A liver stress-endocrine nexus promotes metabolic integrity during dietary protein dilution
Open accessAbstract
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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FGF21 is induced by protein restriction through pathways dependent on ATF4 and NRF2.
“protein restriction through pathways dependent on the transcription factors ATF4 and NRF26,27.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [27]
FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets.
“FGF21 is required for the increases in energy expenditure and the prevention of weight gain associated with low-protein diets26,27.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [27]
FGF21 is induced in response to protein imbalance, specifically dietary-protein dilution.
“Beyond the response to high carbohydrate, FGF21 is induced in response to protein imbalance, specifically dietary-protein dilution26,27,124.”
From Metabolic messengers: FGF21 (2021) · cites this paper as [27]
Hepatic and circulating FGF21 levels increase in response to low-protein content or amino acid deprivation in an ATF4-dependent mechanism.
“Hepatic and circulating FGF21 levels also increase in response to low-protein content or amino acid deprivation [152,[155], [156], [157], [158], [159], [160]] in an ATF4-dependent mechanism [155,161,162].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [156]
The increase in FGF21 in response to low protein results in increased energy expenditure and lower body weight gain.
“This robust increase in FGF21 results in increased energy expenditure and lower body weight gain [155,156,160,163] (Figure 2)”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [156]
FGF21 is absolutely necessary in mice to mediate the effects of low-protein diets.
“FGF21 is absolutely necessary in mice to mediate the effects of low-protein diets (72, 73, 85).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
Low-protein diets, amino acid starvation, and the amino acid-depleting drug asparaginase induce plasma FGF21 levels.
“Low-protein diets (73, 85), amino acid starvation (25, 121), and the amino acid–depleting drug asparaginase (138) also induce plasma FGF21 levels.”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
Protein restriction promotes systemic energy expenditure through elevation in plasma FGF21 levels.
“Interestingly, protein restriction promotes systemic energy expenditure through this elevation in plasma FGF21 levels (73, 85).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
FGF21 is markedly induced in response to protein restriction but not caloric restriction.
“FGF21 is markedly induced in response to protein restriction (25, 73, 85) but not caloric restriction (73, 148).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
NUPR1 is required for normal FGF21 production and associated metabolic remodeling in response to low protein levels.
“In addition, recent studies have identified the liver-integrated stress response–driven nuclear protein 1 (NUPR1) as being required for normal FGF21 production and associated metabolic remodeling in response to low protein levels (85).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
UCP1 is dispensable for FGF21-mediated increases in energy expenditure.
“However, while adipose tissues are critical for these metabolic effects, UCP1 is dispensable for FGF21-mediated increases in energy expenditure (17, 85, 111, 132).”
From Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis (2018) · cites this paper as [85]
Liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans.
“liver FGF21 expression and circulating FGF21 protein levels are increased by the restriction of protein intake in mice, rats, and humans”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [148]
FGF21 is also increased by the restriction of individual amino acids.
“with FGF21 also being increased by the restriction of individual amino acids”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [148]
Although wild-type mice exhibit changes in growth, body composition, food intake, energy expenditure, and glucose metabolism in response to dietary protein restriction, these effects are absent in mice that lack FGF21.
“Although wild-type mice exhibit changes in growth, body composition, food intake, energy expenditure, and glucose metabolism in response to dietary protein restriction, these effects are absent in mice that lack FGF21”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [148]
Reductions in dietary protein intake-or the intake of specific amino acids-increase liver FGF21 mRNA expression and circulating FGF21 protein levels.
“reductions in dietary protein intake—or the intake of specific amino acids—increase liver FGF21 mRNA expression and circulating FGF21 protein levels”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [148]
The increase in FGF21 is absolutely required for metabolic responses to protein restriction.
“this increase in FGF21 is absolutely required for metabolic responses to protein restriction”
From FGF21 and the physiological regulation of macronutrient preference (2020) · cites this paper as [148]
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Renne, U., Langhammer, M., Brenmoehl, J., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0079788 · Cited by 10 · see citing works
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Flippo, K. H., & Potthoff, M. J. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00354-2 · Cited by 311 · see citing works
Hepatokines and metabolism: Deciphering communication from the liver
Jensen-Cody, S. O., & Potthoff, M. J. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2020.101138 · Cited by 252 · see citing works
FGF21 Signals Protein Status to the Brain and Adaptively Regulates Food Choice and Metabolism
Hill, C. M., Laeger, T., Dehner, M., Albarado, D. C., Clarke, B., Wanders, D., Burke, S. J., Collier, J. J., Qualls-Creekmore, E., Solon-Biet, S. M., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.022 · Cited by 229 · see citing works
Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis
BonDurant, L. D., & Potthoff, M. J. (2018) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064800 · Cited by 222 · see citing works
FGF21 Is a Sugar-Induced Hormone Associated with Sweet Intake and Preference in Humans
Søberg, S., Sandholt, C. H., Jespersen, N. Z., Toft, U., Madsen, A. L., von Holstein-Rathlou, S., Grevengoed, T. J., Christensen, K. B., Bredie, W. L. P., Potthoff, M. J., et al. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.04.009 · Cited by 216 · see citing works
Defining the Nutritional and Metabolic Context of FGF21 Using the Geometric Framework
Solon-Biet, S. M., Cogger, V. C., Pulpitel, T., Heblinski, M., Wahl, D., McMahon, A. C., Warren, A., Durrant-Whyte, J., Walters, K. A., Krycer, J. R., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.09.001 · Cited by 212 · see citing works
The impact of dietary protein intake on longevity and metabolic health
Kitada, M., Ogura, Y., Monno, I., & Koya, D. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.04.005 · Cited by 175 · see citing works
“A LPD also enhances EE by increasing sympathetic flux via β-adrenergic receptor signalling to brown adipose tissue (BAT) with the consequent upregulation of uncoupling protein-1 (UCP-1) expression [38–40] and increased FGF21-mediated thermogenesis [33].”
BackgroundInfluentialThe physiological control of eating: signals, neurons, and networks
Watts, A. G., Kanoski, S. E., Sanchez-Watts, G., & Langhans, W. (2022) · Physiological Reviews · doi:10.1152/physrev.00028.2020 · Cited by 168 · see citing works
Hill, C. M., Albarado, D. C., Coco, L. G., Spann, R. A., Khan, M. S., Qualls-Creekmore, E., Burk, D. H., Burke, S. J., Collier, J. J., Yu, S., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-29499-8 · Cited by 117 · see citing works
Kaufman, A., Abuqayyas, L., Denney, W. S., Tillman, E. J., & Rolph, T. (2020) · Cell Reports Medicine · doi:10.1016/j.xcrm.2020.100057 · Cited by 131 · see citing works
Circulating FGF21 in humans is potently induced by short term overfeeding of carbohydrates
Lundsgaard, A.-M., Fritzen, A. M., Sjøberg, K. A., Myrmel, L. S., Madsen, L., Wojtaszewski, J. F. P., Richter, E. A., & Kiens, B. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2016.11.001 · Cited by 126 · see citing works
Self-citationRegulation of longevity by FGF21: interaction between energy metabolism and stress responses
Salminen, A., Kaarniranta, K., & Kauppinen, A. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.05.004 · Cited by 121 · see citing works
FGF21 and the physiological regulation of macronutrient preference
Hill, C. M., Qualls-Creekmore, E., Berthoud, H.-R., Soto, P., Yu, S., McDougal, D. H., Münzberg, H., & Morrison, C. D. (2020) · Endocrinology · doi:10.1210/endocr/bqaa019 · Cited by 99 · see citing works
Hill, C. M., Laeger, T., Albarado, D. C., McDougal, D. H., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2017) · Scientific Reports · doi:10.1038/s41598-017-07498-w · Cited by 97 · see citing works
Fibroblast growth factor-21 controls dietary protein intake in male mice
Larson, K. R., Chaffin, A. T.-B., Goodson, M. L., Fang, Y., & Ryan, K. K. (2019) · Endocrinology · doi:10.1210/en.2018-01056 · Cited by 68 · see citing works
Homeostatic sensing of dietary protein restriction: a case for FGF21
Hill, C. M., Berthoud, H.-R., Münzberg, H., & Morrison, C. D. (2018) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2018.06.002 · Cited by 68 · see citing works
Sex differences in the hormonal and metabolic response to dietary protein dilution
Larson, K. R., Russo, K. A., Fang, Y., Mohajerani, N., Goodson, M. L., & Ryan, K. K. (2017) · Endocrinology · doi:10.1210/en.2017-00331 · Cited by 66 · see citing works
Flippo, K. H., Jensen-Cody, S. O., Claflin, K. E., & Potthoff, M. J. (2020) · Scientific Reports · doi:10.1038/s41598-020-76593-2 · Cited by 49 · see citing works
Zapata, R. C., Singh, A., Pezeshki, A., Avirineni, B. S., Patra, S., & Chelikani, P. K. (2019) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201900088 · Cited by 33 · see citing works
Hypoaminoacidemia underpins glucagon-mediated energy expenditure and weight loss
Hope, D. C. D., Hinds, C. E., Lopes, T., Vincent, M. L., Shrewsbury, J. V., Yu, A. T. C., Davies, I., Scott, R., Jones, B., Murphy, K. G., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100810 · Cited by 32 · see citing works
Adapting to the cold: A role for endogenous fibroblast growth factor 21 in thermoregulation?
Klein Hazebroek, M., & Keipert, S. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00389 · Cited by 27 · see citing works
Laeger, T., Castaño-Martinez, T., Werno, M. W., Japtok, L., Baumeier, C., Jonas, W., Kleuser, B., & Schürmann, A. (2018) · Diabetologia · doi:10.1007/s00125-018-4595-1 · Cited by 17 · see citing works
Hope, D. C. D., & Tan, T. M.-M. (2023) · Peptides · doi:10.1016/j.peptides.2023.170962 · Cited by 16 · see citing works
Role of peptide hormones in the adaptation to altered dietary protein intake
Rose, A. J. (2019) · Nutrients · doi:10.3390/nu11091990 · Cited by 15 · see citing works
- Authors
- Maida, A., Zota, A., Sjøberg, K. A., Schumacher, J., Sijmonsma, T. P., Pfenninger, A., Christensen, M. M., Gantert, T., Fuhrmeister, J., Rothermel, U., Schmoll, D., Heikenwälder, M., Iovanna, J. L., Stemmer, K., Kiens, B., Herzig, S., & Rose, A. J.
- Affiliations
- Helmholtz Munich (DE)
- University of Copenhagen (DK)
- German Cancer Research Center (DE)
- Sanofi (Germany) (DE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Rose, Adam J.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2016-08-22
- Volume
- 126
- Issue
- 9
- Pages
- 3263-3278
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC5004939
- OpenAlex
- W2515394053
- Cited by
- 170
- References
- 77
- Citations by year
- 2026: 7 · 2025: 18 · 2024: 14 · 2023: 21 · 2022: 19 · 2021: 26 · 2020: 15 · 2019: 24 · 2018: 17 · 2017: 7 · 2016: 2
- FWCI
- 8.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- OPUS (Augsburg University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Deutsches Krebsforschungszentrum
- European Foundation for the Study of Diabetes
- Deutsche Forschungsgemeinschaft
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Physiology › Dietary Effects on Health
- Keywords
- type 2 diabetes, glucose homeostasis, FGF21, NUPR1, integrated stress response, non-essential amino acids, obesity
- MeSH terms
- Uncoupling Protein 1, Adipose Tissue, Adult, Animals, Diabetes Mellitus, Type 2, Dietary Proteins, DNA-Binding Proteins, Fibroblast Growth Factors, Glucose, Homeostasis, Humans, Liver, Male, Mice, Inbred C57BL, Mice, Transgenic, Neoplasm Proteins, Obesity, Phenotype, Hepatocytes, Carbohydrate Metabolism, Lipid Metabolism, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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