Cells carefully regulate their metabolism with nested levels of controls (6). First, levels of circulating molecules that serve as feedstock for metabolic pathways change with diet. These include plasma-free fatty acids and amino acids that increase after a meal (7) or plasma ketone bodies and free fatty acids that increase after a prolonged fast (8, 9). Second, allosteric regulation of metabolic enzymes changes flux rates through metabolic pathways in response to concentrations of substrates or products (10–12). Third, there is regulation by hormones (13), often through posttranslational modification of metabolic enzymes. For example, glycogen deposition or depletion is regulated by a protein kinase cascade-modifying glycogen synthase and glycogen phosphorylase downstream of insulin or glucagon (14, 15). AMP-activated Kinase (AMPK) is a master regulator of metabolism that can sense cellular energy status and respond by switching on and off pathways to achieve energy homeostasis (16, 17). AMPK is activated in response to cellular ATP depletion, which can result from low glucose levels, hypoxia, and heat shock. Upon activation, AMPK upregulates pathways replenishing ATP, including fatty acid β-oxidation and autophagy, and downregulates ATP-consuming processes, including lipid synthesis and protein synthesis.
