Cholecystokinin acts in the dorsomedial hypothalamus of young male rats to suppress appetite in a nitric oxide-dependent manner.

Cholecystokinin (CCK) is an appetite-suppressing hormone that acts in the dorsomedial hypothalamus (DMH) in adult rats to suppress food intake. It remains unknown, however, whether CCK has the same affect in young animals, despite the rising prevalence of childhood obesity and drastic need for research in this area. At the synaptic level, CCK has been shown to inhibit putative orexigenic DMH neurons in young male rats by increasing GABA release onto these neurons via a CCK2 receptor and nitric oxide-dependent pathway. Whether this pathway leads to appetite suppression in young rats is not known. We therefore investigated whether intra-DMH administration of CCK, with or without inhibitors of the CCK2 receptor and nitric oxide signaling pathways, affects food intake in young, male, fasted Sprague-Dawley rats. We implanted bilateral guide cannulas into the DMH and allowed animals to recover from the surgery. Animals were then fasted for 24 h, following which they received intra-DMH microinjections of vehicle, CCK-8S, or CCK-8S combined with either LY-225910 (CCK2 receptor antagonist), L-NAME (a nitric oxide synthase inhibitor), or ODQ (a soluble guanylate cyclase inhibitor) and were given access to regular chow. Following a two hour refeeding period during which food intake, latency to feed, and body weight were measured, brains were subsequently removed to confirm cannula placement in the DMH. The effect of CCK on these parameters in rats given a high fat diet were also measured. Here we show that intra-DMH administration of CCK suppresses food intake and body weight in young rats. This effect requires activation of CCK2 receptors and nitric oxide signaling. Finally, CCK has no effect on consumption of a high fat diet when administered into the DMH. Overall, these findings demonstrate a potential pathway through which CCK might suppress appetite in young rats.

Nitric Oxide Acts in the Rat Dorsomedial Hypothalamus to Increase High Fat Food Intake and Glutamate Transmission.

The dorsomedial nucleus of the hypothalamus (DMH) plays an important role in the regulation of energy intake and expenditure. Numerous appetite-regulatory signals present in the DMH, including nitric oxide (NO) and endogenous cannabinoids (eCBs), act to regulate food intake, but whether these signals are involved in regulating high fat food intake remains unknown. We therefore asked whether NO and eCBs, administered alone or in combination, would influence the consumption of high fat food in rats. We implanted bilateral guide cannulas in the DMH of young, male Sprague-Dawley rats for microinjection of vehicle, NO (via the precursor l-arginine), the eCB 2-arachidonylglycerol (2-AG), or a combination of the two signals. Following the intrahypothalamic injections, both high fat food intake and body weight were measured for two hours at which point brains were removed and sectioned to confirm cannula placement in the DMH. Here we show that l-arginine significantly increases high fat food intake when administered into the DMH. This effect is abolished in the presence of 2-AG, which alone has no effect on high fat food intake or body weight. The l-arginine-induced increase in high fat food intake is dependent on NO synthesis, as it is prevented with the NO synthase inhibitor, l-NAME. We also demonstrate that l-arginine increases glutamate transmission onto DMH neurons, an effect that also requires NO synthesis and is abolished with 2-AG. Together, these data indicate that NO acts in the DMH to regulate the consumption of high fat food, possibly by enhancing glutamate signaling at DMH synapses.