 60% (HF) calories from fat. n = 6–8/group. (B) Feed efficiency from mice treated as in A. (C) Body mass accrual in New Zealand Black (NZB) or New Zealand Obese (NZO) mice fed a CD containing 20% caloric energy from protein or a PD containing 5% caloric energy from protein, diluted by added carbohydrate. n = 6–8/group. (D) Feed efficiency from mice treated as in C. (E) Blood glucose excursion during an intraperitoneal glucose tolerance test (IPGTT) in mice from A. AUCg, glucose area under the curve. (F) Blood glucose excursion during an IPGTT in mice from C. (G) Fasting insulin sensitivity index [ISI(f)] from mice as in A. (H) ISI(f) from mice treated as in C. (I) Urinary glucose levels from mice treated as in C. (J) Tissue glucose uptake rates during an IPGTT from mice treated as in C. pgWAT, perigonadal white adipose tissue; scWAT, subcutaneous white adipose tissue; GCM, gastrocnemius complex muscle; BAT, brown adipose tissue. n = 5 or 6/group. (K) ISI(f) was measured from mice at selected time points before and after maintenance on the same diet or a switch (day 56, indicated by a vertical dashed line) to a respective protein-diluted diet. n = 7 or 8/group. Data are the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 for significant effect of dietary protein. #P < 0.05, ##P < 0.01, and ###P < 0.001 for significant effect of dietary fat/strain. §P < 0.05 and §§§P < 0.001 for significant effect of time. Statistical tests used were 2-way ANOVA with Holm-Sidak post-hoc test (B, D–I), unpaired t test (J), and 2-way repeated measures ANOVA with Holm-Sidak post-hoc test (K). See also Supplemental Figure 3.