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 2

Chronic dietary protein dilution promotes a metabolite and hormonal profile reflective of improved metabolic health as well as enhanced glucose metabolism.

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Chronic dietary protein dilution promotes a metabolite and hormonal prof...
(A) Blood and serum metabolites from mice as in Figure 1A. NEFA, nonesterified fatty acids; BCAA, branched-chain amino acids; BHB, β-hydroxybutyrate. (B) Serum insulin levels in mice from Figure 1A. (C) Serum insulin-like growth factor 1 (IGF1) levels in mice from Figure 1A. (D) Serum leptin levels in mice from Figure 1A. (E) Serum thyroxine (T4) levels in mice from Figure 1A. (F) Serum adiponectin levels in mice from Figure 1A. (G) Serum fibroblast growth factor 21 (FGF21) levels in mice from Figure 1A. (H) Blood glucose excursion during an intraperitoneal glucose tolerance test (IPGTT) 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, for 2 weeks. n = 5 or 6/group. (I) Serum insulin excursion in mice treated as in H. (J) Blood glucose excursion during an intraperitoneal insulin tolerance test (IPITT) in mice treated as in H. n = 5 or 6/group. (K) Serum insulin excursion in mice treated as in J. (L) Insulin action index as represented by the maximal change in blood glucose (ΔG) divided by the maximal level of serum insulin (MI) from mice treated as in H. (M) Tissue glucose uptake rates of mice treated as in J. pgWAT, perigonadal white adipose tissue; scWAT, subcutaneous white adipose tissue; GCM, gastrocnemius complex muscle; BAT, brown adipose tissue. n = 6/group. Data are the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001 by unpaired t test (A–G, L, and M) or 2-way repeated measures ANOVA with Holm-Sidak post-hoc test (H–K) for significant differences between CD and PD. See also Supplemental Figure 2.