Metabolic Plasticity. An Evolutionary Perspective on Bipolar Disorder, Insulin Signalling and Ketosis

The emerging field of Metabolic Psychiatry has brought mechanisms of metabolic dysfunction into focus in bipolar disorder research. In this manuscript we highlight the preserved evolutionary roots of mechanisms of metabolic adaptation and their interaction with established mechanisms of circadian dysfunction in bipolar disorder. Throughout evolutionary history, selective pressures in the environment caused many biological organisms to develop patterns of seasonal metabolic adaptation. States of hypometabolism, characterised by reduced basal metabolic rate, suppression of insulin signalling and glucose metabolism, suppressed circadian rhythmicity, and increased reliance on fatty acid and ketone body metabolism were adaptive during states such as torpor and hibernation. Conversely, seasonal hypermetabolic states were advantageous for survival in scenarios such as migration, where increased fatty acid metabolism was also a critical component of physiological adaptations. The mechanisms underpinning these metabolic changes are intricately interlinked with circadian systems, which are responsive to changes in photoperiod and drive patterns of seasonal adaptation. While humans have been largely removed from the selective pressures of our evolutionary predecessors, similar chrono-metabolic mechanisms underlying seasonal adaptation are preserved in human biology, and play important roles in tuning metabolism to environmental cues. In this manuscript we highlight evolutionarily preserved metabolic and circadian mechanisms which are implicated in bipolar disorder pathophysiology, and we compare these to mechanisms which have mediated seasonal metabolic adaptation throughout evolutionary history.