N-acetylaspartate (NAA) is the second most abundant metabolite in the human brain. Quantifiable amounts of NAA are also present in the blood, but its role in the peripheral tissues is largely unknown. First, we determined the acute effects of insulin administration on NAA concentrations; second, we assessed whether circulating NAA levels associate with markers of central and peripheral insulin sensitivity. A total of 24 persons living with obesity and 19 healthy, lean controls, without neurological disorders, underwent a euglycemic hyperinsulinemic clamp combined with fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) imaging of the brain, abdomen, and femoral area. Plasma concentrations of NAA were measured at baseline and ~2 h into the clamp using high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS-MS). Glucose uptake (GU) rates were analysed using a fractional uptake rate. Serum acetate levels were also assessed using nuclear magnetic resonance (NMR) metabolomics. From baseline to steady-state, insulin levels increased from a mean level of 66 to 447 pmol/L (p < 0.0001). Over this period, circulating NAA concentrations decreased by 5% (p = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate (r = −0.36, p = 0.048). Circulating NAA was associated with waist–hip ratio (rho = −0.54, p = 0.0002), steady-state free fatty acids (rho = −0.44, p = 0.003), and directly with HDL cholesterol (rho = 0.54, p = 0.0002), adiponectin (rho = 0.48, p = 0.003), and whole-body insulin sensitivity (rho = 0.34, p = 0.03). Circulating NAA was directly related with skeletal muscle (rho = 0.42, p = 0.01) and visceral adipose tissue GU (rho = 0.41, p = 0.02). Insulin administration leads to a small decrease in circulating NAA levels, and NAA associates consistently with markers of insulin sensitivity. While plasma NAA may be relevant to aspects of whole-body homeostasis, mechanistic insights are needed.

N-Acetylaspartate (NAA) plays a critical role in neuronal function, metabolism, and neurotransmitter release. Evidence from magnetic resonance spectroscopy indicates diminished NAA levels in individuals diagnosed with schizophrenia and bipolar disorder; however, this process is time-consuming, expensive, and not viable in individuals with acute illness exacerbation. In order to address these limitations, we developed a novel method for the quantification of plasma NAA based on tandem mass spectrometry coupled to liquid chromatography (HPLC-MS). Our study aimed to assess whether plasma NAA levels change during hospitalization and whether these changes correlate with symptomatic improvement in patients experiencing acute psychiatric exacerbations. We recruited 31 inpatients with acute symptoms of psychotic (48.39%) and/or mood (51.61%) disorders. Symptom severity was assessed using the brief psychiatric rating scale, Positive and Negative Syndrome Scale, and Clinical Global Impression Scale. Plasma NAA was measured at admission and discharge. We observed a significant decrease in symptom scores and a significant increase in plasma NAA levels between admission and discharge. The initiation of therapy with lithium salts significantly influenced plasma NAA changes. Our study shows that our HPLC-MS method can detect clinically meaningful changes in plasma NAA levels. These results might lay the groundwork for future research exploring the relationship between plasma NAA levels and cerebral NAA levels measured by MRS.