In addition to expression in the arcuate nucleus of the hypothalamus, POMC is also expressed in a group of neurons in the caudal aspect of the nucleus of the solitary tract, the primary site of synapse of vagal afferent fibers. To test the hypothesis that the brainstem POMC neurons may be involved in satiety signaling, we assessed whether genetic or pharmacological blockade of MC4-R could attenuate the ability of CCK to inhibit food intake. CCK-8s was administered to female C57BL/6J MC4-R KO mice and age-matched female C57BL/6J mice. CCK-8 (3 nmol/kg, i.p.) significantly reduced food intake in C57BL/6J mice, from 30 min to 2h following administration, but not in MC4-R KO mice. Similarly, icv (4th ventricle) injection of a subthreshold dose of melanocortin antagonist, SHU9119 (0.375 nmol/4 ml) significantly attenuated the inhibition of food intake induced by i.p. injection of CCK-8s (3 nmol/kg), at 1 h and 2 h post-administration in 16 hr fasted rats .
These data suggest that CCK-8s was likely activating POMC neurons in one or both of the two sites of POMC expression, the arcuate nucleus of the hypothalamus, or the nucleus of the solitary tract in the brainstem . NTS neurons have been previously well-characterized to be activated, using c-fos as a marker, by either electrical or CCK-induced activation of vagal afferent fibers. Injection of CCK-8s (10mg /kg, i.p.) significantly increased c-fos expression in the NTS ; more than 30% of the NTS POMC-EGFP neurons co-expressed c-fos like IR following CCK-8s treatment . Saline treatment alone did not activate any NTS POMC neurons . No significant difference in c-fos expression was found within the hypothalamic ARC between ip saline and CCK-8s treated groups. These data suggest that CCK-induced satiety is dependent upon the central melanocortin system, and activation of brainstem, and not arcuate POMC neurons.
03 - 05 Nov 2003
Society for Endocrinology