Ventromedial Arcuate Nucleus Communicates Peripheral Metabolic Information to the Suprachiasmatic Nucleus

Abstract

The arcuate nucleus (ARC) is crucial for the maintenance of energy homeostasis as an integrator of long- and short-term hunger and satiety signals. The expression of receptors for metabolic hormones, such as insulin, leptin, and ghrelin, allows ARC to sense information from the periphery and signal it to the central nervous system. The ventromedial ARC (vmARC) mainly comprises orexigenic neuropeptide agouti-related peptide and neuropeptide Y neurons, which are sensitive to circulating signals. To investigate neural connections of vmARC within the central nervous system, we injected the neuronal tracer cholera toxin B into vmARC. Due to variation of injection sites, tracer was also injected into the subependymal layer of the median eminence (seME), which showed similar projection patterns as the vmARC. We propose that the vmARC forms a complex with the seME, their reciprocal connections with viscerosensory areas in brain stem, and other circumventricular organs, suggesting the exchange of metabolic and circulating information. For the first time, the vmARC-seME was shown to have reciprocal interaction with the suprachiasmatic nucleus (SCN). Activation of vmARC neurons by systemic administration of the ghrelin mimetic GH-releasing peptide-6 combined with SCN tracing showed vmARC neurons to transmit feeding related signals to the SCN. The functionality of this pathway was demonstrated by systemic injection of GH-releasing peptide-6, which induced Fos in the vmARC and resulted in a reduction of about 40% of early daytime Fos immunoreactivity in the SCN. This observation suggests an anatomical and functional pathway for peripheral hormonal feedback to the hypothalamus, which may serve to modulate the activity of the SCN.

Ghrelin Effects on the Circadian System of Mice

“…It has been reported that the blood-brain barrier border could actually lie at the area between the median eminence and the distal part of the arcuate, indicating that the proximal arcuate could be exposed to circulating neuroactive substances (Shaver et al, 1992). Recently, a reciprocal linkage between the ventromedial arcuate to the SCN was established by means of anterograde and retrograde tracing techniques (Yi et al, 2006). Thus, the fact that the SCN receives an input from the arcuate suggests at least an indirect communication between the general circulation and the SCN.…”

“…Ghrelin may also be synthesized in the hypothalamus (for review, see Horvath et al, 2001). Ghrelin-immunoreactive neurons are present in the paraventricular, dorsomedial, ventromedial, and arcuate nuclei, areas important for circadian output (Cowley et al, 2003;Yi et al, 2006).…”

Differential Effects of Recombinant Adeno-Associated Virus-Mediated Neuropeptide Y Overexpression in the Hypothalamic Paraventricular Nucleus and Lateral Hypothalamus on Feeding Behavior

“…LH-NPY rats, however, consume as much food in the light phase as in the dark phase, probably because of induced wakefulness (Szentirmai and Krueger, 2006). Interestingly, the suprachiasmatic nucleus, which drives the diurnal rhythm of feeding activity, is hypothesized to accomplish this via projections to the LH (Abrahamson et al, 2001), but also direct projections from the suprachiasmatic nucleus to the arcuate nucleus are present (Yi et al, 2006). A continuous stimulation by increased NPY signaling in the LH would therefore explain the increased anticipation to eat as well as the time spent feeding.…”

Interaction between hypothalamic dorsomedial nucleus and the suprachiasmatic nucleus determines intensity of food anticipatory behavior

“…These observations may also provide an explanation as to why in early studies lesioning the ventro medial hypothalamus resulted in diminished FAA, which recovered in time (44,45). We have not studied the effect of DMH lesion for periods longer than 6 wk, but it is possible that over time, the strength of other inhibitory inputs to the SCN [e.g., from the arcuate nucleus (46)] may increase and thus result in recovery of FAA consequent to an increase in inhibitory input to the SCN. Because we have observed a similar mechanism for arcuate-SCN interaction (47), we would like to propose that this is a general feature for hypothalamic structures, allowing them to impose adaptive changes depending on the requirements of the body.…”