Abstract
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.
Key points
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Circulating fasting cues originating from several organs signal hepatocytes during fasting and govern hepatic production of glucose and ketone bodies.
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Hepatic glucose production is mainly controlled by glucagon and glucocorticoids, with contributions from other fasting cues such as adrenaline.
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Gluconeogenesis is dependent on amino acid catabolism, and both processes are markedly transcriptionally regulated.
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Lipolysis in white adipose tissue is controlled by adrenaline, growth hormone and glucocorticoids, leading to a flow of free fatty acids into hepatocytes.
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Free fatty acids serve as both precursors for ketogenesis and signalling cues activating a ketogenic gene programme.
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Fasting cues cooperate with each other to optimize fuel production by synergistic gene induction achieved by several transcriptional mechanisms.
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Goldberg, D., Goldstein, I. Endocrine regulation of the hepatic fasting response: cues, cooperation and consequences. Nat Rev Endocrinol (2026). https://doi.org/10.1038/s41574-025-01228-3
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DOI: https://doi.org/10.1038/s41574-025-01228-3
