The Burrill Report


Researchers have connected the dots between a genetic mutation associated with obesity and a hormone known to control appetite that may add to our knowledge of how we perceive food and how we might treat obesity through drugs that target the hormone ghrelin.

An international team of investigators from the United Kingdom, Germany, and Japan has demonstrated a direct link between the fat mass and obesity-associated protein, or FTO, that is commonly mutated in obese people, and ghrelin, the only peptide hormone known to stimulate appetite. Their results are published in The Journal of Clinical Investigation.

The team found that circulating levels of the active form of ghrelin, acyl-ghrelin, was elevated in people with a mutated gene encoding for FTO and that the neurological response to food cues was also different.

“It's a double hit,” says Rachel Batterham from University College London, who led the study.

FTO was first identified in 2007. In 2010 the mutation directly linked to overeating and obesity was identified. For nearly the past two years researchers had been aware of the gene’s ability to regulate RNA, but now the identification of one of its critical targets may help clinicians identify which patients will be responsive to ghrelin antagonists currently in clinical trials. Subjects with a specific mutation may gain the greatest benefits from preventive and treatment strategies that target the ghrelin system and modulate the reward response to food.

New approaches to treating obesity are needed for those with a genetic predisposition toward the disease. At least 2.8 million people die each year as a result of the complications of being overweight or obese, and in 2008, the most recent year for which global data are available, 44 percent of diabetes, 23 percent of ischemic heart disease and up to 41 percent of certain cancers were attributable to people being overweight or obese.

Circulating levels of acyl-ghrelin alter appetite and food intake, and modulate activity in multiple regions of the brain responsible for both homeostatic and reward-related feeding. While normal subjects have both reduced circulating acyl-ghrelin and hunger after eating, subjects carrying the mutated FTO gene do not. Importantly, these observations held true for both obese and pre-obese subjects participating in the study, indicating that screening for the mutation might be useful in determining treatment strategies that might even be preventive.

“Our studies highlight the utility of combining detailed physiological phenotyping with a parallel assessment of neural function in genotyped subjects before the development of obesity,” says Efthimia Karra, lead author, in the publication’s discussion.

In order to make the direct connection between ghrelin, brain activity, and genetic status, researchers used a multi-pronged approach that included the typical laboratory techniques of cell culture and animal models, while incorporating a specific type of functional MRI that detects active areas in the brain by measuring blood flow on a sample of people with either a mutated or normal variant of the gene for the fat mass and obesity-associated protein.

The altered fMRI response within the hypothalamus to food images seen in obese patients was present in adiposity-matched, normal-weight groups with the FTO mutation prior to the development of increased body-mass-index. That could “potentially play a causative role in mediating the link between FTO-risk alleles and obesity predisposition,” say the authors.

People carrying two copies of the obesity-risk variant of FTO have a 1.7-fold increased risk for obesity compared with people carrying two copies of the low-risk variant. People with the mutation have increased food intake, particularly fat consumption, and impaired satiety.

In treating obesity, the researchers suggest a “genotype-tailored therapeutic approach, targeting the hormonal and neurobiological abnormalities that underlie the development of obesity.”

It’s been only two years since researchers showed that messenger RNA is often chemically modified. Beyond obesity, understanding this modification will likely open new avenues for drug development in other diseases over the years to come.


July 17, 2013
http://www.burrillreport.com/article-researchers_gain_understanding_of_obesity_gene.html