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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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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- 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
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Results > Formation of Bioactive Nitrogen Oxides from Dietary Nitrate.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Rests on an assumption: The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding indicates that at least some of the observed metabolic effects of nitrate are cGMP-independent.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 4
- Probably not a substantial claim. 4
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The effects of sodium nitrate are attributable to nitrate rather than to sodium or other components of the treatment.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Results > Blood Pressure.
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Materials and Methods > Animals.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All animal work was conducted in accordance with the Swedish Animal Research Committee at Karolinska Institutet.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Materials and Methods > Animals.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Ingested nitrate is rapidly absorbed in the small intestine, then actively taken up by the salivary glands and concentrated in saliva.”
§ Dietary inorganic nitrate reverses features of metabolic syndrome in endothelial nitric oxide synthase-deficient mice > Discussion
What the sources say
- Not checked yetcites [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 yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Metadata
- 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 (medical) › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Biochemistry (medical) › 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
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