Oxenkrug Gregory, van der Hart Marieke, Roeser Julien, Summergrad Paul
Department of Psychiatry, Tufts University School of Medicine, USA.
Brains On-Line, S. San Francisco, USA.
Integr Clin Med. 2017;1(1). doi: 10.15761/ICM.1000105. Epub 2017 May 10.
Increased predisposition of schizophrenia patients (SP) to development of obesity and insulin resistance suggested common signaling pathway between metabolic syndrome (MetS) and schizophrenia. Deficiency of kynurenine-3-monooxygenase (KMO), enzyme catalyzing formation of 3-hydroxykynurenine (3-HK) from kynurenine (Kyn), a tryptophan (Trp) metabolite, might contribute to development of MetS as suggested by non-expression of KMO genes in human fat tissue and elevated serum concentrations of Kyn and its metabolites, kynurenic (KYNA) and anthranilic (ANA) acids, in diabetic patients and Zucker fatty rats (ZFR). Markers of KMO deficiency: decreased 3-HK and elevated Kyn, KYNA and ANA, were observed in brains and spinal fluids of SP, and in brains and serum of experimental animals with genetically- or pharmacologically-induced KMO deficiency. However, elevated concentrations of ANA and decreased 3-HK were reported in serum of SP without concurrent increase of Kyn and KYNA. Present study aimed to re-assess serum Kyn metabolites (HPLC-MS) in a sub-group of SP with elevated KYNA. We found increased Kyn concentrations (by 30%) and Kyn:Trp ratio (by 20%) in serum of SP with elevated KYNA concentrations (by 40%). Obtained results and our previous data suggest that peripheral KMO deficiency might be manifested by, at least, two different patterns: elevated ANA with decreased 3-HK; and elevated KYNA and KYN. The latter pattern was previously described in type 2 diabetes patients and might underline increased predisposition of SP to development of MetS. Assessment of peripheral KMO deficiency might identify SP predisposed to MetS. Attenuation of the consequences of peripheral KMO deficiency might be a new target for prevention/treatment of obesity and diabetes in SP.
精神分裂症患者（SP）患肥胖症和胰岛素抵抗的易感性增加，这表明代谢综合征（MetS）和精神分裂症之间存在共同的信号通路。犬尿氨酸-3-单加氧酶（KMO）缺乏，该酶催化色氨酸（Trp）代谢产物犬尿氨酸（Kyn）形成3-羟基犬尿氨酸（3-HK），可能导致MetS的发生，这是因为在人类脂肪组织中KMO基因不表达，且糖尿病患者和Zucker肥胖大鼠（ZFR）的血清中Kyn及其代谢产物犬尿酸（KYNA）和邻氨基苯甲酸（ANA）的浓度升高。在SP的脑和脊髓液中，以及在基因或药物诱导的KMO缺乏的实验动物的脑和血清中，观察到KMO缺乏的标志物：3-HK降低，Kyn、KYNA和ANA升高。然而，有报道称SP血清中ANA浓度升高而3-HK降低，同时Kyn和KYNA没有同时增加。本研究旨在重新评估KYNA升高的SP亚组中的血清Kyn代谢产物（HPLC-MS）。我们发现，KYNA浓度升高（40%）的SP血清中Kyn浓度增加（30%），Kyn:Trp比值增加（20%）。获得的结果和我们之前的数据表明，外周KMO缺乏可能至少以两种不同的模式表现出来：ANA升高伴3-HK降低；以及KYNA和KYN升高。后一种模式先前在2型糖尿病患者中已有描述，可能强调了SP患MetS的易感性增加。评估外周KMO缺乏可能会识别出易患MetS的SP。减轻外周KMO缺乏的后果可能是预防/治疗SP肥胖症和糖尿病的新靶点。
