The cerebral glucose-fatty acid cycle: Evolutionary roots, regulation, and (patho)physiological importance

Abstract

Metabolism under changing fuel supply is controlled by the glucose-fatty acid cycle. Its evolutionary prototypes were programmed to provide optimal resilience in the feast and famine lifestyle of microorganisms. The counterregulatory processes, activated during nutrient deprivation, include hypometabolism and oxidative stress and aim to preserve glucose for anabolic needs and promote the oxidative utilization of fatty acids and ketone bodies. Conserved from bacteria to man, the program ensures the survival of a deprived organism and controls divergent processes—such as sporulation, hibernation, and starvation. The cycle is controlled by the antagonistic insulin/glucocorticoid couple. The pattern of hormone/neurotransmitter changes in a variety of central nervous system (CNS) ontogenetic and accidental/degenerative events is surprisingly uniform: the desensitization/degeneration of proglucolytic agents and activation of prolipolytic hormones/neurotransmitters paralleled by hypometabolism and downregulation of glucose utilization. Thus, probing various brain pathologies (e.g., stroke, traumatic injury, epilepsy, Alzheimer disease) and ontogenetic events (maturation, aging) for metabolic stress signatures reveals their shared heritage as metabolic deprivation syndromes. Neurotransmitters are the dual conveyors of intercellular communication (enabling affective and cognitive processes) and energy homeostasis, establishing a psychosomatic continuum. In this holistic approach, psychosocial stress, depression, and psychosis can be understood as heterogeneous phenotypes of psychosocial/ metabolic stress pathologies.