Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans

Abstract

Olfaction is an integral part of feeding providing predictive cues that anticipate ingestion. Although olfactory function is modulated by factors such as prolonged fasting, the underlying neural mechanisms remain poorly understood. We recently identified ghrelin receptors in olfactory circuits in the brain. We therefore investigated the role of the appetite-stimulating hormone ghrelin in olfactory processing in rodents and humans, testing the hypothesis that ghrelin lowers olfactory detection thresholds and enhances exploratory sniffing, both being related to food seeking. In rats, intracerebroventricular ghrelin decreased odor detection thresholds and increased sniffing frequency. In humans, systemic ghrelin infusions significantly enhanced sniff magnitudes in response to both food and nonfood odorants and air in comparison to control saline infusions but did not affect the pleasantness ratings of odors. This is consistent with a specific effect on odor detection and not the hedonic value of odors. Collectively, our findings indicate that ghrelin stimulates exploratory sniffing and increases olfactory sensitivity, presumably enhancing the ability to locate, identify, and select foods. This novel role is consistent with ghrelin's overall function as a signal amplifier at the molecular interface between environmental and nutritional cues and neuroendocrine circuits controlling energy homeostasis.

Figure 1.

Ghrelin binding in rat brain areas involved in olfactory processing. Biotinylated ghrelin (red fluorescence) binding was found on or in scattered cell bodies in the MOB (A) and hippocampus (C). Biotinylated ghrelin binding was abolished in the MOB (B) and hippocampus (D) when brain tissue was coincubated with unlabeled ghrelin. Arrows point to labeling, presumably at synaptic boutons, on cell bodies of neurons in the external plexiform (EPL), mitral cell (MCL), and granular cell (GCL) layers. Arrowheads point to areas being magnified (a and c). Scale bar: A–D, 10 μm; a, c, 40 μm.

Figure 2.

Ghrelin receptor (GHSR) localization in mouse brain areas involved in sniffing and olfactory behaviors. A, B, Cresyl violet-stained coronal sections of MOB (A) and brain (B), with boxes indicating regions shown at higher magnification in C, D, and G–J. Box 1, MOB glomerular layer (Gloml) (shown in G); box 2, MOB, junction between external plexiform (EPL), mitral cell (MCL), and granular cell (GCL) layers (H); box 3. anterior cortical amygdala (C, I); and box 4, piriform cortex (D, J). C–J, Immunofluorescent and histochemical staining of X-gal in tissues from ko mice. E–J, β-gal immunofluorescence was seen in the pituitary (E) and hypothalamus (F); in cells in the MOB Gloml (G; cell bodies, arrow) and in MOB mitral cells (H; cell body, arrow; dendrite in EPL, arrowhead); and in neurons (arrows) in the cortical amygdala (I) and piriform cortex (J). III, Third ventricle. C, D, Scattered cells positive for β-gal histochemical staining were visible in the cortical amygdala (C) and piriform cortex (D). Scale bar: D–G, I, J, 50 μm; H, 33 μm; C, 100 μm.

Figure 3.

Sniff behavior was recorded for 24 h in rats after intracerebroventricular administration of ghrelin or vehicle control. Intracerebroventricular ghrelin (compared to intracerebroventricular vehicle) resulted in acutely increased sniffing frequency for up to 2 h, and also increased sniffing throughout the dark phase.

Figure 4.

The SMT was administered before and 45 min after human subjects received ghrelin (1, 3, or 5 μg/kg/h) or saline intravenous infusions. Sniff magnitude changes are shown in the presence (hatched, gray, and black bars) or absence (white bar) of ghrelin administration, when the following odorants were presented to subjects in random order: air (B), baby powder (C), banana (D), tomato (E), and rosemary chicken (F). The effect of ghrelin on sniff magnitude changes combining five odor trials is shown in A. *p < 0.05, ***p < 0.001.