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JCI Insight. 2018 Aug 23;3(16). pii: 122156. doi: 10.1172/jci.insight.122156. eCollection 2018 Aug 23.

Oral nitrite restores age-dependent phenotypes in eNOS-null mice.

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Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.
A.J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania, USA.
Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Cardiovascular Research Center Massachusetts General Hospital, Boston, Massachusetts, USA.


Alterations in the synthesis and bioavailability of NO are central to the pathogenesis of cardiovascular and metabolic disorders. Although endothelial NO synthase-derived (eNOS-derived) NO affects mitochondrial long-chain fatty acid β-oxidation, the pathophysiological significance of this regulation remains unclear. Accordingly, we determined the contributions of eNOS/NO signaling in the adaptive metabolic responses to fasting and in age-induced metabolic dysfunction. Four-month-old eNOS-/- mice are glucose intolerant and exhibit serum dyslipidemia and decreased capacity to oxidize fatty acids. However, during fasting, eNOS-/- mice redirect acetyl-CoA to ketogenesis to elevate circulating levels of β-hydroxybutyrate similar to wild-type mice. Treatment of 4-month-old eNOS-/- mice with nitrite for 10 days corrected the hypertension and serum hyperlipidemia and normalized the rate of fatty acid oxidation. Fourteen-month-old eNOS-/- mice exhibited metabolic derangements, resulting in reduced utilization of fat to generate energy, lower resting metabolic activity, and diminished physical activity. Seven-month administration of nitrite to eNOS-/- mice reversed the age-dependent metabolic derangements and restored physical activity. While the eNOS/NO signaling is not essential for the metabolic adaptation to fasting, it is critical for regulating systemic metabolic homeostasis in aging. The development of age-dependent metabolic disorder is prevented by low-dose replenishment of bioactive NO.


Fatty acid oxidation; Metabolism; Nitric oxide; Therapeutics

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