The link between alterations in circadian rhythms and lipid metabolism in bipolar disorder: the lipid droplets hypothesis

Bipolar disorder (BD) is a neuropsychiatric illness characterized by recurrent episodes of mania and depression, leading to profound cognitive and functional impairments, psychiatric and metabolic comorbidities, and substantial healthcare costs. Due to its complex nature and absence of specific biomarkers, BD presents significant daily challenges for clinicians. Therefore, advancing our understanding of BD pathophysiology is essential to identify novel diagnostic biomarkers and potential therapeutic targets. Although its neurobiology remains unclear, disruption of circadian rhythms and lipid alterations have emerged as key hallmarks of BD. As essential components of the brain, lipids play a pivotal role in regulating synaptic activity and neuronal development. Thus, alterations in brain lipids may contribute to the neuroanatomical changes and reduced neuroplasticity observed in BD. The levels of toxic lipids inside the cell are buffered by lipid droplets that regulate the storage of neutral lipids. These dynamic organelles adapt to cellular needs, and their dysregulated accumulation has been linked to various pathological conditions. Notably, lipid droplets and various lipid classes display rhythmic oscillations throughout the 24-hour cycle, suggesting a link between lipid metabolism, circadian rhythms and lipid droplets. In this review, we explore the impairment of circadian rhythms and lipid metabolism in BD, along with evidence demonstrating that circadian clocks regulate the accumulation of lipid droplets. Importantly, we propose the "lipid droplets hypothesis for BD" that considers that the compromised lipid metabolism in BD is intimately associated with alterations in the lipid droplets homeostasis, which can be driven by disturbances in the circadian clocks.