Intermittent metabolic switching, neuroplasticity and brain health

Abstract

During evolution, individuals whose brains and bodies functioned well in a fasted state were successful in acquiring food, enabling their survival and reproduction. With fasting and extended exercise, liver glycogen stores are depleted and ketones are produced from adipose-cell-derived fatty acids. This metabolic switch in cellular fuel source is accompanied by cellular and molecular adaptations of neural networks in the brain that enhance their functionality and bolster their resistance to stress, injury and disease. Here, we consider how intermittent metabolic switching, repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan, with a focus on the neuronal circuits involved in cognition and mood. Such metabolic switching impacts multiple signalling pathways that promote neuroplasticity and resistance of the brain to injury and disease.

Conflict of interest statement

Competing interests statement

The authors declare no competing interests.

Figures

Figure 1. Biochemical pathways involved in the metabolic switch

During fasting and sustained exercise, liver glycogen stores are depleted and lipolysis of triacylglycerols and diacylglycerols in adipocytes generates free fatty acids (FFAs), which are then released into the blood. The FFAs are transported into hepatocytes, where they are metabolized via β-oxidation to acetyl CoA, which is then used to generate the ketones acetone, acetoacetate (AcAc) and β-hydroxybutyrate (BHB). BHB and AcAc are transported from the blood into the brain and then into neurons via monocarboxylic acid transporters (MCTs) in the membranes of vascular endothelial cells and neurons. Within neurons, BHB and AcAc are metabolized to acetyl CoA, which then enters the tricarboxylic acid (TCA) cycle in mitochondria, resulting in the production of ATP and the reducing agents that transfer electrons to the electron transport chain. BHB can also upregulate the expression of brain-derived neurotrophic factor (BDNF) and may thereby promote mitochondrial biogenesis, synaptic plasticity and cellular stress resistance. In addition to blood-borne ketones, astrocytes are capable of ketogenesis, which may provide an important local source of BHB for neurons. Intermittent metabolic switching also increases insulin sensitivity, thereby enhancing uptake and utilization of glucose by neurons. Upon refeeding, ingested carbohydrates (CHO) and glucose stimulate release into the blood of the incretin hormone glucagon-like peptide 1 (GLP1) from enteroendocrine cells in the gut. GLP1 enhances clearance of glucose from the blood by stimulating insulin release from the pancreas and increases the insulin sensitivity of cells. GLP1 crosses the blood–brain barrier and can act directly on neurons to promote synaptic plasticity, enhance cognition and bolster cellular stress resistance. HMG-CoA, 3-hydroxy-3-methylglutaryl-CoA; GT, glucose transporter.

Figure 2. Signalling pathways by which neurons respond to the metabolic switch during fasting and exercise

Increased excitatory synaptic activity triggers Ca2+ influx through plasma membrane channels, resulting in the activation of multiple kinases, including calcium/calmodulin-dependent kinases (Ca2+/CaMK) and mitogen-activated protein kinases (MAPKs), nitric oxide synthase (NOS) and the protein phosphatase calcineurin. Neurotrophic factor signalling pathways are also engaged in response to fasting and exercise, resulting in the activation of signalling pathways involving phosphatidylinositol 3-kinase (PI3K), RACα serine/threonine-protein kinase (AKT) and MAPKs. These activity-dependent and neurotrophic-factor-dependent signalling pathways converge on transcription factors, including cAMP-responsive element-binding protein (CREB), nuclear regulatory factor 2 (NRF2; also known as NFE2L2), nuclear factor-κB (NF-κB) and myocyte-specific enhancer factor 2 (MEF2), which induce the expression of many different genes that encode proteins involved in cellular stress adaptation. Three genes that may be particularly important in the enhancement of neuroplasticity and stress resistance in response to intermittent metabolic switching are those encoding brain-derived neurotrophic factor (BDNF), NAD-dependent protein deacetylase sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). SIRT3 localizes to the mitochondria, where it deacetylates proteins involved in antioxidant defence (superoxide dismutase [Mn], mitochondrial (SOD2)), energy production (isocitrate dehydrogenase [NADP], mitochondrial (IDH2); acetyl CoA synthase 2 (AceCS2; also known as ACSS1); and electron transport chain (ETC) proteins) and protection against apoptosis (cyclophilin D). PGC1 α is a key transcriptional regulator of mitochondrial biogenesis that acts, in part, by upregulating NRF1 and mitochondrial transcription factor A (TFAM), which, in turn, upregulate oxidative phosphorylation, mitochondrial DNA (mtDNA) replication and transcription and mitochondrial protein import. CREB, NRF2 and NF-κB induce the expression of antioxidant enzymes, DNA repair enzymes, anti-apoptotic proteins and protein chaperones and Ca2+-handling proteins. The ketone β-hydroxybutyrate (BHB), which is elevated during fasting and extended exercise, provides an energy substrate for neurons and induces the expression of BDNF. The reduction in availability of glucose and amino acids during fasting and exercise results in a reduction in the AMP:ATP ratio, which activates AMP kinase (AMPK) and, in turn, stimulates autophagy. The reduction in glucose and amino acid availability also reduces activation of mammalian target of rapamycin (mTOR) and further enhances the AMPK-driven autophagy pathway. AMPK activates the serine/threonine-protein kinase ULK1 (ULK1) complex, which stimulates engulfment of damaged proteins and organelles in autophagosomes, which, in turn, fuse with lysosomes. Collectively, activation of these different pathways in response to the metabolic switch bolsters neuronal bioenergetics, improves Ca2+ handling and protects against oxidative, excitotoxic and proteotoxic stress. AC, acetyl group; LC3-PE, light chain 3– phosphatidylethanolamine; NAM, nicotinamide adenine mononucleotide; OXPHOS, ETC complexes involved in oxidative phosphorylation.

Figure 3. Model for how intermittent metabolic switching may optimize brain performance and increase resistance to injury and disease

Intermittent metabolic switching (IMS) involves repeating time periods of a bioenergetic challenge (fasting and/or exercise) when the metabolic switch is on (that is, liver glycogen stores are depleted and ketones are produced) and recovery periods (eating, resting and sleeping) when the metabolic switch is off. When the metabolic switch is on, levels of circulating ketones, ghrelin and myokines are elevated, whereas levels of glucose, leptin, insulin and pro-inflammatory cytokines are maintained at low levels. Adaptive responses of neurons to fasting and exercise include utilization of ketones as an energy substrate; increased expression of brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2); activation of the transcription factors cAMP-responsive element-binding protein (CREB) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), which induce the expression of genes involved in synaptic plasticity, neurogenesis and mitochondrial biogenesis; and upregulation of autophagy and DNA repair pathways. During the bioenergetic challenge, activity of the mammalian target of rapamycin (mTOR; also known as serine/threonine-protein kinase mTOR (MTOR) and mechanistic target of rapamycin) pathway and global protein synthesis are reduced in neurons, and levels of pro-inflammatory cytokines in the brain are reduced. Collectively, the pathways activated when the metabolic switch is on enhance neuronal stress resistance and bolster repair and recycling of damaged molecules. When the metabolic switch is off, circulating levels of glucose, leptin, insulin and pro-inflammatory cytokines increase, whereas levels of ketones, ghrelin and myokines decrease. In brain cells, the mTOR pathway is active, protein synthesis increases and mitochondrial biogenesis occurs during the recovery period. The activation state of neurotrophic signalling and adaptive cellular stress-response pathways may decrease when the metabolic switch is off. Cycles of IMS may optimize brain health by promoting synaptic plasticity and neurogenesis, improving cognition, mood, motor performance and autonomic nervous system (ANS) function and bolstering resistance of neurons to injury and neurodegenerative disease. SIRT, NAD-dependent protein deacetylase sirtuin.