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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.
Citation Information: J Clin Invest. 2016;126(9):e85946. https://doi.org/10.1172/JCI85946.
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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MD Neinast, C Jang, S Hui, DS Murashige, Q Chu, RJ Morscher, X Li, L Zhan, E White, TG Anthony, JD Rabinowitz, Z Arany |
Cell Metabolism | 2018 |
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Overexpression of CYB5R3 and NQO1, two NAD + -producing enzymes, mimics aspects of caloric restriction
A Diaz-Ruiz, M Lanasa, J Garcia, H Mora, F Fan, A Martin-Montalvo, AD Francesco, M Calvo-Rubio, A Salvador-Pascual, MA Aon, KW Fishbein, KJ Pearson, JM Villalba, P Navas, M Bernier, R de Cabo |
Aging Cell | 2018 |
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Low- and high-protein diets do not alter ex vivo insulin action in skeletal muscle
Z Li, ML Rasmussen, J Li, CH Olguín, JR Knudsen, O Søgaard, AB Madsen, TE Jensen |
Physiological Reports | 2018 |
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Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
T Laeger, T Castaño-Martinez, MW Werno, L Japtok, C Baumeier, W Jonas, B Kleuser, A Schürmann |
Diabetologia | 2018 |
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Periodized low protein-high carbohydrate diet confers potent, but transient, metabolic improvements
Z Li, ML Rasmussen, J Li, C Henriquez-Olguin, JR Knudsen, AB Madsen, E Sanchez-Quant, M Kleinert, TE Jensen |
Molecular Metabolism | 2018 |
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Effects of timing of food intake and fat/carbohydrate ratio on insulin sensitivity and preconditioning against renal ischemia reperfusion injury by calorie restriction
JS Reynolds, W Peng, T Chu, JR Mitchell |
Nutrition and Healthy Aging | 2018 |
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Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
AM Lundsgaard, AM Fritzen, KA Sjøberg, LS Myrmel, L Madsen, JF Wojtaszewski, EA Richter, B Kiens |
Molecular Metabolism | 2017 |
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Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution
A Maida, JS Chan, KA Sjøberg, A Zota, D Schmoll, B Kiens, S Herzig, AJ Rose |
Molecular Metabolism | 2017 |
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Low protein-induced increases in FGF21 drive UCP1-dependent metabolic but not thermoregulatory endpoints
CM Hill, T Laeger, DC Albarado, DH McDougal, HR Berthoud, H Münzberg, CD Morrison |
Scientific Reports | 2017 |
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Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase
RJ Al-Baghdadi, IA Nikonorova, ET Mirek, Y Wang, J Park, WJ Belden, RC Wek, TG Anthony |
Scientific Reports | 2017 |
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Restoration of metabolic health by decreased consumption of branched-chain amino acids: A low BCAA diet restores metabolic health
NE Cummings, EM Williams, I Kasza, EN Konon, MD Schaid, BA Schmidt, C Poudel, DS Sherman, D Yu, SI Apelo, SE Cottrell, G Geiger, ME Barnes, JA Wisinski, RJ Fenske, KA Matkowskyj, ME Kimple, CM Alexander, MJ Merrins, DW Lamming |
The Journal of Physiology | 2017 |
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