Fig. 3. Orchestration of metabolic pathways.

A schematic depiction of the interconnection between key metabolic pathways and pharmacological interventions. IIS and TOR signaling are activated upon energy availability and are connected via the serine/threonine kinase AKT. IIS promotes AKT activation in a PI3K- and PDK1-dependent manner. AKT in turn phosphorylates FOXO transcription factors and thereby prevents nuclear translocation. AKT and AMPK act antagonistically to regulate TOR signaling through inhibitory and activating phosphorylation of TSC2, respectively. AMPK and sirtuin activity are both induced by low-energy conditions. AMPK can possibly stimulate sirtuins by elevating the production the NAD⁺ biosynthetic enzyme Nampt, which increases the NAD⁺/NADH ratio. Vice versa, sitruins might deacetylate LKB1, which targets the AMPK-related kinase MARK1 ultimately enhancing AMPK phosphorylation. Sirtuin and AMPK signaling also promote FOXO-mediated transcriptional activity, either by direct deacetylation (−Ac) or by the phosphorylation-dependent activation of histone deacetylases (HDACs), respectively. Moreover, AMPK can block IIS by induction of the PIP₃ phosphatase PTEN. Several pharmacological interventions are available that reduce (▼) or stimulate (▲) the activity of the different metabolic pathways and are in part used to treat metabolic disorders in human patients. See text for details.