Participation of neuronal metabolism in the regulation of energy balance

Central or peripheral administration of the FAS inhibitor C75 reduces food intake and body weight in rodents. We and others have reported that the CNS is a critical site of action. Despite being anorexic, C75 administration in lean mice leads to a hypothalamic neuropeptide profile similar to the fed state (elevated POMC/CART, decreased NPY/AgRP) suggesting a specific influence on hypothalamic regulatory pathways. Of interest is that obese animals and animals on a high fat diet are sensitive to the effects of C75 suggesting its actions are upstream of systems like leptin and insulin that can become desensitized in obesity. We hypothesized that carbohydrate utilization, rather than fatty acid oxidation, is important for C75's effects. To test this hypothesis we placed animals on a high-fat ketogenic diet and, after confirming they were ketotic, tested the efficacy of C75 to reduce food intake and body weight. Consistent with our hypothesis, there was no difference between C75 and vehicle in ketotic animals. To confirm metabolic state, and not diet content, was responsible for C75 resistance, we allowed each animal to consume either a sucrose or saccharin solution in addition to the ketogenic diet. C75 sensitivity was completely restored in animals that received the sucrose solution while animals that received the saccharin solution remained insensitive. These results suggest that C75's effect is mediated by carbohydrate utilization in brain and that some aspect of glycolysis or glucose oxidation is capable of influencing endogenous energy sensing mechanisms.