Propionate regulation of feed intake

Ruminant diets that include large amounts of readily-fermentable starch are known to limit feed intake. Experiments conducted over the past 20 years have indicated that physiological changes in rumen osmolality, rumen pH, or plasma insulin concentration do not consistently explain hypophagic responses to highly fermentable diets. Meanwhile, evidence has accumulated in a number of species that hepatic oxidation of fuels stimulates satiety, and the rapid increase in propionate flux to the liver during meals likely results in oxidation of some propionate. Six studies were conducted to evaluate the hypothesis that hepatic oxidation of propionate limits feed intake in lactating dairy cattle. In a crossover experiment including 32 cows with a wide range of production levels, increased dietary starch fermentability depressed dry matter intake (DMI) 8% but did not alter digestible DMI. Although consistent with the hepatic oxidation hypothesis, these results could also be explained by other proposed mechanisms for regulation of intake. Evidence from both ruminant and non-ruminant studies has suggested that propionate may directly stimulate leptin secretion. Therefore, 2 experiments were conducted utilizing pulse-dose and intermediate-term propionate infusions to evaluate whether this mechanism is important in lactating cows. Based on the small, non-linear effects of propionate administration on leptin secretion that were observed, we concluded that leptin does not likely mediate intake depression by propionate. We then conducted a set of experiments using the glucose analog phlorizin to increase glucose demand and gluconeogenic capacity. By increasing the potential for glucose production from absorbed propionate, we expected to decrease the proportion of propionate that was oxidized, and in turn, increase feed intake. Evidence from 3 experiments suggested that glucose demand was increased by phlorizin treatment, and measurement of transcript abundance for potentially rate-limiting gluconeogenic enzymes indicated that hepatic gluconeogenic capacity was increased by phlorizin treatment. However, phlorizin treatment also consistently stimulated lipolysis, which likely increased hepatic fatty acid oxidation. This confounding effect probably played a role in the lack of an effect on feed intake, and prevented assessment of the hepatic oxidation hypothesis. Finally, we tested the hypothesis that more rapid infusion of propionate during meals would overwhelm hepatic gluconeogenic capacity to a greater extent, resulting in quicker satiety and smaller meals. However, we did not find differences in feeding behavior in response to infusion of 1.2 mol of Na propionate over the course of 5 or 15 minutes during meals. In conclusion, these experiments have not added to the existing evidence for the hepatic oxidation hypothesis for ruminants. Nevertheless, progress has been made toward understanding the mechanism for propionate regulation of feed intake, because leptin has been ruled out as a necessary mediator of this response, and because glucose demand has been shown to have little influence on DMI in the short-term.