A metabolic switch to turn off obesity

October 27, 2016
This is an image of a weight scale. Credit: CDC/Debora Cartagena

You've tried all the diets. No matter: you've still regained the weight you lost, even though you ate well and you exercised regularly! This may be due to a particular enzyme in the brain: the alpha/beta hydrolase domain-6 enzyme, better known as ABHD6. A study published this week in Cell Reports demonstrates that when this enzyme is blocked in certain neurons of the mouse hypothalamus, it becomes impossible for them to lose weight, even if they adhere to an ideal regimen... ideal for mice that is!

A research team at the University of Montreal Hospital Research Centre (CRCHUM) has generated genetically engineered mice, deprived of the ABHD6 enzyme in a localized area of the brain, namely in a specific population of . Alexandre Fisette, postdoctoral researcher at CRCHUM and first author of the study, explains that, "under normal conditions of housing and food, these mice are identical to normal mice. However, when challenged, they are unable to adapt. They no longer consume food after a fast, they cannot maintain their body temperature during exposure to cold, and they are more susceptible to become obese when fed a high-fat diet. What's more, once they are obese and we try to make them lose weight by feeding them a normal diet, they do not lose weight."

The researchers have discovered that this enzyme acts as a sort of switch for the body's adjustment to extremes. "It is a mechanism we had not suspected. Strikingly, the absence of one single enzyme within a precise region of the brain completely disrupts the normal metabolism and prevents the mice from losing weight," comments Thierry Alquier, CRCHUM researcher and professor at the University de Montréal.

Is there an identical process taking place in humans? Thierry Alquier thinks that clinical studies will be required to find out. However, according to Alquier, "ABHD6 has a key role in the rebound effect that is often observed after a dietary regimen. People who experience difficulty losing weight might have a deficiency of this enzyme."

Weight is controlled by several signals. Scientists have known for a long time that endocannabinoids - molecules secreted by the brain - are involved in the ingestion of nutrients and the expenditure of energy. The endocannabinoids stimulate appetite. Thus, this is an interesting area of exploration in the search for an appetite-suppressant drug. But all the products developed until now have been associated with serious side effects.

The pursuit of the ABHD6 enzyme appears to be promising. In 2014, the team of Marc Prentki, another CRCHUM researcher, discovered that this enzyme breaks down endocannabinoids. Blocking ABHD6 in peripheral organs and adipose tissues protects against obesity and against type 2 diabetes.

"We know today that ABHD6 plays a completely different role in certain neurons of the hypothalamus. Blocking the enzyme in this location promotes obesity, whereas blocking it elsewhere in the body has beneficial effects," emphasizes Stephanie Fulton, CRCHUM researcher and study co-author.

Multiple signals and neuronal networks are involved in regulating the balance of energy so as to maintain a stable body weight. "We have shown the critical part played by the ABHD6 enzyme in preserving homeostasis in specific neurons of the hypothalamus. But we don't know what happens when we block the in the entire brain. This is what we are currently investigating in an ongoing study," the researcher explains.

Many more years of research will be needed to develop an effective treatment for obesity. As science advances, we learn that management does indeed take place inside the head, but that it is not necessarily a question of lack of will.

Explore further: Understanding the causes of type 2 diabetes to treat it more effectively

More information: Alexandre Fisette et al, α/β-Hydrolase Domain 6 in the Ventromedial Hypothalamus Controls Energy Metabolism Flexibility, Cell Reports (2016). DOI: 10.1016/j.celrep.2016.10.004

Related Stories

Understanding the causes of type 2 diabetes to treat it more effectively

November 11, 2015
To date, no cure has been found for type 2 diabetes, the most common form of this chronic disease which affects nearly 2.5 million Canadians. Marc Prentki's research seeks to understand how the functioning of the cells of ...

Novel drug target linked to insulin secretion and type 2 diabetes treatment

May 26, 2014
A signal that promotes insulin secretion and reduces hyperglycemia in a type 2 diabetes animal model is enhanced by the inhibition of a novel enzyme discovered by CHUM Research Centre (CRCHUM) and University of Montreal researchers. ...

Rap1, a potential new target to treat obesity

October 21, 2016
Scientists at Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute have discovered a new mechanism in the mouse brain that regulates obesity. The study, which appears ...

Rap1, a potential new target to treat obesity

September 13, 2016
Scientists at Baylor College of Medicine, the National Institutes of Health and Virginia Tech Carilion Research Institute have discovered a new mechanism in the mouse brain that regulates obesity. The study, which appears ...

How the brain controls appetite

September 20, 2016
Prof. Eun-Kyoung Kim's research team in the Department of Brain and Cognitive Sciences has uncovered the mechanisms behind the enzyme that controls our appetite in response to low glucose availability in the brain.

Liver tells all and reveals truth about fat

April 20, 2012
Dr Barbara Fam from the University's Molecular Obesity Laboratory group at Austin Health with Associate Professor Sof Andrikopoulos have discovered that the liver can directly talk to the brain to control the amount of food ...

Recommended for you

Hibernating ground squirrels provide clues to new stroke treatments

November 17, 2017
In the fight against brain damage caused by stroke, researchers have turned to an unlikely source of inspiration: hibernating ground squirrels.

Age and gut bacteria contribute to multiple sclerosis disease progression

November 17, 2017
Researchers at Rutgers Robert Wood Johnson Medical School published a study suggesting that gut bacteria at young age can contribute to multiple sclerosis (MS) disease onset and progression.

Molecular guardian defends cells, organs against excess cholesterol

November 16, 2017
A team of researchers at the Harvard T. H. Chan School of Public Health has illuminated a critical player in cholesterol metabolism that acts as a molecular guardian in cells to help maintain cholesterol levels within a safe, ...

Prototype ear plug sensor could improve monitoring of vital signs

November 16, 2017
Scientists have developed a sensor that fits in the ear, with the aim of monitoring the heart, brain and lungs functions for health and fitness.

Ancient enzyme could boost power of liquid biopsies to detect and profile cancers

November 16, 2017
Scientists are developing a set of medical tests called liquid biopsies that can rapidly detect the presence of cancers, infectious diseases and other conditions from only a small blood sample. Researchers at The University ...

FDA to crack down on risky stem cell offerings

November 16, 2017
U.S. health authorities announced plans Thursday to crack down on doctors pushing stem cell procedures that pose the gravest risks to patients amid an effort to police a burgeoning medical field that previously has received ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.