Rebelos Eleni, Honka Miikka-Juhani, Latva-Rasku Aino, Rajander Johan, Salminen Paulina, Anastasiou Ioanna A, Kounatidis Dimitris, Tentolouris Nikolaos, Campi Beatrice, Dardano Angela, Daniele Giuseppe, Saba Alessandro, Ferrannini Ele, Nuutila Pirjo
Turku PET Centre, University of Turku, 20014 Turku, Finland.
Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy.
Int J Mol Sci. 2025 May 26;26(11):5107. doi: 10.3390/ijms26115107.
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 ([F]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 ( < 0.0001). Over this period, circulating NAA concentrations decreased by 5% ( = 0.01), similarly in both groups. The change in NAA was inversely related with the change in plasma acetate ( = -0.36, = 0.048). Circulating NAA was associated with waist-hip ratio ( = -0.54, = 0.0002), steady-state free fatty acids ( = -0.44, = 0.003), and directly with HDL cholesterol ( = 0.54, = 0.0002), adiponectin ( = 0.48, = 0.003), and whole-body insulin sensitivity ( = 0.34, = 0.03). Circulating NAA was directly related with skeletal muscle ( = 0.42, = 0.01) and visceral adipose tissue GU ( = 0.41, = 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-乙酰天门冬氨酸（NAA）是人类大脑中含量第二丰富的代谢物。血液中也存在可量化的NAA，但其在周围组织中的作用很大程度上尚不清楚。首先，我们确定了胰岛素给药对NAA浓度的急性影响；其次，我们评估了循环NAA水平是否与中枢和外周胰岛素敏感性标志物相关。共有24名肥胖者和19名无神经系统疾病的健康瘦人对照组接受了正常血糖高胰岛素钳夹试验，并结合大脑、腹部和股部区域的氟脱氧葡萄糖正电子发射断层扫描（[F]FDG-PET）成像。在基线和钳夹试验约2小时时，使用高效液相色谱-串联质谱法（HPLC-MS-MS）测量血浆NAA浓度。使用分数摄取率分析葡萄糖摄取（GU）率。还使用核磁共振（NMR）代谢组学评估血清乙酸盐水平。从基线到稳态，胰岛素水平从平均66 pmol/L增加到447 pmol/L（<0.0001）。在此期间，两组循环NAA浓度均下降了5%（=0.01）。NAA的变化与血浆乙酸盐的变化呈负相关（=-0.36，=0.048）。循环NAA与腰臀比（=-0.54，=0.0002）、稳态游离脂肪酸（=-0.44，=0.003）相关，与高密度脂蛋白胆固醇（=0.54，=0.0002）、脂联素（=0.48，=0.003）和全身胰岛素敏感性（=0.34，=0.03）直接相关。循环NAA与骨骼肌（=0.42，=0.01）和内脏脂肪组织GU（=0.41，=0.02）直接相关。胰岛素给药导致循环NAA水平略有下降，且NAA与胰岛素敏感性标志物始终相关。虽然血浆NAA可能与全身稳态的某些方面相关，但仍需要深入的机制研究。
