Melanocortinergic modulation of cholecystokinin-induced suppression of feeding through extracellular signal-regulated kinase signaling in rat solitary nucleus

Endocrinology. 2005 Sep;146(9):3739-47. doi: 10.1210/en.2005-0562. Epub 2005 Jun 16.

Abstract

Signals from the gut and hypothalamus converge in the caudal brainstem to control ingestive behavior. We have previously shown that phosphorylation of ERK1/2 in the solitary nucleus (NTS) is necessary for food intake suppression by exogenous cholecystokinin (CCK). Here we test whether this intracellular signaling cascade is also involved in the integration of melanocortin-receptor (MCR) mediated inputs to the caudal brainstem. Using fourth ventricular-cannulated rats and Western blotting of NTS tissue, we show that the MC4R agonist melanotan II (MTII) rapidly and dose-dependently increases phosphorylation of both ERK1/2 and cAMP response element-binding protein (CREB). Sequential administration of fourth ventricular MTII and peripheral CCK at doses that alone produced submaximal stimulation of pERK1/2 produced an additive increase. Prior fourth 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 MAPK kinase 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, cAMP receptor protein-Rp isomer, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cholecystokinin / pharmacology*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Eating / drug effects*
  • Eating / physiology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fourth Ventricle
  • Injections, Intraventricular
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Male
  • Melanocyte-Stimulating Hormones / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Corticotropin / antagonists & inhibitors
  • Receptors, Melanocortin / agonists*
  • Solitary Nucleus / drug effects*
  • Solitary Nucleus / physiology
  • alpha-MSH / analogs & derivatives*
  • alpha-MSH / pharmacology

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Receptors, Corticotropin
  • Receptors, Melanocortin
  • acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide
  • SHU 9119
  • alpha-MSH
  • Melanocyte-Stimulating Hormones
  • Cholecystokinin
  • Extracellular Signal-Regulated MAP Kinases