Fibroblast growth Factor-21 promotes ketone body utilization in neurons through activation of AMP-dependent kinase

Energy supply to the brain is essential to ensure correct neuronal function, and glucose is the main fuel utilized by neurons. In metabolically challenging situations when glucose availability is restricted, brain cells may switch to alternative carbon substrates. This ensures energy supply to preserve the functions of the central nervous system. In this regard, ketone bodies, a by-product of fat metabolism, play a key role. They can replace glucose as the main source of ATP in the brain when glucose availability is very low, such as during fasting, extenuating exercise, or pathological situations such as diabetes. However, the mechanisms through which brain cells reprogram their metabolism are not fully understood. Fibroblast growth factor-21 (FGF21) is an endocrine hormone that contributes to modulate systemic adaptation to fasting, and it is known to regulate ketone body metabolism in peripheral tissues. However, its role in the brain, except for neuroendocrine regions, has not been studied in depth. In this work, we have used a combination of cell biology, biochemistry and extracellular flux analysis to examine the role of FGF21 in neuronal metabolism. We show that FGF21 increases the ability of neurons to utilize ketone bodies in cortical neurons as illustrated by a larger mitochondrial respiratory capacity in the presence of ketone bodies. Finally, we observe that the effect of FGF21 is mediated through a mechanism partly dependent on AMP-dependent kinase (AMPK). We propose that this mechanism could contribute to prepare the brain for fasting, thus preventing metabolic decline. •Cortical neurons need external fuel supply.•Cortical neurons need external cues to utilize ketone bodies efficiently.•FGF21 enhances the ability of neurons to use ketone bodies.•AMPK mediates the effect of FGF21 in ketone body metabolism.