Control of food intake by fatty acid oxidation and ketogenesis.

Fatty acid oxidation seems to provide an important stimulus for metabolic control of food intake, because various inhibitors of fatty acid oxidation (mercaptoacetate, methyl palmoxirate, R-3-amino-4-trimethylaminobutyric acid) stimulated feeding in rats and/or mice, in particular when fed a fat-enriched diet, and long-term intravascular infusion of lipids reduced voluntary food intake in various species, including humans. The feeding response to decreased fatty acid oxidation was due to a shortening of the intermeal interval with meal size remaining unaffected. Thus, energy derived from fatty acid oxidation seems to contribute to control of the duration of postmeal satiety and meal onset. Since inhibition of glucose metabolism by 2-deoxy-D-glucose affects feeding pattern similarly, and spontaneous meals were shown to be preceded by a transient decline in blood glucose in rats and humans, a decrease in energy availability from glucose and fatty acid oxidation seems to be instrumental in eliciting eating. Since the feeding response of rats to inhibition of fatty acid oxidation was abolished by total abdominal vagotomy and pretreatment with capsaicin destroying non-myelinated afferents and attenuated by hepatic branch vagotomy, fatty acid oxidation in abdominal tissues, especially in the liver, apparently is signalled to the brain by vagal afferents to affect eating. Brain lesions and Fos immunohistochemistry were employed to identify pathways within the brain mediating eating in response to decreased fatty acid oxidation. According to these studies, the nucleus tractus solitarii (NTS) of the medulla oblongata represents the gate for central processing of vagally mediated afferent information related to fatty acid oxidation. The lateral parabrachial nucleus of the pons seems to be a major relay for pertinent ascending input from the NTS. In particular the central nucleus of the amygdala, a projection area of the parabrachial nucleus, appears to be crucial for eating in response to decreased fatty acid oxidation. As ketones are products of hepatic fatty acid oxidation that are released into the circulation and peripheral (and central) administration of 3-hydroxybutyrate reduced voluntary food intake in rats, ketones being utilized as fuels by the peripheral and central nervous system might contribute to control of eating by fatty acid oxidation, especially when high levels of circulating ketones occur. Whether a modulation of the hepatic membrane potential resulting from changes in the rate of fatty acid oxidation and/or ketogenesis represent a signal for control of eating transmitted to the brain by vagal afferents remains to be established. Recent in vivo studies investigating the effects of mercaptoacetate on the hepatic membrane potential and on afferent activity of the hepatic vagus branch are consistent with this notion. Further investigations are necessary to delineate the coding mechanisms by which fatty acid oxidation and/or ketogenesis modulate vagal afferent activity.