The return of malonyl-CoA to the brain: Cognition and other stories

Nutrients, hormones and the energy sensor AMP-activated protein kinase (AMPK) tightly regulate the intracellular levels of the metabolic intermediary malonyl-CoA, which is a precursor of fatty acid synthesis and a negative regulator of fatty acid oxidation. In the brain, the involvement of malonyl-CoA in the control of food intake and energy homeostasis has been known for decades. However, recent data uncover a new role in cognition and brain development. The sensing of malonyl-CoA by carnitine palmitoyltransferase 1 (CPT1) proteins regulates a variety of functions, such as the fate of neuronal stem cell precursors, the motility of lysosomes in developing axons, the trafficking of glutamate receptors to the neuron surface (necessary for proper synaptic function) and the metabolic coupling between astrocytes and neurons. We discuss the relevance of those recent findings evidencing how nutrients and metabolic disorders impact cognition. We also enumerate all nutritional and hormonal conditions that are known to regulate malonyl-CoA levels in the brain, reflect on protein malonylation as a new post-translational modification, and give a reasoned vision of the opportunities and challenges that future research in the field could address. •Malonyl-CoA is a lipid metabolite tightly regulated by nutrients, hormones and AMPK.•Malonyl-CoA has other roles in the brain beyond being a satiating signal.•CPT1A and CPT1C proteins act as sensors of malonyl-CoA levels in the brain.•CPT1A controls the metabolic plasticity of astrocytes and the fate of neuronal stem cell precursors.•CPT1C regulates axon growth and synaptic strength through the control of lysosome motility and AMPA receptor trafficking.