Metabolic syndrome (MetS) is a widespread multi-component pathological condition characterized by meta-inflammation and cellular dysfunction. MetS and other metabolic diseases (metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular-kidney-metabolic syndrome (CKMS)) stem from the disorder of energy metabolism and changes in the structure and function of specialized organelles such as lipid droplets, endoplasmic reticula, mitochondria, and nuclei. The discovery of lipid droplets within the nucleus and the investigation of their functions across various cell types in both health and disease provide a foundation for discussing their role in the development and progression of metabolic syndrome. This review examines studies on lipid droplets in the nucleus, focusing on pathways of formation, structure, and function. The importance of (nuclear) lipid droplets in liver and brain is emphasized in the context of inflammation associated with obesity, MetS, and liver disease. This suggests that these structures are promising targets for the development of effective drugs against diseases associated with dysregulation of energy metabolism.