Endocrine regulation of the hepatic fasting response: cues, cooperation and consequences

Upon fasting, mammals undergo a fasting response in which the liver’s main role is producing fuel (glucose and ketone bodies) to supply extra-hepatic tissues. Glucose is produced by glycogenolysis and gluconeogenesis, and ketone bodies are produced by ketogenesis, which is preceded by lipolysis and fatty acid oxidation. Hepatic fuel production during fasting is controlled by hormonal and metabolic cues, collectively termed here ‘fasting cues’. In this Review, we discuss fasting cues that directly signal hepatocytes and whose plasma levels increase upon fasting, namely, glucagon, glucocorticoids, growth hormone, adrenaline, free fatty acids, asprosin and GP73. We outline the fasting-dependent increases in blood levels of these cues, how they regulate transcription and the metabolic consequences of these cues in hepatocytes. We put particular emphasis on their role in directing fuel production. The perception of endocrine control of fuel production is shifting from the classic ‘counter-regulatory’ notion that fasting cues are simply opposing insulin action, to the realization that fasting cues cooperate with each other to elicit a synergistic response and also complement each other’s actions indirectly. We discuss these modes of crosstalk and cooperation between fasting cues and describe the effects of signal integration on the transcriptional and metabolic response to fasting.