Ghrelin-Induced Food Intake Is Mediated via the Orexin Pathway

Abstract

The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.

Ghrelin in obesity and endocrine diseases

“…Interplay between ghrelin and orexin (Toshinai et al, 2003) suggests that arousal and wakefulness may be required for ghrelin's orexigenic effect (Olszewski et al, 2008). Mice with double knockout (KO) of NPY/AgRP genes completely lack the orexigenic action of ghrelin, confirming that these neuropeptides mediate and are essential for the orexigenic effect of this peptide hormone (Chen et al, 2004).…”

Lack of starvation-induced activation of AMP-activated protein kinase in the hypothalamus of the Lou/C rats resistant to obesity

“…However, although the ghrelin-induced food intake is thought to be mediated via the orexin pathway in the hypothalamus, 29 no clear-cut differences in mRNA levels of orexin (Table 1) or of the neuropeptide itself 26 were found between the two strains of rat. In addition, ghrelin-deficient mice exhibited normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides and their feeding behavior was not affected, indicating that ghrelin is probably not an essential regulator of food intake and has, at best, a redundant role in the regulation of appetite.…”

Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats

“…GHS-Rs are present in the LH (31). Ghrelin-containing axons project to the LH and form direct synaptic contact with orexin-producing neurons (57). Intracerebroventricular or local application of ghrelin into the LH of rats activates orexin cells (24,37,57,67).…”