Feed and energy intake of ruminant animals can change dramatically in response to changes in diet composition or metabolic state, and such changes are poorly predicted by traditional models of feed intake regulation. Recent work suggests that temporal patterns of fuel absorption, mobilization, and metabolism affect feed intake in ruminants by altering meal size and frequency. Research with nonruminants suggests that meals can be terminated by signals carried from the liver to the brain via afferents in the vagus nerve and that these signals are affected by hepatic oxidation of fuels and generation of ATP. We find these results consistent with the effects of diet on feed intake of ruminants. Of fuels metabolized by the ruminant liver, propionate is likely a primary satiety signal because its flux to the liver increases greatly during meals. Propionate is utilized for gluconeogenesis or oxidized in the liver and stimulates oxidation of acetyl CoA. Although propionate is extensively metabolized by the ruminant liver, there is little net metabolism of acetate or glucose, which may explain why these fuels do not consistently induce hypophagia in ruminants. Lactate is metabolized in the liver but has less effect on satiety, probably because of greater latency for reaching the liver within meals and because of less hepatic extraction compared with propionate. Hypophagic effects of fatty acid oxidation in the liver are likely from delaying hunger rather than promoting satiety because beta-oxidation is inhibited during meals by propionate. A shortage of glucose precursors and increased fatty acid oxidation in the liver for early lactation cows lead to a lack of tricarboxylic acid (TCA) cycle intermediates, resulting in a buildup of the intracellular acetyl-CoA pool and export of ketone bodies. In this situation, hypophagic effects of propionate are likely enhanced because propionate entry into the liver provides TCA cycle intermediates that allow oxidation of acetyl-CoA. Oxidizing the pool of acetyl-CoA rather than exporting it increases ATP production and likely causes satiety despite the use of propionate for glucose synthesis. A better understanding of metabolic regulation of feed intake will allow diets to be formulated to increase the health and productivity of ruminants.