Lab mice living in a rich, stimulating environment do not become obese when given an unlimited food supply because a brain chemical called neurotrophic factor makes them convert energy-storing white fat cells into energy-burning brown fat cells. The scientists who discovered the biological mechanism that switches on this conversion process believe it opens the door to new obesity treatments.
They write about their discovery in the September issue of the journal Cell Metabolism.
Led by Dr. Matthew J. During, professor of neuroscience, of neurological surgery and of molecular virology, immunology and medical genetics at Ohio State University Medical Center, the researchers found that the trigger switches on a biological pathway that starts in the hypothalamus, a part of the brain that helps regulate energy balance, and ends in white fat cells.
During told the press that:
“One of the holy grails of obesity therapy is to understand how to switch white fat to brown fat, and this study describes a new way to do exactly that.”
“Our findings suggest that we can potentially induce this transformation by modifying our lifestyle or by pharmacologically activating this brain-fat pathway,” he added.
The pathway is called the hypothalamic-adipocyte axis, and During and colleagues also found that it stimulates the growth of brown-like fat cells within depots of white fat.
The axis became active when they placed lab mice into an enriched environment, with a stimulating variety of social and physical challenges.
Dr Lei Cao, assistant professor of molecular virology, immunology and medical genetics, is lead and corresponding author of the study. She said that obesity is the result of chronic energy surplus stored as lipid in white fat.
“Increasing the output of energy is always attractive for obesity treatment, which is why the discovery of brown fat in adult humans caused much excitement a few years ago,” said Cao, but until this study the only way we knew how to induce brown fat was through exposure to chronic cold.
“Our research reveals a novel way of doing this without cold exposure,” she explained:
“We show that animals living in an enriched environment become lean and resistant to diet-induced obesity, even in the presence of unlimited food.”
Last year, Cao and colleagues published a paper in Cell that described how enriching environment by itself stopped cancer growth in animals. And before that, they had also published evidence that mice living in physically and socially more complex housing had better brain health, enhanced memory and learning.
It was while they were doing those studies that they noticed the mice living in the richer environments were also leaner than those living in standard laboratory containers, even though they were fed on the same, unlimited diets.
So they decided to compare the body fat types of the mice living in these two environments.
As far as we know, mammals have two types of fat tissue: white and brown adipose tissue (WAT and BAT respectively). WAT and BAT differ in at least three ways. They do different things, they have a different molecular chemistry and they have different structures.
BAT burns energy as heat and helps regulate body temperature and body weight. It has recently become a potential target for obesity treatment because PET scans show evidence that deposits of BAT can be triggered in response to cold, write the researchers in their background information.
WAT mops ups excess energy and was previously thought to be a passive organ that didn’t do much except simply provide heat storage, insulation and cushioning. But more recent studies have shown WAT is more versatile and complex than we imagined and is highly adaptive to external stimuli. And scientists have also discovered BAT-like cells inside depots of WAT cells in rodents and humans: white fat concealing brown fat-like cells.
These concealed BAT-like cells are called “brown-in-white cells” or “brite cells”, or beige cells. And while we still don’t know much about them, it is known that these energy burning cells within WAT become even more prolific when exposed to prolonged periods of cold and other stimuli.
So for this study the researchers used data collected when they had 15 to 20 mice in large boxes fitted out with running wheels, wooden toys, tunnels, a maze, nesting material, and an unlimited supply of food and water.
And they also had control mice in small groups of 5 housed in standard lab containers, without the toys, but with the same unlimited supply of food and water.
This is what the data showed:
- Animals in the enriched environment showed a significant reduction in abdominal WAT (nearly half that of the controls).
- Running in a wheel alone did not explain the changes in body composition and metabolism of the animals in the enriched containers.
- When fed a high fat diet, the animals in the enriched environments put on 29% less weight than control mice and stayed lean, with no change in food intake.
- The mice in the enriched environment also had higher body temperatures than the controls, suggesting that it was higher energy output that was helping them resist obesity, not appetite suppression.
The researchers suggest the enriched environment caused the mice to have more of a protein called brain-derived neurotrophic factor (BDNF) which is made in the hypothalamus. Higher levels of BDNF activate genes specific to brown fat such as Prdm16 and Ucp1, and suppress white fat genes such as Resn.
Blocking BDNF, on the other hand, appears to reverse this “browning” effect.
The authors suggest their findings show that living in rich environments protected the mice against becoming obese by turning white fat into brown fat. This happened through the hypothalamic-sympathoneural-adipocyte axis pathway which stimulated the hypothalamus to increase BDNF, which in turn increased the sympathetic nerve output to white fat, which resulted in the “browning” of the white fat and burning of stored energy.
The team now plan to find out which elements of environmental enrichment are essential for this “browning” effect: is it the sensory, motor, cognitive, or social stimulation, or perhaps a bit of each?
Written by Catharine Paddock PhD