Controlling fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), are closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of the lipid raft, participate in adipogenesis and lipogenesis by preferentially recruiting effectors, such as perilipin for LD fusion or transporters for fatty acid uptake. Adipocyte-like cells having increased stomatin expressions exhibit higher levels of fatty acid uptake and LD growth or enlargements. Moreover, transgenic mice fed with a high-fat diet showed increased stomatin expression that facilitated progression of obesity and caused insulin resistance and hepatic impairments. Conversely, inhibitions of stomatin by gene knockdown or pharmacological treatments could block not only LD growth but also adipogenic differentiation through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involved ERK signaling; however, an alternate pathway also exist. Amongst various anti-obesity measures, stomatin serves as another potential therapeutic target.