Stimulation of eating by the second messenger cAMP in the perifornical and lateral hypothalamus

Abstract

Despite intense study of neurotransmitters mediating hypothalamic controls of food intake, little is known about which second messengers are critical for these mechanisms. To determine whether adenosine 3',5'-cyclic monophosphate (cAMP) might participate in these mechanisms, we injected the membrane-permeant cAMP analog 8-bromo-cAMP (8-BrcAMP) hypothalamically in satiated rats. Injection of 8-BrcAMP (10-100 nmol) into the perifornical (PFH) and lateral hypothalamus (LH) dose dependently stimulated food intake of up to 15.7 g in 2 h. Significantly smaller responses were obtained with thalamic injections. In contrast to the strong stimulatory effects of PFH and LH 8-BrcAMP, cAMP and 8-bromo-guanosine 3',5'-cyclic monophosphate (100 nmol) were ineffective, suggesting a chemically specific, intracellular action. Consistent with this, combined PFH injection of 7-deacetyl-7-O-(N-methylpiperazino)-tau-butyryl-forskolin dihydrochloride and 3-isobutyl-1-methylxanthine, agents that increase endogeneous cAMP, stimulated eating of up to 9.9 g in 2 h. These results demonstrate that increases in PFH/LH cAMP can elicit complex, goal-oriented behavior, suggesting an important role for cAMP in hypothalamic mechanisms stimulating food intake.

The Second Messenger cAMP Elicits Eating by an Anatomically Specific Action in the Perifornical Hypothalamus

“…The present study confirms that injection of drugs that increase endogenous cAM P can stimulate intense eating (Gillard et al, 1997a), and it is the first to show that this effect is attributable to actions specifically in the PFH. We have shown previously that 100 nmol of cAM P itself, which does not cross cell membranes appreciably, does not stimulate eating in the PF H and L H (Gillard et al, 1997a), suggesting that the membrane-permeant cAM P analog 8-br-cAM P stimulates eating via an intracellular action on local cell bodies or processes rather than via osmotic effects or activation of adenosine receptors. Consistent with this, we demonstrated in the present study that combined PF H injection of the phosphodiesterase inhibitor IBMX, which reduces the breakdown of cAM P, and the AC stimulator M PB forskolin, which stimulates cAM P production, significantly stimulates eating of up to 8.8 Ϯ 2.0 gm (Fig.…”

“…Additionally, the eating elicited by THAL injections might be mediated by biochemical mechanisms distinct from those that produce eating after PF H and L H injections. This was suggested by our previous evidence that the cGM P analog 8-br-cGMP was completely ineffective in eliciting eating after injection into the PFH or L H but did elicit a feeding response after THAL injection that was equivalent to that elicited by 8-br-cAM P injected into that site (Gillard et al, 1997a). Further supporting local, rather than thalamic, actions of PF H injections is the current finding that agents that increase endogenous cAMP (IBMX and MPB forskolin) stimulated eating after injection into the PFH but not the THAL.…”

“…The activity of individual neurons in these areas is modulated in vitro (Cheng et al, 1988) by several neurotransmitters that affect eating, suggesting that individual cells may integrate the effects of a variety of feeding-related neurochemicals. Recent evidence suggests that the cAMP-synthesizing enzyme adenylyl cyclase (AC) may function as a coincidence detector for activation of a variety of metabotropic receptors (Lustig et al, 1993), and we have shown that PFH and LH microinjection of the cAMP analog 8-bromocAMP (8-br-cAMP) or drugs that increase levels of endogenous cAMP elicits a robust eating response in satiated animals (Gillard et al, 1997a). These findings may suggest that cAMP in a population of LH and/or PFH neurons might participate in integrating the feeding-stimulatory and feeding-inhibitory effects of some neurotransmitters.…”

Leptin inhibits insulin secretion by activation of phosphodiesterase 3B.

“…In addition, we mapped the expression of PDE3B in the mouse central nervous system through in situ hybridization. Of particular interest is the expression of PDE3B in the arcuate nucleus and lateral hypothalamus (data not shown), where cAMP may play a role in appetite control (27,28). Currently, we are investigating the potential functional roles of PDE3B in mediating leptin-regulated food intake.…”

Lateral Hypothalamic Signaling Mechanisms Underlying Feeding Stimulation: Differential Contributions of Src Family Tyrosine Kinases to Feeding Triggered Either by NMDA Injection or by Food Deprivation

“…In contrast, Tyr-P-linked activation of a leptin receptor isoform (Li and Friedman, 1999;Hegyi et al, 2004) described in the LHA (Fei et al, 1997;Elmquist et al, 1998;Iqbal et al, 2001) could trigger downstream effectors that potentially interact with Src (Chaturvedi et al, 1998;Hung and Elliott, 2001). Additionally, serine-threonine protein kinases implicated in feeding stimulation (Gillard et al, 1997(Gillard et al, , 1998aSheriff et al, 1997) could cross-signal with LHA PTKs (Nijholt et al, 2000;Schmitt and Stork, 2002). How Src family PTKs help transfer feeding signals within LHA neurons is unclear, but our results suggest that some of this transfer involves Pyk2 and Src recruitment without significant alterations in NMDA-R subunit Tyr-P.…”