Friday, April 15, 2011

Hunger Hormone Enhances Sense of Smell

ResearchBlogging.orgThe smell of coffee wafting through the air this morning may have inspired me to write about this Journal of Neuroscience paper from Dr. Jenny Tong and colleagues at the University of Cincinnati. Their work showed the effects of the appetite-stimulating hormone ghrelin on the olfactory system. It seems only logical that hunger should have effects on food-seeking behavior, including the detection of food smells. This study sheds light on the mechanisms through which ghrelin modulates olfactory processing in both rats and humans.

But first, a little background on the wonders of the olfactory system. I am not a systems or behavioral neuroscientist, but if I was, I would totally study olfaction. The olfactory system appeals to my interests in cellular, molecular, and developmental neuroscience. We all have tons of olfactory receptor neurons (ORNs), each of which somehow expresses only a single odorant receptor gene (out of approximately 1000, in humans). And each ORN, depending on which receptor it expresses, sends its axon into the olfactory bulb, where it joins up with the axons of all other ORNs expressing that receptor in a beautiful structure called a glomerulus. To get a sense of how cool that is, observe this image from Feinstein and Mombaerts (2004) showing mouse ORNs expressing an olfactory receptor called M71, labelled in blue:

Mouse ORNs, from Feinstein and Mombaerts, 2004

Check it out: neurons in the olfactory epithelium inside the nose (left side of the image) are exposed to the air, which allows them to bind to inhaled odorant molecules. They send their axons through a bone (the ethmoid) in olfactory nerve fibers that converge on the appropriate glomerulus (near the upper right corner). Glomeruli occur in stereotyped locations, residing in the same part of the olfactory bulb in every individual. What's not shown here is that there are ~2000 distinct glomeruli in the bulb, and ORNs always find the right ones. The olfactory system, in short, is really cool.

Studying olfaction doesn't just provide a great excuse to say words like "glomerulus" (Latin for "a small ball;" from the same root as "conglomerate," as in to roll a bunch of disparate things into a ball). The system is a minor miracle of carefully regulated gene expression, axon pathfinding, and tricky neural coding used to translate the activation of ORNs into a downright Proustian experience. Perhaps that's why the first people to figure some of this stuff out received a Nobel Prize.

But enough of my olfactory fangirling. Back to Dr. Tong and her colleagues, who were interested in how this elegant system functions after the glomeruli have formed and the animal is out there in the world, sniffing for food. Specifically, they wanted to know how changes in nutritional state affect olfaction. Do hungry animals differ from satiated animals in their food-seeking olfactory processes? To test this, the researchers specifically measured two factors important for functional olfaction: sniffing behavior and olfactory detection thresholds (that is, how sensitive are the ORNs to very low levels of an odorant?). They found that ghrelin enhances both.

Neuroendocrinologists have identified a bunch of hormones and neuropeptides that contribute to sensations of hunger and satiety, but the main "hunger hormone" is ghrelin. Ghrelin is produced in the stomach and circulates throughout the body to stimulate feelings of hunger and increase food intake. (After learning about ghrelin in our first year systems neuroscience course, my classmates and I frequently invoked it at lunch time. "Are you ghrelin?" "Yeah, I'm ghrelin like a felon!" ... it was a timely joke in 2008, okay?) Interestingly, ghrelin receptors are found on facial motor neurons involved in sniffing movements, which implies that this hormone may regulate food-seeking behavior in part by inducing animals to start sniffing for their next meal.

For this study, the researchers first showed that ghrelin receptors are found not only in "sniff neurons" in the facial motor nuclei, but also in the olfactory bulb itself. This provides a mechanism through which ghrelin can modulate not just sniffing but also olfactory sensitivity. They confirmed that ghrelin increases olfactory sensitivity in rats by measuring whether the rats could detect very low levels of an odor in their drinking water. After rats were conditioned to avoid an odor (odorized water was paired with a drug that made the rats feel sick), Dr. Tong and colleagues measured how much the rats drank from a bottle of pure water versus a bottle containing very low concentrations of the odor. Rats that were given an infusion of ghrelin avoided the odorized water, even when the odor was diluted by a factor of 10-10. Untreated rats still drank from the most dilute odorized water bottles, indicating that they were unable to detect the odor at such low concentrations. This implies that ghrelin binding to olfactory brain regions lowers the threshold of odor detection -- in other words, 'hungry' animals are more sensitive to smells. There does seem to be a maximum level of ghrelin-mediated olfactory sensitivity, however: rats that fasted overnight were more sensitive to odors than rats that had recently eaten, but treating the fasting rats with ghrelin did not further improve their ability to detect very weak odors.

Dr. Tong et al. also showed that ghrelin increased exploratory sniffing in rats "using a video-based, fully automated behavior analysis system (HomeCageScan, Clever Sys) that recognizes, records, and quantifies the movement of the nose tip while the animal was either fully or partially reared in a home-cage environment." (That is not even close to the funniest/weirdest sentence from an olfaction paper, either. My favorite is from Stowers et al., 2002: "The time required to discover a hidden cookie (latency) is similar in mutant and wild-type mice," followed by a graph of "cookie latency." Cookie latency is a standard measure in the olfactory behavior literature. This particular paper contains other LOLs, though -- it's about how mice that lack a certain ion channel lose the ability to distinguish between males and females, and thus display indiscriminate mating behavior. End immature parenthetical.)

The researchers also measured sniffing behavior in humans. Here, I think, is where the Materials and Methods section of the paper becomes really awesome:

Sniffing behavior was evaluated using the sniff magnitude test (SMT) as described previously. Briefly, a canister was placed ∼2 cm beneath the nose, and subjects were instructed to take a single, natural sniff as would be taken when sampling a perfume or food. The stimuli used were as follows: nonodorized air, baby power odor (baby power fragrance oil, 50% dilution, The Good Scents Co.), banana odor (isoamyl acetate, 1% dilution, Sigma-Aldrich), and tomato odor and rosemary chicken odor (both undiluted, formulated by Givaudan). Three sniffing trials were collected for each odorant and six for air. A specialized software program identified the initiation of sniffing, recorded sniff pressure at 10 ms intervals, summed sniff pressures, and measured each sniff's duration during a 5 s sampling period. The sum of the pressure values was defined as the sniff magnitude. The subjects were also asked to rate the pleasantness of the odors immediately after each trial using a visual analog scale [scores ranging from −5 (slightly unpleasant) to 15 (best smell ever)]. The order of stimulus presentation was randomized. The average sniff magnitude and odor pleasantness ratings were used for data analysis.

Subjects were given the SMT after an infusion of saline or of varying levels of ghrelin. The result was that the cumulative sniff magnitude was significantly increased by all doses of ghrelin, but not by saline. Ghrelin treatment had no significant effect on the pleasantness rating of any odor, however. (I wonder why the scale doesn't go below -5? Artificial banana odor sounds more than "slightly unpleasant" to me. Certainly nowhere near "best smell ever.")

In sum, ghrelin increases an olfactory food-seeking behavior (sniffing) in both rats and humans, as well as olfactory sensitivity in rats. No measurements of odor detection threshold were made in humans, however, which I found a bit disappointing. It would be unethical to induce conditioned odor aversions in humans, but it seems like it should be possible to ask people to discriminate between scented and unscented samples, or between two different odors at very low concentrations. Perhaps it was too difficult to design that study, or to recruit enough participants interested in receiving i.v. ghrelin infusions. (Perhaps a "ghrelin like a felon" TV commercial would be helpful?)

One surprising result of this study was that ghrelin levels had no effect on sniffing for food odors vs. non-food orders, nor on how participants rated the pleasantness of individual odors. Other studies have shown that feelings of hunger increase human preferences for food odors, but these results imply that those effects are not due specifically to the action of ghrelin. Rather, ghrelin seems to upregulate food-seeking behaviors like sniffing without necessarily affecting the hedonic value (pleasantness) of food-related cues. Perhaps other appetite and satiety hormones, like orexin and leptin, are involved in food odor preferences in hungry individuals. This just goes to show that even the most basic biological drives (everyone eats!) aren't as simple as we might expect.


Tong J, Mannea E, Aimé P, Pfluger PT, Yi CX, Castaneda TR, Davis HW, Ren X, Pixley S, Benoit S, Julliard K, Woods SC, Horvath TL, Sleeman MM, D'Alessio D, Obici S, Frank R, & Tschöp MH (2011). Ghrelin enhances olfactory sensitivity and exploratory sniffing in rodents and humans. Journal of Neuroscience, 31 (15), 5841-5846 PMID: 21490225

Feinstein P, & Mombaerts P (2004). A contextual model for axonal sorting into glomeruli in the mouse olfactory system. Cell, 117 (6), 817-31 PMID: 15186781

Stowers L, Holy TE, Meister M, Dulac C, & Koentges G (2002). Loss of sex discrimination and male-male aggression in mice deficient for TRP2. Science, 295 (5559), 1493-500 PMID: 11823606


  1. Interesting. I was ill the past few days with something that made it impossible to keep down food. Today I find certain certain odors overpowering -- apparently my natural gas meter has a leak -- that were not noticeable before.
    Other factors might account for some of the newfound sensitivity -- such as my girlfriend's not smoking in my presence -- so I can't consider hunger as the sole factor.

    1. I just recently went through the same thing. That is why I am searching the internet. I had the flu and after that I think this is hormone related. I was nauseated and the smell of food made me even more sicker. I did not want to smell or eat anything, other than crackers and juice. I am trying to find out, what is going on with me and I have a dr. appt. next week.