Ketone bodies (KB) are produced during prolonged fasting or carbohydrate restriction and can act as oxidative fuel sources and metabolic signals. Increased KB concentrations reduces food intake in rodents [1] and in humans [2], although the mechanisms are poorly understood. Ketones may influence appetite via changes in circulating gut hormones [2] and hypothalamic AMPK phosphorylation [3]. We utilized a novel ketone ester (KE) to investigate the effect of ketosis on appetite, insulin and glucose and in non-obese, healthy volunteers. Methods: Following favorable ethical review, volunteers (n = 15) completed a randomized, blinded, cross-over study. Following an overnight fast subjects consumed 395mg/kg KE, or isocaloric dextrose (CHO), as citrus flavored drinks. Drinks were taste, tonicity and colour matched. Blood samples were obtained at regular intervals via an intravenous catheter. Appetite was assessed at baseline (BL) and at identical intervals to blood sampling after drink ingestion. Appetite was assessed as the mean of a 3 measure visual analogue scale (desire to eat, hunger, fullness) and expressed as a percentage. Blood samples were analysed for β-hydroxybutyrate (BHB), glucose and insulin. Values are means ±SEM. Two way repeated measures ANOVA with Sidak Post Hoc corrections were performed. Significance was considered as p < 0.05. Results: Blood BHB increased from 0.16 mM (± 0.02 mM) at BL to 3.16 mM (± 0.14 mM) 1h post-KE. BHB concentration remained below 0.3 mM in CHO. Appetite fell after both drinks and rose slowly over the course of the study. Appetite was significantly lower (greater satiety) between 1-3h on KE vs. CHO (p<0.05), with a maximal difference of 16.2 % (± 5%) at 2.5h. Total insulin area under curve (AUC) was significantly higher following CHO (1972 mU/L min-1 vs. KE = 1010 mU/L min-1). Blood glucose was unchanged between conditions. Conclusion: Blood glucose and insulin play a pivotal a role in energy balance and appetite [4, 5]. Insulin would normally correlate with decreased appetite [4]. Despite lower insulin following KE, appetite was significantly lower vs. CHO, suggesting an insulin independent mechanism for the changes in appetite during ketosis. This suggests that nutritional ketosis may provide a novel metabolic strategy to modulate appetite and may offer an alternative to drug or surgical interventions to reduce body weight.