Energy homeostasis is regulated by a constant dialogue between metabolic and hormonal sensors in the periphery and the brain. Long chain fatty acids (LCFA) provide an important metabolic substrate that is sensed by specialized receptors and transporters located on metabolic sensing neurons that are widely distributed throughout the brain. These neurons alter their activity in response to a variety of other metabolic substrates and hormones. The LCFA receptor/transporter CD36 regulates LCFA sensing in more than half of the ventromedial hypothalamic (VMH) metabolic sensing neurons. Depletion of rat VMH CD36 alters body weight, food intake, carcass fat deposition, insulin sensitivity and linear growth depending upon the strain and age of rat used. But neuronal FA sensing is also markedly influenced by astrocyte-produced ketone bodies, especially in the face of high fat diet intake. This ketone production overrides the CD36-mediated FA sensing pathway and thereby alters food intake. Thus, neuronal FA sensing plays an important role in regulating energy homeostasis and is markedly influenced by dietary fat content.