Nitric Oxide Signaling in Metabolic Disorders

Nitric oxide (NO) operates as a key regulator of vascular tone, neurotransmission and cellular metabolism. In metabolic tissues, NO is synthesised by three main nitric oxide synthase (NOS) isoforms: endothelial (eNOS), neuronal (nNOS) and inducible (iNOS). Constitutive NOS activity supports insulin-mediated glucose uptake in skeletal muscle and adipose tissue, maintains microvascular perfusion in pancreatic islets and promotes mitochondrial biogenesis. By contrast, sustained induction of iNOS in response to pro-inflammatory stimuli leads to excessive NO production, S-nitrosylation of insulin receptor substrates and disruption of signalling pathways that control glucose and lipid homeostasis. This imbalance contributes to insulin resistance, dyslipidaemia and hepatic steatosis. Advances in understanding the spatial and temporal regulation of NO generation have revealed cross-talk with adipokines, redox sensors and nutrient-sensitive kinases. Restoring this balance through modulation of NOS activity or NO bioavailability holds promise for alleviating metabolic dysfunction and its cardiovascular sequelae.

Research from Nature Portfolio

Recent studies using loss-of-function models have illuminated the dual role of NO in energy balance and insulin action. In rodent models lacking iNOS, early alterations in hepatic and adipose nitrite content led to compromised insulin signalling, dysregulated gluconeogenesis and heightened adiposity despite normal mitochondrial respiration. These findings establish a direct link between impaired NO status and systemic insulin resistance. Complementary work in hypothalamic circuits demonstrated that S-nitrosation of insulin receptors and downstream kinase Akt by iNOS mediates central insulin resistance, altering feeding behaviour and energy expenditure. Inhibiting this modification restored central insulin sensitivity and normalised energy homeostasis, highlighting the importance of compartmentalised NO signalling in both peripheral and central regulation of metabolism.

Nitric Oxide Signaling in Metabolic Disorders publication trend

The graph below shows the total number of articles in nitric oxide signaling in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Nitric oxide (NO): A gaseous signalling molecule produced by NOS that modulates vascular, neural and metabolic processes.

Endothelial NOS (eNOS): Constitutive enzyme in endothelial cells; generates NO to promote vasodilation and insulin-mediated glucose uptake.

Inducible NOS (iNOS): Enzyme upregulated by inflammatory stimuli; produces high NO levels, leading to nitrosative stress and insulin resistance.

S-nitrosylation: Post-translational modification of protein cysteines by NO; can alter enzyme activity and signalling cascades.

Insulin resistance: Impaired cellular response to insulin resulting in reduced glucose uptake and disrupted metabolic homeostasis.

References

1. Enhancing Muscle Intracellular Ca2+ Homeostasis and Glucose Uptake: Passive Pulsatile Shear Stress Treatment in Type 2 Diabetes. Biomedicines (2023).
2. Redox Regulation of Lipid Mobilization in Adipose Tissues. Antioxidants (2021).
3. Functional Relationship between Leptin and Nitric Oxide in Metabolism. Nutrients (2019).
4. Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance. Scientific Reports (2017).
5. iNOS promotes hypothalamic insulin resistance associated with deregulation of energy balance and obesity in rodents. Scientific Reports (2017).