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

Area of Science:

• Cardiovascular and metabolic research
• Nitric oxide (NO) signaling pathways
• Mitochondrial fatty acid metabolism

Background:

• Alterations in NO synthesis and bioavailability are key in cardiovascular and metabolic diseases.
• Endothelial NO synthase (eNOS)-derived NO influences mitochondrial fatty acid oxidation, but its role in disease pathogenesis is not fully understood.

Purpose of the Study:

• To investigate the role of eNOS/NO signaling in metabolic adaptation to fasting.
• To determine the contribution of eNOS/NO signaling to age-induced metabolic dysfunction.

Main Methods:

• Utilized eNOS knockout (eNOS-/-) mice and wild-type littermates.
• Assessed metabolic parameters including glucose tolerance, lipid profiles, fatty acid oxidation, and ketogenesis.
• Administered nitrite to eNOS-/- mice to replenish bioactive NO levels.
• Evaluated metabolic function and physical activity in young and aged mice.

Main Results:

• Four-month-old eNOS-/- mice showed glucose intolerance, dyslipidemia, and reduced fatty acid oxidation, but adapted metabolically to fasting via ketogenesis.
• Nitrite treatment in young eNOS-/- mice corrected hypertension, hyperlipidemia, and normalized fatty acid oxidation.
• Aged (14-month-old) eNOS-/- mice exhibited significant metabolic derangements, including reduced fat utilization, lower resting metabolic rate, and decreased physical activity.
• Long-term nitrite administration reversed age-dependent metabolic decline and restored physical activity in eNOS-/- mice.

Conclusions:

• eNOS/NO signaling is not essential for fasting-induced metabolic adaptation.
• eNOS/NO signaling is critical for maintaining metabolic homeostasis during aging.
• Low-dose NO replenishment can prevent age-dependent metabolic disorders and restore physical activity.