ArticleThe Journal of clinical investigation2016
A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
123 citing papers in PubMed, 166 citations in OpenAlex.
- Trial
- Dietary Protein Reduction During Isocaloric Conditions Reduces Body Weight in Men With Overweight or Obesity.Obesity (Silver Spring, Md.) · 2026Trial
- Effects of a two-week modified ketogenic diet on circulating lipoprotein subclasses, GDF15, and FGF21 in obese adults.Journal of translational medicine · 2025Trial
- Meal sugar-protein balance determines postprandial FGF21 response in humans.American journal of physiology. Endocrinology and metabolism · 2023Trial
- Trial
- AKR-001, an Fc-FGF21 Analog, Showed Sustained Pharmacodynamic Effects on Insulin Sensitivity and Lipid Metabolism in Type 2 Diabetes Patients.Cell reports. Medicine · 2020Trial
- Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.JCI insight · 2018Trial
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Female resistance to the metabolic benefits of protein restriction is reversed by ovariectomy in mice.bioRxiv : the preprint server for biology · 2026Article
- FGF21 signals through hindbrain neurons to alter food intake and energy expenditure during dietary protein restriction.Cell reports · 2026Article
- A nutrient-hormone axis pivots an energy trade-off between resting thermogenesis and movement expenditure.Journal of sport and health science · 2026Article
- A low-protein diet drives short- and long-term improvements in metabolic health in a mouse model of sleeve gastrectomy.Cell reports. Medicine · 2025Article
- Dietary isoleucine content modulates the metabolic and molecular response to a Western diet in mice.Molecular metabolism · 2025Article
- Decision-Making Scores and Hunger Susceptibility: A Positive Correlation Mediated by Fasting FGF21 Independently of Body Fat.Nutrients · 2025Article
- Tissue-Specific Effects of Dietary Protein on Cellular Senescence Are Mediated by Branched-Chain Amino Acids.Aging cell · 2025Article
- Comparative Single-Cell Transcriptomic Landscape Reveals the Regulatory Mechanisms of Lactation during Selective Breeding in Asian Water Buffalo.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Manipulating dietary protein and amino acids in the common marmoset Callithrix jacchus impacts circulating metabolites and FGF21 levels.Scientific reports · 2025Article
- Brain amino acid sensing for organismal amino acid homeostasis.Open biology · 2025Review
- Dietary macronutrient content and energy intake in the mouse: hedonic or homeostatic override?Obesity (Silver Spring, Md.) · 2025Article
- The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21.Science advances · 2025Article
63 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
17 authors at 5 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.