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 1

Chronic dietary protein dilution promotes feed inefficiency, leanness, and heightened energy expenditure.

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Chronic dietary protein dilution promotes feed inefficiency, leanness, a...
(A) Body mass accrual over 16 weeks in mice fed a control diet (CD) containing 20% caloric energy from protein (CD) or a protein-diluted (PD) diet containing 5% caloric energy from protein, diluted by added carbohydrate. n = 5 or 6/group. (B) Tissue/organ mass at necropsy at 16 weeks in mice from A. pgWAT, perigonadal white adipose tissue; GCM, gastrocnemius complex muscle; BAT, brown adipose tissue. (C) Food energy (E) intake from individually housed mice during days 77–105 by mice from A. (D) Feed efficiency in individually housed mice from A during days 77–105. (E) 24-hour averaged oxygen consumption rate (VO2) in mice fed CD or PD before (pre) and during 3 weeks at an ambient temperature of 22°C and a subsequent 2 weeks at 30°C. Values are mean rates over a 3-day period at the end of each period when values were stable. n = 10/group. (F) 24-hour-averaged CO2 production rate (VCO2) from mice as in E. (G) Daily urinary urea production rate (22°C) from mice as in E. (H) Nutrient oxidation rates (22°C) calculated from indirect calorimetry values as well as urea production. Pro, protein; Cho, carbohydrate. Data are the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by 2-way repeated measures ANOVA with Holm-Sidak post-hoc test (A, E, and F), unpaired t test (B–D and G), or 1-way ANOVA with Holm-Sidak post-hoc test (H) for significant differences between CD and PD. See also Supplemental Figure 1.