Diet- and metabolic state-dependent remodeling of the mouse brain lipidome

The hypothalamus and brainstem are key hubs of metabolic control that undergo dynamic molecular adaptations in response to changes in energy availability. This remodeling is associated with changes in the expression and activity of enzymes linked to energy homeostasis but also importantly, lipid metabolism. Given that lipids account for [~]50% of the brains dry weight, it is likely that lipid metabolism is a major determinant of brain function. Therefore, understanding how the hypothalamic and brainstem lipidome adapts to metabolic perturbation is key to understanding tissue function and metabolic health. Here we characterize the remodeling of [~]750 lipid species in mouse hypothalamus and brainstem, as well as the cerebrospinal fluid and plasma, in response to a metabolic challenge (an Ad Libitum-Fasting-Refeeding cycle). We show that around 45% and 36% of lipids in the hypothalamus and brainstem respectively, exhibit reversible, nutritional state-dependent remodeling during this metabolic challenge, and that this remodeling is substantially impacted by long-term high fat diet intervention. Of note, targeted analysis of specific lipids revealed that certain fatty acids were affected by this intervention in the hypothalamus and brainstem, most strikingly defined by the reversible fasting-induced increase in linoleic acid (18:2)-containing phosphatidylcholines in both the hypothalamus and brainstem, an effect that is abolished by high fat diet intervention. Such precise and intervention-specific regulation of linoleic acid (18:2)-containing phosphatidylcholines provides a previously unrecognized role for this lipid in the physiological response to fasting. Thus, these findings demonstrate that the brain lipidome undergoes robust, nutritional state-dependent remodeling, and provide a comprehensive resource for investigating its role in regulating metabolic adaptations.