Metabolic sensing neurons in the ventromedial hypothalamus (VMH) alter their activity when ambient levels of metabolic substrates such as glucose and fatty acids (FA) change. To assess the relationship between high fat diet (60%; HFD) intake on feeding and serum and VMH FA levels, rats were trained to eat a low fat (13.5%; LFD) or a HFD in 3h/d and were monitored with VMH FA microdialysis. Despite having higher serum levels, HFD rats had lower VMH FA levels but ate less from 3-6 h of refeeding than did LFD rats. However, VMH β-hydroxybutyrate (β-OHB) and VMH/serum β-OHB levels were higher in HFD rats during the first 1h of refeeding suggesting that VMH astrocyte ketone production mediated their reduced intake. In fact, using calcium imaging in dissociated VMH neurons, ketone bodies overrode normal FA sensing, primarily by exciting neurons that were either activated or inhibited by oleic acid. Importantly, bilateral inhibition of VMH ketone production with a 3-hydroxy-3-methylglutaryl-CoA synthase inhibitor reversed the 3-6h HFD-induced inhibition of intake but had no effect in LFD-fed rats. These data suggest that a restricted HFD intake regimen inhibits caloric intake as a consequence of FA-induced VMH ketone body production by astrocytes.
- Received July 12, 2013.
- Accepted December 21, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.