During fasting conditions, adipose tissue lipolysis provides FA fuel to other organs. Excess FA supply to liver or heart leads to a rapid increase in LD biogenesis. Based on present studies, it can be hypothesized that perilipin 5, already present in the cytosol, is rapidly recruited to the surface of a nascent pool of LDs and regulates LD TAG hydrolysis, being a novel protein kinase A (PKA) downstream target, by modifications in its scaffolding properties for ATGL and CGI-58, controlling FA utilization through recruitment of mitochondria to LDs by its C-terminal domain and finally protecting mitochondria against lipotoxicity. Perilipin 2 coats a pool of constitutive droplets which are not coupled to specific use.