A High-fat Diet Induces a Loss of Midbrain Dopaminergic Neuronal Function That Underlies Motor Abnormalities

Movement defects in obesity are associated with peripheral muscle defects, arthritis, and dysfunction of motor control by the brain. Although movement functionality is negatively correlated with obesity, the brain regions and downstream signaling pathways associated with movement defects in obesity are unclear. A dopaminergic neuronal pathway from the substantia nigra (SN) to the striatum is responsible for regulating grip strength and motor initiation through tyrosine hydroxylase (TH) activity-dependent dopamine release. We found that mice fed a high-fat diet exhibited decreased movement in open-field tests and an increase in missteps in a vertical grid test compared with normally fed mice. This motor abnormality was associated with a significant reduction of TH in the SN and striatum. We further found that phosphorylation of c-Jun N-terminal kinase (JNK), which modulates TH expression in the SN and striatum, was decreased under excess-energy conditions. Our findings suggest that high calorie intake impairs motor function through JNK-dependent dysregulation of TH in the SN and striatum.

NAD(P)H: Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 Polymorphisms in Papillary Thyroid Microcarcinoma: Correlation with Phenotype

PURPOSE: NAD(P)H:Quinone Oxidoreductase 1 (NQO1) C609T missense variant (NQO1*2) and 29 basepair (bp)-insertion/deletion (I29/D) polymorphism of the NRH:Quinone Oxidoreductase 2 (NQO2) gene promoter have been proposed as predictive and prognostic factors for cancer development and progression. The purpose of this study is to investigate the relationship between NQO1/NQO2 genotype and clinico-pathological features of papillary thyroid microcarcinoma (PTMC). MATERIALS AND METHODS: Genomic DNA was isolated from 243 patients; and clinical data were retrospectively analyzed. NQO1*2 and tri-allelic polymorphism of NQO2 were investigated by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: PTMC with NQO1*2 frequently exhibited extra-thyroidal extension as compared to PTMC with wild-type NQO1 (p=0.039). There was a significant relationship between I29/I29 homozygosity of NQO2 and lymph node metastasis (p=0.042). Multivariate analysis showed that the I29/I29 genotype was associated with an increased risk of lymph node metastasis (OR, 2.24; 95% CI, 1.10-4.56; p=0.026). CONCLUSION: NQO1*2 and I29 allele of the NQO2 are associated with aggressive clinical phenotypes of PTMC, and the I29 allele represents a putative prognostic marker for PTMC.