Is There a Direct Link Between the Sense of Smell and Obesity?

Both of these mice ate the same high-fat diet. The one on the right was altered to remove its sense of smell.  (Andrew Dillin and Celine Riera/UC Berkeley)

Molecular biologist Celine Riera was walking down a street in France earlier this month when she smelled freshly baked croissants.

“I wasn’t hungry,” she says, “but I had to have one.”

Riera’s scent cells began sending a message to her body: “Hey, Celine, you’re about to eat food. Get ready to store it as fat to use later.”

But what if her scent cells never sent that signal? Is it possible she could eat that croissant and perhaps not store it as fat? Does our sense of smell direct our body’s decisions on when to store fat and when to burn it?

Riera’s latest research offers a start to answering just that.

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Riera is the lead author on a study released this month from UC Berkeley’s Dillin Lab and published in Cell Metabolism. It found that mice who lost their sense of smell burned more energy and fat while eating the same amount of food as mice who could smell just fine.

Same Diet, Two Results

The study tested two groups of mice that had been genetically modified to be susceptible to diphtheria in the sensory receptors in their noses. Researchers injected one group with the diphtheria toxin, temporarily wiping out their sense of smell. Both groups of mice were then fed a high-fat diet. After 12 weeks, the mice who could smell weighed 16 percent more than those who couldn’t. And the difference was made up entirely of fat.

The mice who couldn’t smell also seemed to be protected from other consequences of high-fat diets, such as inflammation in fat tissues, and insulin resistance that can lead to diabetes.

In a second experiment, researchers allowed a group of mice with typical smell to eat a high-fat diet, then injected half of the obese mice with diphtheria toxin. After they lost their sense of smell, these mice lost weight and showed less insulin resistance.

On the left is a close-up of the inside of the nose of a mouse who can smell, while the right is a mouse who can't.
To test the effects of smell on weight gain, researchers knocked out the olfactory neurons (stained in red) of mice before feeding them a high-fat diet. On the left is a close-up of the inside of the nose of a mouse who can smell, while the right is a mouse who can't. (Andrew Dillin and Celine Riera/UC Berkeley)

In both experiments, the mice that couldn’t smell weren’t eating less, nor were they more physically active.

So why were the mice who couldn’t smell expending more energy? Researchers say the answer has to do with a link between scent and metabolism.

The Link Between Scent and Metabolism

“We know that smell was integrated with us eating,” says Andrew Dillin, professor of molecular and cell biology at UC Berkeley and head of the Dillin Lab. “It wasn’t known that the sense of smell was actually driving metabolic rate.”

In other words, research had already established that when we’re hungry, our body sends out hormones and other signals that turn up our sense of smell so we can more find food more easily, dulling it once we’re well-fed.

What Riera and colleagues discovered is that when we smell food, the scent also sets in motion a chain reaction of nerves, hormones and physiological functions that change our metabolism and tell our bodies to store the food we’re about to eat.

The mice who couldn’t smell showed signs of a revved-up metabolism and their energy-storing white fat was turning to brown fat, which is easier to burn. These clues led researchers to find that these mice had far more noradrenaline in their systems. Noradrenaline is one of those chemicals that makes you feel that “adrenaline rush.”

It turns out, knocking out the mice’s sense of smell sends a signal to the hypothalamus - the part of the brain that regulates metabolism - to activate the sympathetic nervous system. The sympathetic nervous system regulates the “fight, flight or freeze,” response, and it was causing the mice to burn more energy and fat.

Unanswered Questions

Dr. Robert Lustig, a professor of pediatrics in the Division of Endocrinology at UC San Francisco says he hasn’t seen any previous study demonstrate this link between smell and metabolism, but that when he saw it, he thought, “Well, that makes sense.”

Lustig researches metabolic disorders -- specifically, how the hypothalamus plays a role in obesity.

What’s novel about Riera’s study, he says, is that it provides experimental evidence that, at least in mice, there’s a direct link between smell and metabolism, resulting in weight gain or loss.

Lustig believes the pathway between smelling your food and gaining weight, at least in humans, probably goes through a cranial nerve called the vagus nerve.

“We know that smell activates the vagus nerve,” he says. “We know activating vagus nerve increases the amount of insulin. What we don’t know in humans is that the whole pathway is connected.”

Lustig says that question remains unanswered, and that the UC Berkeley study doesn’t examine whether the vagus nerve is involved.

Can This Help Humans?

So far, the link between smell and metabolism is confined to mice. It also only applies to preventing severe weight gain or facilitating weight loss in mice who are already obese. There's no evidence that knocking out the sense of smell affects the weight of average mice.

Riera, having completed her post-doctoral work at Berkeley, has just opened her own lab at Cedars-Sinai Medical Center in Los Angeles, where she plans to continue her work in mice and, perhaps someday, expand upon it in clinical research with humans.

She hopes to look at how these findings can be integrated into treatment for food addiction and binge-eating among some people with obesity. Maybe, Riera says, interfering with sense of smell can offer an obesity treatment that steps in to inhibit the food addiction, and does so in a manner less invasive than weight-loss surgery. So far, there isn’t a treatment that safely blocks smell for humans, but Riera believes the nose may hold the key to treating obesity.

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“We think that with olfaction we find maybe a milder way to do that,” she says. “Maybe if you can find a way to block the olfactory input, it would help.”

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