The (Wh)olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N)utrition (WHEN) Model. How the hungry brain signals the homeostatic drive via the endocannabinoidome-gut microbiome axis. The consumption of a balanced diet leads to the endogenous synthesis of N-acyl-ethanolamines, 2-monoacylglycerols, N-acyl-amino acids, and hence also helps defining a healthy gut microbial ecosystem. The entwined matrix between the brain and gut, integrated with genetics, bioactive lipids, and lipid mediators 'interplay' acts on, among others, white and brown adipocytes, regulating energy homeostasis. Note (alphabetical order): 2-MAGs, 2-monoacylglycerols; NAAs, N-acyl-amino acids; NAEs, N-acyl-ethanolamines.