Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through ERK signaling in rat solitary nucleus

Abstract

Signals from the gut and hypothalamus converge in the caudal brainstem to control ingestive behavior. We have previously shown that phosphorylation of the extracellular-signal regulated kinase (ERK1/2) in the solitary nucleus (NTS) is necessary for food intake suppression by exogenous CCK. Here, we test whether this intracellular signaling cascade is also involved in the integration of melanocortin-receptor mediated inputs to the caudal brainstem. Using 4 th ventricular-cannulated rats and Western blotting of NTS tissue, we show that the MC4R agonist MTII rapidly and dose-dependently increases phosphorylation of both ERK1/2 and CREB. Sequential administration of 4 th ventricular MTII and peripheral CCK at doses that alone produced submaximal stimulation of pERK1/2 produced an additive increase. Prior 4 th ventricular administration of the MC4R antagonist SHU9119 completely abolished the CCK-induced increases in pERK and pCREB and in freely feeding rats, SHU9119 significantly increased meal size and satiety ratio. Prior administration of the MEK-inhibitor U0126 abolished the capacity of MTII to suppress 2-h food intake and significantly decreased MTII-induced ERK phosphorylation in the NTS. Furthermore, pretreatment with the cAMP inhibitor, cAMPS-Rp, significantly attenuated stimulation of pERK induced by either CCK or MTII. The results demonstrate that activation of the ERK pathway is necessary for peripheral CCK and central MTII to suppress food intake. The cAMP→ERK→CREB cascade may thus constitute a molecular integrator for converging satiety signals from the gut and adiposity signals from the hypothalamus in the control of meal size and food intake. Copyright © 2005 by The Endocrine Society.