Role of VMH ketone bodies in adjusting caloric intake to increased dietary fat content in

25 26 The objective of this study was to determine the potential role of astrocyte-derived ketone bodies 27 in regulating the early changes in caloric intake of diet induced-obese (DIO) vs. diet resistant 28 (DR) rats fed a 31.5% fat high-energy (HE) diet. After 3 d on chow or HE diet, DR and DIO rats, 29 were assessed for their ventromedial hypothalamic (VMH) ketone bodies levels and neuronal 30 ventromedial hypothalamic nucleus (VMN) sensing using microdialysis coupled to continuous 31 food intake monitoring and calcium imaging in dissociated neurons, respectively. DIO rats ate 32 more than DR rats over 3 d of HE diet intake. On day 3 of HE diet intake, DR rats reduced their 33 caloric intake while DIO rats remained hyperphagic. Local VMH astrocyte ketone bodies 34 production was similar between DR and DIO rats during the first 6 h after dark onset feeding but 35 inhibiting VMH ketone body production in DR rats on day 3 transiently returned their intake of 36 HE diet to the level of DIO rats consuming HE diet. In addition, dissociated VMN neurons from 37 DIO and DR rats were equally sensitive to the largely excitatory effects of β-hydroxybutyrate. 38 Thus, while DR rats respond to increased VMH ketone levels by decreasing their intake after 3 d 39 of HE diet, this is not the case of DIO rats. These data suggest that DIO inherent leptin resistance 40 prevents ketone bodies inhibitory action on food intake. 41