We know fatty, sugary foods can transform our waistlines. Much less is known about how they might transform the brain. Now, researchers have found that switching a mouse from standard chow to more fattening fare changes the activity of certain neurons that regulate eating, wearing out the cellular “brakes” that limit intake. If the same is true for people, the finding could help explain our tendency to overeat.
Changing an animal’s diet “is a subtle manipulation,” says Randy Seeley, a behavioral neuroscientist at the University of Michigan Nutrition Obesity Research Center in Ann Arbor who was not involved in the work. “The fact that you can go in and see different properties of these cells is an amazing finding.”
Neurobiologist Garret Stuber and a team at the University of North Carolina at Chapel Hill wanted to understand the brain changes that accompany obesity. They were particularly interested in an area at the bottom of the brain known to regulate feeding, called the lateral hypothalamus. With collaborators in the United Kingdom, Stuber—now at the University of Washington in Seattle—sequenced RNA from cells in this area of the mouse brain and grouped them according to what genes they expressed. By comparing gene expression between obese mice on a high-fat diet and control animals on a standard one, the researchers identified a subset of neurons that changed most dramatically with the obesity-inducing diet.
That set expressed the gene for an excitatory signaling molecule, glutamate. The researchers used a two-photon microscope to observe these so-called glutamatergic cells in the brains of living mice. They endowed the cells with a gene that made them fluoresce when they took up calcium—an indicator of neural firing. Then they watched the cells while mice lapped calorie-rich sugar water from a spout. If a lean mouse had just eaten, the neurons were more active in response to the sugar than if it had just been fasting. The cells seemed to act as a brake, signaling, “That’s enough!”
But as lean mice became obese from a diet high in fat and sugar, these cells became less lively. By 12 weeks after the diet switch, the glutamatergic cells were roughly 80% less active in response to the sugar drink, the team reports today in Science.
The study is one of the first to use calcium imaging to observe brain activity in animals long-term, says Lora Heisler, a neuroscientist at the University of Aberdeen in the United Kingdom. It’s “a clever approach” to investigating how obesity develops, she says. One interpretation of the study: Regularly eating sweet, fatty foods “change[s] the way that our brain’s appetite centers function,” she says. “And by making the brain less responsive to the sweet stuff, it means that we will eat more than we need to.”
But the study doesn’t distinguish which changed the neural activity: a feature of the diet or the weight gain itself. It also doesn’t prove the change in brain activity itself caused the animals to overeat and gain weight, Seeley notes. The taste of the new diet might have prompted mice to up their calories—worn-out brake or no. “You probably haven’t tasted rodent chow,” he says. “I have. It’s terrible. It is dry, salty, bland grossness.” High-fat mouse diets, on the other hand, usually “taste like sugar cookie dough.” Still, he says, the reduced activity of the glutamatergic neurons might have perpetuated obesity in the mice by failing to tamp down their appetites even as their weight climbed.
“There are a lot of interesting areas for appetite in the brain. This paper makes the case that these neurons deserve additional attention,” says Scott Sternson, a neuroscientist at the Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Virginia. If future studies reveal a receptor present on this subset of neurons—but absent from most other cells—researchers could try to target it with drugs to selectively bump up activity. But that won’t be easy. Strongly stimulating these neurons is apparently unpleasant; mice in the study avoided electrical zaps to the area. So the approach would require a delicate tap on the appetite brake, Sternson says, “not slamming on it full-force.”