Mildly compromised tetrahydrobiopterin cofactor biosynthesis due to Pts variants leads to unusual body fat distribution and abdominal obesity in mice

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor for the aromatic amino acid hydroxylases, alkylglycerol monooxygenase, and nitric oxide synthases (NOS). Inborn errors of BH4 metabolism lead to severe insufficiency of brain monoamine neurotransmitters while augmentation of BH4 by supplementation or stimulation of its biosynthesis is thought to ameliorate endothelial NOS (eNOS) dysfunction, to protect from (cardio-) vascular disease and/or prevent obesity and development of the metabolic syndrome. We have previously reported that homozygous knock-out mice for the 6-pyruvolytetrahydropterin synthase (PTPS; Pts-ko/ko) mice with no BH4 biosynthesis die after birth. Here we generated a Pts-knock-in (Pts-ki) allele expressing the murine PTPS-p.Arg15Cys with low residual activity (15% of wild-type in vitro) and investigated homozygous (Pts-ki/ki) and compound heterozygous (Pts-ki/ko) mutants. All mice showed normal viability and depending on the severity of the Pts alleles exhibited up to 90% reduction of PTPS activity concomitant with neopterin elevation and mild reduction of total biopterin while blood L-phenylalanine and brain monoamine neurotransmitters were unaffected. Yet, adult mutant mice with compromised PTPS activity (i.e., Pts-ki/ko, Pts-ki/ki or Pts-ko/wt) had increased body weight and elevated intra-abdominal fat. Comprehensive phenotyping of Pts-ki/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 BH4-biosynthesis 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.

Changes in nucleus accumbens gene expression accompany sex-specific suppression of spontaneous physical activity in aromatase knockout mice

“…(associated with glycosylation of amino acids (UniProt, 2019)) were differentially expressed within males and females. It is noteworthy that a previous study genetically downregulated systemic Pts expression in C57B1/6J mice, resulting in significantly impaired BH4 synthesis in liver and brain (Korner et al, 2016). While systemic ablation of Pts is not a viable mutation, mice with significantly reduced Pts expression were obese with impaired glucose and lipid metabolism.…”

“…While systemic ablation of Pts is not a viable mutation, mice with significantly reduced Pts expression were obese with impaired glucose and lipid metabolism. In particular, these mice had elevated intrabdominal fat, particularly in males (Korner et al, 2016). Their findings determined that downregulation of Pts contributed to increased body weight and elevated intrabdominal fat, particularly in males, with alterations in glucose and lipid metabolism in both sexes potentially via reduced eNOS function (Korner et al, 2016).…”

“…In particular, these mice had elevated intrabdominal fat, particularly in males (Korner et al, 2016). Their findings determined that downregulation of Pts contributed to increased body weight and elevated intrabdominal fat, particularly in males, with alterations in glucose and lipid metabolism in both sexes potentially via reduced eNOS function (Korner et al, 2016). Unfortunately, analyses of behaviors that may have contributed to obesity, namely reduced physical activity, were not analyzed in this previous work.…”

“…6b). Key correlations with Pts (a necessary gene for catecholamine synthesis (Korner et al, 2016)), Per3 (a gene known to regulate circadian rhythm (Dewandre, 2018)), and Cryab (a member of the small heat shock protein family that may associate with cellular stress resistance (Stelzer et al, 2016)) are highlighted below.…”

Genomics of Lithium Action and Response

“…BH 4 aids the production of nitric oxide and monoamine neurotransmitter synthesis. However, a mouse knockout of Pts alters metabolism and abdominal fat distribution without an overt central nervous system phenotype or perturbation of neurotransmitter levels [48]. There are other SNPs in this study that fall marginally below the genome-wide statistical threshold but which have intriguing links to established psychiatric biology, suggesting that larger surveys are required.…”