How does obesity trick the brain into sending a signal that says to keep on eating?
Many experts point the finger at overeating and a sedentary lifestyle as the root causes of the obesity epidemic.
However, any action that we take has consequences at the molecular level, and experts know little detail about how our brains behave as the readings on the scales slowly go up.
Scientists from the Department of Psychiatry at the University of North Carolina in Chapel Hill, along with collaborators in the United States, Sweden, and the United Kingdom, sought to unravel the molecular pathways at play in the brains of mice with obesity.
Garrett Stuber, a professor of neurobiology who has now moved to the Center for the Neurobiology of Addiction, Pain, and Emotion at the University of Washington in Seattle, is the senior author of the team’s results, which feature in the journal Science.
Identifying the ‘brake on feeding’
Stuber and his collaborators study a specific area of the brain called the lateral hypothalamic area (LHA).
“The LHA has long been known to play [a] role in promoting feeding behavior, but the exact cell types that contribute to feeding within this brain structure are not well-defined,” explained Stuber about his research to Medical News Today.
Analyzing gene expression in individual cells in the LHA in obese mice and comparing it to that in normal mice, the team found prominent changes in vesicular glutamate transporter type-2 (Vglut2)–expressing neurons. These cells use glutamate as their fast-acting neurotransmitter.
However, changes in gene expression do not necessarily equate to changes in function.
Stuber dug deeper and used a combination of techniques to visualize individual LHAVglut2 neurons when the team gave mice sucrose, a common sugar comprising glucose and fructose.
The researchers found that sucrose consumption resulted in the cells’ activation. However, the response was nuanced. Mice that were not very hungry showed strong activation of their LHAVglut2 neurons, whereas those that had fasted for 24 hours had an attenuated response.
Stuber and his colleagues, therefore, suggest that LHAVglut2 neurons play a role in the suppression of feeding by telling our brain when to stop eating. They call this the “brake on feeding.”
“We hypothesize that the excitatory LHAVglut2 signal represents the activation of a brake on feeding to suppress further food intake,” they write.
Next, the team investigated how obesity affects the activity of these cells in mice that ate a high fat diet for 12 weeks to induce obesity.
“Whereas LHAVglut2 neurons from control mice maintained their responsivity to sucrose consumption, LHAVglut2 neurons from [the high fat diet] mice became progressively less responsive to sucrose consumption and less active at rest,” the team writes in the study paper.
In other words, the neurons did not send such a strong “stop eating” signal to the brain when the mice consumed sugar or when the mice were resting. Instead, the animals overate and developed obesity.
Obesity ‘impairs break on food intake’
When MNT asked whether he was surprised to see such a stunted response by the cells, Stuber explained, “Yes, the imaging results, which show that LHA glutamate cells are downregulated by high fat diet exposure (our experimental model of obesity) was surprising to us.”
“When these neurons are activated, mice halt sucrose licking and avoid locations paired with LHAVglut2 stimulation. Thus, activation of LHAVglut2 neurons may serve as a brake on feeding,” comments Stephanie Borgland, a professor at the Hotchkiss Brain Institute at the University of Calgary in Canada, in an accompanying Perspective article in Science.
“Given that activation of these neurons also leads to escape and avoidance behaviors, these neurons may be involved in the switch from foraging to escaping to promote survival, which is consistent with other homeostatic functions of the hypothalamus.”
“While our work has focused on the LHA, it is critical to note that many other interconnected brain regions and cell types are also likely modulated by obesity,” Stuber told MNT. “This includes cell types in the arcuate and periventricular hypothalamus, as well as other brain regions.”
Indeed, earlier this year, MNT reported that when scientists from The Rockefeller University in New York City, NY, stimulated dopamine 2 receptor neurons (hD2R) in the hippocampus of mice, the animals ate less. The researchers suggested that this neuronal circuit prevents mice from overeating.
Meanwhile, Stuber and his colleagues are continuing their investigations into the LHA, where they plan to look at other neuronal subtypes.
As for how applicable Stuber’s findings are to humans, he explained, “We think that our […] data will reveal novel genetic and therapeutic targets that could, someday, be translatable to humans.”