Both of these mice are on a high-fat diet. Can you guess which one has an intact sense of smell? (Cell Metabolism)
Having an exceptionally keen sense of smell would seem to be an unmitigated blessing: It can provide early warning of dangers, detect the presence of an attractive mate, and enhance the gustatory delight of a delicious meal.
But when you’re a mouse (or, perhaps, a human) and fattening food is all around, a new study finds that those with little or no ability to detect odors may have a key advantage. While mice with an intact sense of smell grow obese on a steady diet of high-fat chow, their littermates who have had their sense of smell expunged can eat the same food yet remain trim.
If you’re thinking this is a cautionary tale about the effect of enhancing gustatory delight on portion control, you’re on the wrong track.
In fact, the mice with an impaired sense of smell did not eat less of the high-fat chow than did their peers with normal olfaction. Nor did they move around more in their cages, or expel more of their food before extracting its nutrients.
Instead, a report published Wednesday in the journal Cell Metabolism underscores that our sense of smell is lashed together with a broad range of seemingly unrelated basic functions, including metabolism and stress response.
Mice stripped of their sense of smell burn fat differently — more intensively — than do mice whose olfaction is normal, the new study found. They typically have higher levels of adrenaline — the “go” signal in the body’s fight-or-flight system — than do mice with an intact sense of smell. And even when all they eat is high-fat chow, they don’t appear as likely as capable smellers to develop such afflictions as fatty liver or the kind of dangerous fat deposits that settle around the midsection.
In one of three experiments reported in the paper, researchers disabled the specialized olfactory brain cells of mice who were made fat on a diet of high-fat chow. The effect was rapid and robust: Those mice lost roughly a third of their body weight. And the weight they lost was virtually all from fat.
“I was shocked — the effect was so robust,” said UC Berkeley stem cell biologist and geneticist Andrew Dillin, the study’s senior author. “I was convinced they were just eating less. When it became clear they weren’t, I thought, ‘Wow, this is incredibly interesting.’”
In another experiment, researchers created “super-smellers” — mice with an exceptionally acute sense of smell — by disabling a specialized receptor in the brain’s olfactory system. Even when the smells the mice were tested on were “social,” such as the scent of an unknown member of the opposite sex, the champion smellers were at greater risk for weight gain and impaired metabolism than were mice with normal or low olfactory acuity.
Indeed, all kinds of hormonal signals, including many that play a role in appetite and fat storage, get dialed differently in mice with an impaired sense of smell, the researchers found.
Adrenaline, for instance, plays a role in an animal’s response not only to threats but to stresses such as cold. In mice with low-functioning olfactory neurons, higher adrenaline levels appeared to activate special stores of energy-intensive “brown fat” to burn white fat as fuel, and to convert some white fat stores to brown fat.
The collective effect of those differing signals was consistently to protect the smell-impaired mouse from the unhealthy effects of overconsumption, the researchers discovered.
The new study is a far cry from establishing that all the same dynamics are at play in humans. But while mice probably rely on their sense of smell more than humans, they can tell us a lot about human obesity, Dillin said. And these findings do suggest an intriguing way to help those with obesity lose some weight and improve their metabolic function without having to change what, or how much, they eat, he added.
Researchers know that when people lose their sense of smell — an effect seen in certain strokes, brain injuries and neurodegenerative diseases — their appetites wane, they eat less, and (no surprise) they lose weight. It’s also well known that the acuity of our sense of smell rises and falls depending on circumstance: It’s at its zenith when we haven’t eaten in several hours, and plummets just after we’ve had a meal.
The first observation suggests that smell piques or sustains interest in eating directly. The second suggests that smell may set off a host of signals about the body’s energy needs that work indirectly to affect metabolic function. That side of the equation is a lot less obvious, and has been studied far less.
The new research suggests that reducing olfactory cues might do more than help overweight people shed pounds. It may also right some of the metabolic and hormonal signals that get pushed out of whack as a person accumulates too much fat.
“The potential of modulating olfactory signals in the context of the metabolic syndrome or diabetes is attractive,” write the authors of the new study. “Even relatively short-term loss of smell improves metabolic health and weight loss, despite the negative consequences of being on a high-fat diet.”
Dillin said there are a number of directions in which this research could be taken next. Researchers could look at broad populations of people, testing the acuity of their olfactory sense and, over time, measuring how that tracks with their propensity toward weight gain or metabolic abnormality.
As for human trials of impaired olfaction, Dillin said a clothes pin on the nose won’t work: Our mouths also admit olfactory information. But some chemical agents, including one currently used as a pesticide, are known to knock out humans’ sense of smell temporarily. If such compounds could be used safely on humans, it might be possible to gauge how weight and metabolism are affected when olfaction is altered.
In the meantime, study first author Celine Riera, a post-doctoral fellow in Dillin’s lab, plans to tease out the role that the brain’s hypothalamus — a master regulator of everything from involuntary bodily functions to sleep and emotional response — may play in translating smells into fat-burning commands.
Funding for the new research came from the Howard Hughes Medical Institute, the Glenn Center for Research on Aging, and the American Diabetes Assn.
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