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Loss of Arylformamidase with Reduced Thymidine Kinase Expression Leads to Impaired Glucose Tolerance Alison J

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Loss of Arylformamidase with Reduced Thymidine Kinase Expression Leads to Impaired Glucose Tolerance Alison J © 2015. Published by The Company of Biologists Ltd | Biology Open (2015) 4, 1367-1375 doi:10.1242/bio.013342 RESEARCH ARTICLE Loss of arylformamidase with reduced thymidine kinase expression leads to impaired glucose tolerance Alison J. Hugill1,*, Michelle E. Stewart2,*, Marianne A. Yon1,*, Fay Probert2,3, I. Jane Cox3, Tertius A. Hough2, Cheryl L. Scudamore2, Liz Bentley1, Gary Wall1, Sara E. Wells2,* and Roger D. Cox1,*,‡ ABSTRACT steps, generating metabolites including kynurenic acid (KYNA), Tryptophan metabolites have been linked in observational studies quinolonic acid, xanthurenic acid (XA), and nicotinamide with type 2 diabetes, cognitive disorders, inflammation and immune (reviewed Stone and Darlington, 2002). system regulation. A rate-limiting enzyme in tryptophan conversion is It has been suggested that dysregulation of XA and kynurenine arylformamidase (Afmid), and a double knockout of this gene and (KYN) derivatives are involved in insulin resistance and insulin thymidine kinase (Tk) has been reported to cause renal failure and secretion (reviewed Oxenkrug, 2013). XA excretion has been abnormal immune system regulation. In order to further investigate reported to be elevated in the urine of patients with diabetes and in possible links between abnormal tryptophan catabolism and diabetes alloxan- and streptozotocin- induced diabetic rats (Hattori et al., and to examine the effect of single Afmid knockout, we have carried 1984; Ikeda and Kotake, 1986). Similarly, a metabolomic analysis out metabolic phenotyping of an exon 2 Afmid gene knockout. These in rhesus macaques, comparing normal and spontaneously diabetic mice exhibit impaired glucose tolerance, although their insulin animals, identified elevated KYNA in urine as a biomarker of sensitivity is unchanged in comparison to wild-type animals. This diabetes (Patterson et al., 2011). Further, serum KYN and Trp have phenotype results from a defect in glucose stimulated insulin secretion been correlated with measures of insulin resistance and beta cell and these mice show reduced islet mass with age. No evidence of a function in patients with hepatitis-C (Oxenkrug et al., 2013). renal phenotype was found, suggesting that this published phenotype Consistent with these metabolites being biomarkers for diabetes, resulted from loss of Tk expression in the double knockout. However, increased serum KYN, KYNA and 3-hydroxy-KYN has also been despite specifically removing only exon 2 of Afmid in our experiments associated with diabetic retinopathy (Munipally et al., 2011). we also observed some reduction of Tk expression, possibly due to Similarly Trp has been found to be elevated in urine of patients with a regulatory element in this region. In summary, our findings support progressive diabetic kidney disease (van der Kloet et al., 2012). a link between abnormal tryptophan metabolism and diabetes and Studies in vitro have found that metabolites of KYNA and XA highlight beta cell function for further mechanistic analysis. inhibit second phase insulin release in rat islets, inhibit insulin biosynthesis and that XA binds to circulating insulin (Kotake et al., KEY WORDS: Arylformamidase, Kynurenine, Tryptophan, Diabetes, 1975; Noto and Okamoto, 1978; Okamoto, 1975; Rogers and Insulin secretion Evangelista, 1985). A number of Trp metabolites have emerged as regulators of the INTRODUCTION activity of neurotransmitters and have been linked to cognitive Type 2 diabetes (T2D) is a complex disease resulting from the disorders (reviewed Stone and Darlington, 2013). Kynurenic acid interaction of environmental factors such as obesity, which accounts may act as an endogenous antagonist of glutamate NMDA receptors for 80–85% of the risk, and multiple genetic factors. The disease is and as a negative allosteric modulator of nicotinic acetylcholine characterized by hyperglycemia due to defects in insulin secretion receptors, and a reduction in KYNA has been shown to improve and/or insulin action. Diabetes causes significant mortality and cognitive function in rodents and non-human primates (Kozak et al., morbidity as a result of complications that develop over prolonged 2014). Consistent with this, KYNA has also been linked with periods of time. Diabetes is a major health problem globally with an behavioral plasticity in C. elegans, with fasting leading to reduced estimated 382 million people affected in 2013, and a projected KYNA and activation of NMDA-receptor expressing inter-neurons. figure of 592 million by 2035 (International Diabetes Federation, This results in activation of a neuropeptide-Y (NPY) like signaling 2013; http://www.idf.org/diabetesatlas). axis, promoting feeding when food becomes available (Lemieux The essential amino acid tryptophan (Trp) is required for et al., 2015). Increased brain expression of tryptophan 2,3- protein synthesis and to make the neurotransmitter serotonin. Trp dioxygenase (TDO), one of the enzymes in the first step of the is metabolized in the tryptophan-kynurenine pathway in multiple pathway, has also been linked to Alzheimer’s disease in transgenic mice and human tissue (Wu et al., 2013). 1Mammalian Genetics Unit, Medical Research Council Harwell, Oxford, Finally, Trp catabolism has been linked with suppression of Oxfordshire OX11 0RD, UK. 2Mary Lyon Centre, Medical Research Council Harwell, inflammation and regulation of immunity (Romani et al., 2008; Oxford, Oxfordshire OX11 0RD, UK. 3Institute of Hepatology, Foundation for Liver Research, 69-75 Chenies Mews, London WC1E 6HX, UK. reviewed McGaha et al., 2012). *These authors contributed equally to this work The enzyme arylformamidase (AFMID, also known as kynurenine ‡ formamidase) catalyzes the second step of Trp conversion in the Author for correspondence ([email protected]) pathway to nicotinic acid, NAD(H), and NADP(H), hydrolyzing This is an Open Access article distributed under the terms of the Creative Commons Attribution N-formyl-L-kynurenine (FKYN) to L-kynurenine (Pabarcus and License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. Casida, 2002, 2005). The Afmid and thymidine kinase (Tk) genes are adjacent to one another in the genome and transcribed in opposite Received 8 July 2015; Accepted 1 September 2015 directions, with their ATG initiation codons only 170 bp apart Biology Open 1367 RESEARCH ARTICLE Biology Open (2015) 4, 1367-1375 doi:10.1242/bio.013342 (Dobrovolsky et al., 2005). Simultaneous inactivation of both Afmid concentrations ranging from ∼29 to 52 mM (data not shown). and Tk genes in mice by deletion of both first exons, results in the Based on these data we decided to carry out comprehensive elimination of FKYN hydrolysis in the liver and residual (13%) phenotyping to fully characterize the phenotype and understand its hydrolysis in the kidney (Dobrovolsky et al., 2005). In addition, causes. The Tm1a allele is a gene trap expressing LacZ and contains plasma concentrations of Trp are unaltered but FKYN, KYN and a selectable neomycin cassette; therefore we decided to convert it to KYNA are elevated, also liver and kidney levels of nicotinamide a full exon 2 deletion allele carrying only the LacZ reporter. This derivatives remain the same, indicating that the KYN pathway is was achieved by using a β-actin Cre recombinase giving germline disturbed but functional in double knockout mice (Dobrovolsky et al., deletion. The Cre was then bred out before generating the animals 2005). Double knockout mice also exhibit kidney failure and an for phenotyping. abnormal immune system with mice usually dying before 6 months Five cohorts were bred for separate dedicated phenotyping of age (Dobrovolsky et al., 2005, 2003). experiments. A cohort of 11 male and 8 female homozygous In order to further investigate the functional consequences, for knockout (Afmidtm1b/tm1b) mice on a C57BL6/NTac background type 2 diabetes, of loss of AFMID in vivo, we have characterized an were bred for the IMPC phenotyping pipeline (http://www. exon 2 knockout of the Afmid gene using the EUCOMM allele mousephenotype.org/impress) (Fig. 1A,B). Two further cohorts of Afmidtm1b(EUCOMM)Wtsi (Skarnes et al., 2011), available through the 10 males for each homozygous, heterozygous (Afmidtm1b/+) and International Mouse Phenotyping Consortium (IMPC, https://www. wild-type (Afmid+/+) genotype were bred, one for longitudinal mousephenotype.org/). blood based tests and one for urine analysis (Fig. 1A). A smaller We have found that mice homozygous for the tm1b deleted allele cohort of males of each genotype were also bred for pathology have impaired glucose tolerance due to reduced insulin secretion analysis at varying time points (16 weeks, n=5 Afmid+/+ and n=7 associated with reduced islet mass. There was no evidence of renal Afmidtm1b/tm1b; 46 weeks, n=8 Afmid+/+ and n=9 Afmidtm1b/tm1b; disease in these Afmidtm1b/tm1b mice, unlike the double Afmid and Tk Fig. 1A). Finally a cohort of 11 Afmidtm1b/tm1b and 11 Afmid+/+ and knockout, suggesting that the renal traits are due to complete loss of 10 Afmidtm1b/+ females were generated to investigate developing Tk. This study further implicates KYN pathway metabolites in glucose phenotypes in older female mice (Fig. 1A). diabetes. Expression of Afmid and Tk in total RNA RESULTS In order to verify loss of expression of the Afmid gene transcript in Initial data from limited numbers of Afmid Tm1a allele mice Afmidtm1b/tm1b knockout animals and to establish whether the exon 2 indicated that they had a strong diabetes phenotype, for example six deletion affected expression of the immediately adjacent Tk gene, males around 21 weeks of age had free fed blood glucose we carried out qRT-PCR on liver and kidney total RNA. The Fig. 1. Overview of five phenotyping cohorts. (A) A cohort of 11 male and 8 female Afmidtm1b/tm1b mice on a C57BL6/NTac background were bred for the IMPC phenotyping pipeline (1). Two further cohorts of 10 males for each Afmidtm1b/tm1b, Afmidtm1b/+ and Afmid+/+ genotype were bred for blood based tests and one for urine analysis (2,3). A smaller cohort of 5–9 males of each genotype was also bred for pathology analysis (4).
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