(A) Insulin signaling mediates macronutrients metabolism. Following canonical IRS-PI3K-PDK1-Akt insulin signaling, feeding activates IRS phosphorylation at multiple tyrosine sites and activates PI3K and Akt (phosphorylation at Thr308), which phosphorates FoxO1 (Ser256), retains it in the cytoplasm, and suppresses the expression of gluconeogenic genes, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), while fasting promotes gluconeogenesis. Upon feeding, activated Akt suppresses glycogen synthesis via phosphorylation of GSK3 (Ser9 and Ser21). Akt induces glycolysis via FoxO1 phosphorylation and activation of glucokinase gene expression. Akt stimulates protein synthesis via mTORC1 signaling pathway. Akt activates lipid synthesis via phosphorylation of TSC and FoxO1, which activates mTORC1 and SREBP1c and the lipogenic gene. Additionally, glucocorticoid receptor (GR) transcriptionally suppresses IRS1 and promotes IRS2 expression, and IRS1 (on Ser1101) and IRS2 (on Ser1149) could be posttranslationally modified by glycosylation (O-GlcNAc), but how it interferes with phosphorylation is not known. Akt could be mediated by lncRNA, either activation or suppression. (B) Insulin signaling regulates mitochondrial metabolism (mitochondrial biogenesis, fusion, and fission, mitophagy). Insulin signaling mediates mitochondrial biogenesis via FoxOs-mediated Tfam, NRF1, and PGC1α. FoxOs affect mitochondrial dynamics mainly through transcriptionally up-regulate the fusion proteins Mfn1/2 and down-regulate fission protein Drp1. Additionally, FoxOs post-transcriptionally suppress mitochondrial fission via promoting microRNA-484 (miR-484) expression and its binding with Fis1 mRNA and suppresses Fis1 translation. FoxOs promote mitophagy through transcriptional regulation of PINK1 and BNIP3.