Fig 5.
Bioenergenesis neurotransmitter pathways with differentially expressed genes between frontal cortex and hypothalamus. A solid line with arrowhead indicates a direct reaction or transport. A dashed line with arrowhead indicates more than one steps involved in passages. The RNA levels of genes in red or green colors were expressed significantly higher or lower in the frontal cortex than in hypothalamus, respectively. If the changes in RNA levels were not significant (p>0.05) or less than 1.25-fold, the gene symbols or enzymes are not shown in the flow chat. The mean expression levels, standard deviations, fold changes, p-values, false discovery rate (FDR) and the full name of genes are listed in Table 2. (A) Bioenergenesis neurotransmitter pathways include glycolysis, fatty acid synthesis, and neurotransmitter synthesis in cytoplasm and β-oxidation, TCA cycle and OXPHOS, REDOX, and neurotransmitter synthesis in mitochondria. Double dashed lines represent the inner and outer mitochondrial membranes, of which a portion was enlarged to illustrate OXPHOS complexes I, II, III, IV and V with differentially expressed genes in each complex. A proton (H+) flow and ATP synthesis are indicated. REDOX enzyme (GSTZ1) is involved in removal of ROS (e.g. O2-). Mitochondrial and cytoplasmic enzymes with the RNA levels higher in the frontal cortex than in hypothalamus for synthesis of neurotransmitters (gray ovals) include GLS2 and GPT for synthesis of the most abundant excitatory neurotransmitter L-glutamate, GAD1 and ABAT for the most abundant inhibitory neurotransmitter γ-aminobutyric acid [GABA], DDC for dopamine, histamine and serotonin, and AGXT for serine and glycine. SLC25A18 and SLC25A22 are involved in transport of L-glutamate across mitochondrial membranes. (B) Insulin signaling pathway. Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates. This leads to activation of phosphoinositide-3-kinase (PIK3CB and PIK3R3) and growth factor receptor-bound protein (GRB2). The activated PIK3CB and PIK3R3 lead to upregulation insulin-responsive genes including hexokinase 2 (HK2). HK2 localizes to the outer mitochondrial membrane and phosphorylates glucose into glucose-6-phosphate, the first rate-limiting step of glycolysis pathway. PIK3CB and PIK3R3 also activate protein synthesis, of which 22 of 23 genes displayed RNA levels higher in the frontal cortex than in hypothalamus (Table 1). Mitogen-activated protein kinase kinase (MAP2K2) plays a critical role in mitogen growth factor signal transduction, and its downregulation suggests decreased activities in transferring the GRB2 signal for proliferation and differentiation. (C) PPARD signaling pathway. Peroxisome proliferator-activated receptor delta (PPARD) is a nuclear hormone receptor and transcriptional regulator and is involved in fatty acid transport and oxidation via binding to DNA and regulating transcription.