Obesity and type 2 diabetes are major worldwide public health issues where there appears to be a relationship between total fat intake and obesity. In addition, the mechanisms of long-term and excessive high-fat diet (HFD) intake in the development of obesity still need to be elucidated. The ventromedial hypothalamus (VMH) is a major site involved in the regulation of glucose and energy homeostasis where "metabolic sensing neurons" integrate metabolic signals from the periphery. Among these signals, fatty acids (FA) modulate the activity of VMH neurons utilizing the FA translocator/CD36 which plays a critical role in the regulation of energy and glucose homeostasis. During low fat diet (LFD) intake, FA are oxidized by VMH astrocytes to fuel their on-going metabolic needs. However, HFD intake causes VMH astrocytes to utilize FA to generate ketones bodies. We postulate that these astrocyte-derived ketone bodies are exported to neurons where they produce excess ATP and ROS which override CD36-mediated FA sensing and act as a signal to decrease short-term food intake. On HFD, VMH astrocyte-produced ketones reduce elevated caloric intake to LFD levels after 3 d in rats genetically-predisposed to resist (DR) diet-induced obesity (DIO), but not leptin resistant DIO rats. This suggests that, while VMH ketone production on HFD can contribute to protection from obesity, the inherent leptin resistance overrides this inhibitory action of ketone bodies on food intake. Thus, astrocytes and neurons form a tight metabolic unit that is able to monitor circulating nutrients in order to alter food intake and energy homeostasis.