Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the “strengthening” of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer’s and Parkinson’s diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress.
The higher cognitive functions of the human brain depend upon the expansion and increased density and complexity of the neocortex during evolution (Rakic, 2009). The enhanced abilities of the human brain to plan complex behaviors, make decisions, and process emotional and social contexts came with hefty energy requirements. Although it is only 2% of the total body weight, the brain accounts for 20% of an individual’s energy expenditure at rest (Kety, 1957; Sokoloff, 1960). Among brain cells, neurons expend 70–80% of the total energy, with the remaining portion being utilized by glial cells (astrocytes, oligodendrocytes, and microglia) (Harris et al, 2012; Hyder et al, 2013). Organisms allocate their available energy among the competing needs of maintenance, growth, reproduction, and, particularly in primates, higher cortical functions (communication, imagination, and creativity). A growing body of evidence suggests that metabolic adaptations within the brain and whole body played important roles in the expansion of the cerebral cortex during primate evolution. Several studies comparing the expression of genes and regulatory regions in brains of various primates have shown an up-regulation of genes and metabolites involved in oxidative metabolism and mitochondrial functions in human brains (Grossman et al, 2001, 2004; Ca´ceres et al, 2003; Uddin et al, 2004; Haygood et al, 2007). Furthermore, recent evidence indicates that an increase in metabolic rate, coupled with a higher predisposition to deposit fat and changes in the allocation of energy supplies, was crucial for the evolution of brain size and complexity (Pontzer et al, 2016). Understanding the metabolic signatures of different brain cells, and their metabolic interactions, will not only advance our understanding of how the brain functions and adapts to environmental demands, but may also elucidate the propensity of the human brain to age-related neurodegenerative disorders. In recent years, it has become evident that metabolic alterations strongly influence the instigation and progression of many neurodegenerative disorders. Decreases in glucose and oxygen metabolic rates of brain cells occur during normal aging (Hoyer, 1982a) and are further exacerbated in disorders such as Alzheimer’s (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s (PD), and Huntington’s (HD) diseases (Hoyer, 1982b). In this review article, we summarize the current knowledge of neural cell energy metabolism in the contexts of normal brain function, adaptive neuroplasticity, and the pathogenesis of neurodegenerative disorders.