Lipid digestion and absorption are closely regulated to achieve maximal assimilation. Cholecystokinin (CCK) is the key regulator of the gastrointestinal responses to fat, and is secreted by enteroendocrine cells (EEC) in response to luminal free fatty acids. The mechanisms by which EEC sense fatty acids remain unresolved, but could be attractive targets in strategies aiming to alter food intake and digestion. Previous evidence suggested that aggregates of insoluble fatty acids were principally detected, rather than free fatty acids in solution. Supportive observations followed which demonstrated that latex microparticles of similar size to fatty acid aggregates also activated CCK secretion via a rise in intracellular calcium. However, in the current report we show that this effect of latex microparticles is not specific to EEC. Three other cell types exposed to the microparticles also responded with a rise in intracellular calcium, and this occurred independently of any ability to sense fatty acids. In addition, latex microparticles operate via entry of extracellular calcium whilst fatty acids stimulate release of calcium from intracellular stores. Therefore fatty acids do not act upon the same pathway as latex microparticles. Nonetheless activating nutrient sensing cells by non-nutrient luminal factors that are not absorbed from the gut remains a potentially novel means to manipulate gut function and satiety. © 2009 Elsevier Ltd. All rights reserved.