Mice engineered to lack a sense of smell lose weight on a high-fat diet, researchers report July 5th in the journal Cell Metabolism. The mice ate just as much as counterparts with unaltered senses, yet lost an average of about 16 percent of their body weight. The weight loss was almost entirely from fat. In addition, mice with an enhanced sense of smell gain more weight than mice with typical olfactory abilities despite similar diets.
"It's one of the most interesting discoveries to come out of my lab," says principle investigator Andrew Dillin, professor of molecular and cell biology at the University of California, Berkeley. "What's happening to those calories?"
Dillin and his team initially suspected that mice without the ability to smell ate less. But when they measured food intake, the mice ate just as much as the control group. They also ruled out differences in nutrient absorption and excretion. "Weight gain isn't purely a measure of the calories taken in. It's also related to how those calories are perceived," says Dillin.
He had expected the loss of smell to have some effect on feeding. The senses of smell and taste become heightened in anticipation of a meal. After feeding, the senses are dramatically reduced. "There is a known link between food intake and sense of smell," says Dillin.
But the change in weight after the loss of smell was visibly noticeable. For instance, two mice fed the same high-fat diet both became obese. After Dillin's team eliminated the sense of smell in one of those mice, its weight dropped by about a third, to 33 grams. The other mouse maintained a weight of 49 grams. "I never expected turning off smell would have such dramatic weight-loss effects," says Dillin.
Because the weight change was so substantial, Dillin and colleagues created a second mouse model lacking a sense of smell. The first mouse model was engineered to lose its olfactory sensory neurons, the cells that detect odors and relay the information into the brain, when given a certain drug. Dillin worried that the process killed more than just olfactory sensory neurons. In the second mouse model, his team ablated olfactory sensory neurons using an inhaled virus, producing a similar loss of olfactory sensory neurons with a lower chance of affecting cells outside the olfactory system.
The results remained the essentially the same, with slightly less weight loss in the second mouse model.
Since most of the weight lost was fat, Dillin's team zoomed in on changes in fat deposits in the animals. They found that brown fat deposits were actively burning. In addition, the body's other form of fat, white fat, was transforming into brown fat and burning. "The mice with no sense of smell had turned on a program to burn fat," says Dillin.
The team also found high levels of adrenaline in the blood of these animals. The team traced this signal back to the sympathetic nervous system, which under normal circumstances governs the fight-or-flight response as well as responses to extremes, such as cold. Under these stressful conditions, the body energizes itself by triggering a release of catecholamines, or adrenaline, "which is known to turn on this brown-fat-burning program," says Dillin.
The team has not yet determined the link between the olfactory sensory neurons and the sympathetic nervous system, but they believe the signaling flows through the hypothalamus. First author Celine Riera, a post-doctoral fellow in Dillin's lab, plans to tease out this neural signaling pathway in her future research.
Whether or not humans respond similarly to loss of smell is unknown.
In casual conversation, Dillin shared his results with colleague Jens Brüning, Director of the Max Planck Institute for Metabolism Research. It turned out that Brüning had created a super-smelling mouse. "It has the opposite phenotype," says Brüning.
Brüning's super-smeller mice eat just as much as their control counterparts, but gain even more weight, predominantly body fat. Because the fat-burning program is off by default, it isn't clear how an enhanced sense of smell is linked to weight gain.
This work was supported by the Howard Hughes Medical Institute, the Glenn Center for Research on Aging, and the American Diabetes Association.
Cell Metabolism, Riera et al.: "The sense of smell impacts metabolic health and obesity." http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30357-1
Cell Metabolism (@Cell_Metabolism), published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. Visit: http://www.