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Inborn errors of BH<jats:sub>4<\/jats:sub> metabolism lead to severe insufficiency of brain monoamine neurotransmitters while augmentation of BH<jats:sub>4<\/jats:sub> by supplementation or stimulation of its biosynthesis is thought to ameliorate endothelial NOS (eNOS) dysfunction, to protect from (cardio\u2010) vascular disease and\/or prevent obesity and development of the metabolic syndrome. We have previously reported that homozygous knock\u2010out mice for the 6\u2010pyruvolytetrahydropterin synthase (PTPS; <jats:italic>Pts<\/jats:italic>\u2010ko\/ko) mice with no BH<jats:sub>4<\/jats:sub> biosynthesis die after birth. Here we generated a <jats:italic>Pts<\/jats:italic>\u2010knock\u2010in (<jats:italic>Pts<\/jats:italic>\u2010ki) allele expressing the murine PTPS\u2010p.Arg15Cys with low residual activity (15 % of wild\u2010type <jats:italic>in vitro<\/jats:italic>) and investigated homozygous (<jats:italic>Pts<\/jats:italic>\u2010ki\/ki) and compound heterozygous (<jats:italic>Pts<\/jats:italic>\u2010ki\/ko) mutants. All mice showed normal viability and depending on the severity of the <jats:italic>Pts<\/jats:italic> alleles exhibited up to 90 % reduction of PTPS activity concomitant with neopterin elevation and mild reduction of total biopterin while blood L\u2010phenylalanine and brain monoamine neurotransmitters were unaffected. Yet, adult mutant mice with compromised PTPS activity (i.e., <jats:italic>Pts<\/jats:italic>\u2010ki\/ko, <jats:italic>Pts<\/jats:italic>\u2010ki\/ki or <jats:italic>Pts<\/jats:italic>\u2010ko\/wt) had increased body weight and elevated intra\u2010abdominal fat. Comprehensive phenotyping of <jats:italic>Pts<\/jats:italic>\u2010ki\/ki mice revealed alterations in energy metabolism with proportionally higher fat content but lower lean mass, and increased blood glucose and cholesterol. Transcriptome analysis indicated changes in glucose and lipid metabolism. Furthermore, differentially expressed genes associated with obesity, weight loss, hepatic steatosis, and insulin sensitivity were consistent with the observed phenotypic alterations. We conclude that reduced PTPS activity concomitant with mildly compromised BH<jats:sub>4<\/jats:sub>\u2010biosynthesis leads to abnormal body fat distribution and abdominal obesity at least in mice. This study associates a novel single gene mutation with monogenic forms of obesity.<\/jats:p>","DOI":"10.1007\/s10545-015-9909-6","type":"journal-article","created":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T07:47:16Z","timestamp":1454312836000},"page":"309-319","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Mildly compromised tetrahydrobiopterin cofactor biosynthesis due to <i>Pts<\/i> variants leads to unusual body fat distribution and abdominal obesity in mice"],"prefix":"10.1002","volume":"39","author":[{"given":"Germaine","family":"Korner","sequence":"first","affiliation":[{"name":"Division of Metabolism University Children's Hospital Z\u00fcrich Steinwiesstrasse 75 Z\u00fcrich CH\u20108032 Switzerland"},{"name":"Affiliated with the Neuroscience Center Zurich (ZNZ) University of Zurich and ETH Zurich Z\u00fcrich Switzerland"},{"name":"Children's Research Center (CRC) Z\u00fcrich 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