Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice
Open accessAbstract
The metabolic syndrome is a clustering of risk factors of metabolic origin that increase the risk for cardiovascular disease and type 2 diabetes. A proposed central event in metabolic syndrome is a decrease in the amount of bioavailable nitric oxide (NO) from endothelial NO synthase (eNOS). Recently, an alternative pathway for NO formation in mammals was described where inorganic nitrate, a supposedly inert NO oxidation product and unwanted dietary constituent, is serially reduced to nitrite and then NO and other bioactive nitrogen oxides. Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions. In humans, this dose corresponds to a rich intake of vegetables, the dominant dietary nitrate source. Nitrate administration increased tissue and plasma levels of bioactive nitrogen oxides. Moreover, chronic nitrate treatment reduced visceral fat accumulation and circulating levels of triglycerides and reversed the prediabetic phenotype in these animals. In rats, chronic nitrate treatment reduced blood pressure and this effect was also present during NOS inhibition. Our results show that dietary nitrate fuels a nitrate–nitrite–NO pathway that can partly compensate for disturbances in endogenous NO generation from eNOS. These findings may have implications for novel nutrition-based preventive and therapeutic strategies against cardiovascular disease and type 2 diabetes.
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TL;DR
Dietary sodium nitrate supplementation in eNOS-deficient mice increased bioactive nitrogen oxides and reversed several features of metabolic syndrome, including visceral fat, circulating triglycerides, and a prediabetic glucose phenotype. Chronic nitrate also lowered blood pressure in rats, with the effect still present during NOS inhibition.
Key findings
- Acute nitrate (0.1 mmol·kg−1 i.p.) increased plasma nitrite and tissue nitros(yl)ation products in eNOS-deficient mice; chronic nitrate increased tissue S-nitrosothiols/nitros(yl)ation products without significantly changing plasma/tissue nitrate and nitrite versus controls.
- In aged eNOS−/− mice, chronic sodium nitrate (0.1 mmol·kg−1·d−1; 85 mg·L−1, 1 mM in drinking water for 8–10 wk) reduced body weight over a 7-wk observation period, reduced visceral fat, and lowered circulating triglycerides.
- After 10 wk of nitrate supplementation, glucose tolerance was almost normalized in eNOS−/− mice; fasting blood glucose, HbA1c, and the proinsulin/insulin ratio were lower than in untreated eNOS−/− mice. Nitrate had no effect on glucose tolerance in young wild-type or nNOS-deficient mice.
- In rats, chronic nitrate (same dose for 8 wk) lowered mean arterial pressure throughout a 3-d observation period, and this difference persisted after L-NAME (1 g·L−1); L-NAME’s pressor effect was delayed by 12 h in nitrate-treated animals. No firm evidence of increased mitochondrial biogenesis or tissue cGMP was found.
Methods
- Aged eNOS-deficient mice (mean 16 mo, range 14–22 mo) were randomized to sodium nitrate in drinking water (85 mg·L−1, 1 mM) for 8–10 wk or control; acute experiments used 0.1 mmol·kg−1 i.p. Rats received the same nitrate dose for 8 wk for telemetric blood pressure measurements, followed by L-NAME (1 g·L−1).
- Nitrate, nitrite, and nitros(yl)ation products were measured by chemiluminescence. Glucose tolerance tests were performed after 14 h fasting with i.p. glucose (2 g·kg−1); HbA1c, insulin, and proinsulin were measured after 14 h fasting. Body weight was recorded weekly for 7 wk; visceral adipose tissue and triglycerides were measured at termination.
- Statistics used mean ± SEM with 5–15 animals per group; two-tailed independent Student’s t test, ANOVA with Bonferroni or Dunnett’s post hoc tests, and P < 0.05 considered significant.
Limitations
- The paper states that the reason for the 12-h delay in the L-NAME blood-pressure response in nitrate-treated rats is not known, and that the importance of enterosalivary nitrate cycling and bacteria-derived nitrite formation in mice is yet to be determined.
- The paper states that long-term human intervention studies are warranted and that the exact mechanisms underlying metabolic syndrome remain unsettled; it also notes that failure to detect increased tissue cGMP does not exclude cGMP-mediated effects.
- Evident from the text: findings are from animal models (aged eNOS-deficient mice and rats), not humans; sample sizes were modest (5–15 per group), and the eNOS-deficient model may not fully represent human metabolic syndrome.
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- Findingown data
Dietary supplementation with sodium nitrate reverses several features of metabolic syndrome in eNOS-deficient mice, at doses similar to those derived from eNOS under normal conditions.
“Here we show that several features of metabolic syndrome that develop in eNOS-deficient mice can be reversed by dietary supplementation with sodium nitrate, in amounts similar to those derived from eNOS under normal conditions.”
- Also stated in: § Discussion · plain
“The results presented herein show that dietary supplementation with inorganic nitrate attenuates several features of metabolic syndrome in aged eNOS-deficient mice.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
- Also stated in: § Discussion · plain
- Findingown data
After chronic low-dose nitrate administration, plasma and tissue levels of nitrate and nitrite were not significantly different from those in control animals receiving no nitrate supplementation.
“With chronic low-dose administration of nitrate, plasma and tissue levels of nitrate and nitrite were not significantly different from those seen in control animals receiving no nitrate supplementation.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
- Interpretationown data
At least some of the observed metabolic effects of nitrate are cGMP-independent.
“This finding indicates that at least some of the observed metabolic effects of nitrate are cGMP-independent.”
Quote in the paperSubstantial claim - Interpretationreasoning
The present findings are highly relevant from a nutritional perspective because the amount of nitrate used is readily achievable via a normal diet.
“The present findings are highly relevant from a nutritional perspective as well, as the amount of nitrate used is readily achievable via a normal diet.”
Quote in the paperSubstantial claim - Interpretationreasoning
The oxidized end-product nitrate may serve as a long-lived reservoir for NO-like bioactivity in tissues.
“Thus, in addition to the second-by-second regulation of vascular tone by eNOS-derived NO, its oxidized end-product nitrate may serve as a long-lived reservoir for NO-like bioactivity in tissues.”
Quote in the paperSubstantial claim
- May combine two claims. 4
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataIn the present study, no increase in tissue cGMP formation was detected after nitrate, but significant formation of nitros(yl)ation products, including S-nitrosothiols, was detected in tissues after nitrate administration.
“In the present study, we failed to detect an increase in tissue cGMP formation after nitrate, but we did detect significant formation of nitros(yl)ation products, including S-nitrosothiols, in the tissues after nitrate administration.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
May combine two claims.
InterpretationreasoningThe very modest amount of dietary nitrate had profound biological effects, supporting the possibility that endogenous nitrate levels are already sufficient to affect cellular processes.
“The fact that this very modest amount had such profound biological effects supports the intriguing possibility that endogenous nitrate levels are already sufficient to affect cellular processes.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationnone givenNOS-independent NO formation seemed to have prevented the initial blood-pressure response during NOS inhibition in nitrate-treated animals.
“The reason for this is not known, but apparently NOS-independent NO formation seemed to have prevented the initial blood-pressure response during NOS inhibition.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoningeNOS-deficient mice were randomly assigned to treatment groups to ensure that each group had the same average age and weight.
“The eNOS-deficient mice were obtained from Jackson Laboratories and were randomly assigned to treatment groups to ensure that each group had the same average age (mean 16 mo, range 14–22 mo) and weight.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal work was conducted in accordance with the Swedish Animal Research Committee at Karolinska Institutet.
“All animal work was conducted in accordance with the Swedish Animal Research Committee at Karolinska Institutet.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe lack of effect of nitrate on glucose tolerance in young wild-type and nNOS-deficient mice is consistent with the theory that metabolic effects of nitrate might be related to a reduction in oxidative stress, which is absent or less pronounced in these mice.
“This result is consistent with the theory that metabolic effects of nitrate might be related to a reduction in oxidative stress, which is indeed absent or less pronounced in these mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIngested nitrate is rapidly absorbed in the small intestine, then actively taken up by the salivary glands and concentrated in saliva.
“Ingested nitrate is rapidly absorbed in the small intestine, then actively taken up by the salivary glands and concentrated in saliva.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [18] Lundberg JO, Govoni M. Inorganic nitrate is a possible source for systemic generation of nitric oxide. Free Radic Biol Med. 2004;37:395–400. doi: 10.1016/j.freeradbiomed.2004.04.027. [[DOI](https://doi.org/10.1016/j.freeradbiomed.2004.04.027)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/15223073/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Free%20Radic%20Biol%20Med&title=Inorganic%20nitrate%20is%20a%20possible%20source%20for%20systemic%20generation%20of%20nitric%20oxide&author=JO%20Lundberg&author=M%20Govoni&volume=37&publication_year=2004&pages=395-400&pmid=15223073&do source
Not checked in the free run.
- cites [22] Gladwin MT, et al. The emerging biology of the nitrite anion. Nat Chem Biol. 2005;1:308–314. doi: 10.1038/nchembio1105-308. [[DOI](https://doi.org/10.1038/nchembio1105-308)] [[PubMed](https://pubmed.ncbi.nlm.nih.gov/16408064/)] [[Google Scholar](https://scholar.google.com/scholar_lookup?journal=Nat%20Chem%20Biol&title=The%20emerging%20biology%20of%20the%20nitrite%20anion&author=MT%20Gladwin&volume=1&publication_year=2005&pages=308-314&pmid=16408064&doi=10.1038/nchembio1105-308&)] source
Not checked in the free run.
The paper relies on this without support.
The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
“NaNO3 was added to the drinking water during 8 to 10 wk at a concentration of 85 mg·L−1 (1 mM).”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent studies demonstrate improvements of insulin resistance in humans and animals as a result of dietary nitrate/nitrite enhancing NO availability in plasma and tissues.
“the therapeutic potential of dietary nitrate/nitrite has been supported by recent studies demonstrating the improvements of insulin resistance in humans and animals as a result of its enhancing the NO availability in plasma and tissues [65,66,67,68].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [66]
Endogenous production of nitrate from NO oxidation is an order of magnitude greater than dietary intake.
“the endogenous production of nitrate from NO oxidation (mainly via reaction with oxy-hemoglobin) has long been recognized to be an order of magnitude greater than dietary intake as shown in the late 1970s [7] and more recently in studies using eNOS-deficient mice [45].”
From Nitrate reduction to nitrite, nitric oxide and ammonia by gut bacteria under physiological conditions (2015) · cites this paper as [45]
NOS3 dependent NO production plays an important role in regulating steady state plasma nitrite levels, while also influencing nitrate, nitroso, and nitrosyl products in tissues.
“NOS3 dependent NO production plays an important role in regulating steady state plasma nitrite levels, while also influencing nitrate, nitroso, and nitrosyl products in tissues [72, 73].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [72]
Long-term dietary nitrate consumption can reverse metabolic parameters associated with eNOS dysfunction that are associated with the development of cardiovascular disease.
“Recent work from Carlström et al reveals that long term dietary nitrate consumption can reverse metabolic parameters associated with eNOS dysfunction that are associated with the development of cardiovascular disease [72].”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [72]
Daily administration of 85 mg/L−1 nitrate in drinking water for 8-10 weeks decreases body weight, plasma triglycerides, and visceral fat while improving glucose tolerance and fasting blood glucose levels in eNOS deficient mice.
“It was found that daily administration of 85 mg/L−1 in the drinking water for 8–10 weeks decreased body weight, plasma triglycerides, and visceral fat while improving glucose tolerance and fasting blood glucose levels in eNOS deficient mice.”
From Inorganic nitrite therapy: historical perspective and future directions (2011) · cites this paper as [72]
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“This leads to downstream signaling to induce a wide spectrum of biological responses including hypoxic vasodilation [8], stimulation of angiogenesis [23], modulation of glucose metabolism [24], augmentation of exercise efficiency [20], regulation of mitochondrial function [9,25,26] and tolerance to I/R [22,27–29] (Fig.”
BackgroundNitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation
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- Authors
- Carlström, M., Larsen, F. J., Nyström, T., Hezel, M., Borniquel, S., Weitzberg, E., & Lundberg, J. O.
- Affiliations
- Uppsala University (SE)
- Karolinska Institutet (SE)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-09-27
- Volume
- 107
- Issue
- 41
- Pages
- 17716-17720
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2955084
- OpenAlex
- W2074172668
- Cited by
- 382
- References
- 43
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 18 · 2023: 21 · 2022: 24 · 2021: 15 · 2020: 31 · 2019: 22 · 2018: 25 · 2017: 33 · 2016: 33 · 2015: 30 · 2014: 31 · 2013: 22 · 2012: 29
- FWCI
- 16.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wenner-Gren Foundation
- European Commission
- Kommunfullmäktige, Stockholms Stad
- Karolinska Institutet
- Vetenskapsrådet
- Svenska Läkaresällskapet
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Biochemistry › Phytochemicals and Antioxidant Activities
- Keywords
- dietary nitrate, sodium nitrate, metabolic syndrome, endothelial nitric oxide synthase, nitrate-nitrite-NO pathway, visceral fat accumulation, triglycerides, prediabetes, blood pressure, cardiovascular disease prevention, type 2 diabetes, eNOS-deficient mice
- MeSH terms
- Analysis of Variance, Animals, Blood Pressure, Body Weight, Mice, Mutant Strains, Nitrates, Nitrogen Oxides, Triglycerides, Dietary Supplements, Metabolic Syndrome, Intra-Abdominal Fat, Mice, Rats, Nitric Oxide Synthase Type III
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.
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.
What counts as a claim ›How we measure confidence ›How we check this ›
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