‘Sensing’ of long chain fatty acids by the hypothalamus reduces food intake and suppresses hepatic glucose production in rodents, however, the precise mechanisms involved in central fatty acid sensing are not fully understood. Fatty acid translocase (FAT/CD36) is a highly conserved protein that is a major regulator of fatty acid uptake in most tissues. Fat/Cd36 deletion in the ventromedial hypothalamus reduced the responsiveness of glucose-excitatory neurons to fatty acids (1), suggesting an important role for FAT/CD36 in energy homeostasis. We tested the importance of neuronal FAT/CD36 in energy homeostasis by examining the metabolic phenotype of mice lacking FAT/CD36 in forebrain neurons. Forebrain neuron-specific Cd36 null mice (Cd36-NKO) were generated by crossing Cd36 flox/flox mice with mice bearing a Cre transgene under the control of a calcium/calmodulin-dependent protein kinase II alpha promoter. Mice were fed a standard chow or high fat diet for 12 weeks. Regardless of the diet, body mass gain and the fat mass of mice did not differ between genotypes. Daily food intake and energy expenditure were not different between genotypes when mice were fed a chow diet; however, when fed a high-fat diet, both food intake (17%) and energy expenditure (14%) were increased in Cd36-NKO compared with Wt mice. Blood glucose and plasma insulin levels following both a 4 h fast and during an oral glucose tolerance test were not different between genotypes. Finally, targeted delivery of an adeno-associated virus encoding Cd36 into the arcuate nucleus of mice did not impact body weight, food intake or energy expenditure. Together these data suggests that hypothalamic neuronal FAT/CD36 plays a minor role in regulating energy homeostasis.