New research conducted by a University team in tandem with the University of Buenos Aires has revealed the influence certain segments of DNA in the brain have on the regulation of appetite and weight, in addition to influencing obesity.
According to a University press release, this study is the first to document exactly how a brain cell gene is involved in weight regulation functions.
The team was led by Malcolm Low, professor of molecular and integrative physiology, and Marcelo Rubinstein, professor of physiology and biology at the University of Buenos Aires.
The research focused on genetic triggers inside a specific type of neuron in the brain called a proopiomelanocortin, or POMC, located in the hypothalamus. Previous studies of the role of POMC neurons in regulating sensations like fullness or hunger have shown that neurons without POMC can cause obesity in both animals and humans.
However, according to the new research, obesity can also result when certain genetic triggers are missing from the POMC neurons — even if the neurons themselves are present. Low and Rubinstein’s study focused on these triggers and their impacts on regulating weight.
The study identified the genetic triggers as enhancers named nPE1 and nPE2, which are attached to a transcription factor called Islet 1 that is then attached to the POMC neuron.
Low said enhancers help distinguish different cells in the body from each other.
“Every cell in the body has the same DNA, but they’re all very different. And the way that comes about is the little DNA sequences called enhancers,” Low said. “They’re responsible for determining the expressions of genes in certain cells. The ones we’ve discovered are very specific for turning on this POMC gene.”
The study was conducted on mice in two parts and published in two separate papers. Low said in the first paper, published in Proceedings of the National Academy of Sciences, they removed the enhancers nPE1 and nPE2 in the mice. In the second paper, published in PLoS Genetics, they removed only the transcription factor, Islet 1. Both times, mice became obese.
Low said the findings showed that nPE1 and nPE2, as well as Islet 1, are necessary for a fully functioning POMC gene and the healthy regulation of weight and appetite.
“The transcription factor is a protein and it recognizes the letters of the DNA sequence and binds to it very specifically,” he said. “The one factor can bind to both of the enhancers. So they probably act as a unit when all of them are bound.”
Though the study was not conducted on humans, Low said he was confident there is a significant link to human obesity. He noted that scientists already know that when children have mutated POMC genes they can become dangerously obese, which suggests that the likelihood of specifically enhancer mutations causing similar issues is high.
“We have every reason to believe that would be true because we’ve compared the sequence of these enhancers and they’re almost identical in every mammal,” Low said.
In an e-mail interview, Rubinstein wrote that he also believes the translation to humans is quite probable due to the similar location and roles POMC neurons play in mice and humans.
“Mice born without the enhancers nPE1 and nPE2 are genetically programmed to have an impaired satiety circuit and will be hyperphagic and obese,” Rubinstein wrote. “Since these systems are extremely conserved at the genetic, anatomical and physiological level it is highly likely that humans without these enhancers will have the same phenotype as mice do.”
First-year Medical student Stephan Diljak, president of the University’s chapter of the American Medical Student Association, said he believes study was important because it has the potential to lead to a drug that could help people deal with obesity.
Additionally, both Low and Diljak spoke to the importance of this study in proving that though fitness and healthy eating are key factors in maintaining a healthy weight, genes do also play a crucial role in the obesity problem facing many people.
Diljak said the study has the power to disprove common misunderstandings people have about obesity and its causes, as well as the methods used to combat it.
“When a lot of people think about obesity, they think about eating associated with this — stuff like McDonald’s — basically not exercising and not doing anything about it,” Diljak said. “Diet and exercise are really, really important, but they aren’t cures for everyone.”
Low said he believes scientific advances such as this one have helped transform the field of weight regulation in past years, removing common misconceptions about weight such as the idea that obesity is caused by a lack of self-control.
“We think now that the propensity to become overweight is partly in our genes and is certainly exacerbated by the availability of cheap calories and reduced exercise,” he said. “So it’s a combination of many things, but we know the genetic part is there and we also know that these POMC neurons are just one part of a very complicated system in the brain.”