Seeking Solutions to Obesity

"This proves that [the gene] MC4R is an important, if not the most important, controller of weight." "[And the new pathway provides an obvious target for drugs to protect against obesity]."

Sadaf Farooqi, MBChB, PhD, professor of metabolism and medicine, University of Cambridge

"We think regulation of hunger and satiety is the key."
"There is food everywhere. If you are a little bit hungry and someone puts out a big plate of doughnuts at your meeting, who’s going to reach for the doughnuts?”
Cecilia Lindgren, professor of genomic endocrinology and metabolism, University of Oxford

Two studies published April 18 in the journal Cell have shone new light on the role genetics can play in developing obesity—or protecting against it.  CardiovascularBusiness

Those among us who always seem to be able to eat whatever they like and never gain weight are both admired and resented by the infinitely greater number of people who crave food constantly and frequently overdo it, ending up gaining weight that then threatens to impair their health and longevity, New research has revealed that the people who always look so trim have a faulty gene responsible for their unusual metabolism.

That genetic alteration in that relatively small number of people who don't seem to ever gain weight actually mutes their appetite so they are in fact not all that enthusiastic about eating. On the more positive end of the spectrum, not only do they remain physiologically spare but these people who never consume much food or think constantly about their next meal, have a reduced chance of becoming diabetic or struggling with heart disease.

The U.K. Biobank which has data on a half million people aged 40 to 60, formed the basis of the study published in the journal Cell, while a second study also published in the same journal made use of data from the same population to develop a genetic risk score for obesity which can help predict as early as childhood who would be at high risk for obesity.

The findings from both studies, when taken together, confirm that there are biological reasons for the reality that some people struggle with their weight and others have no need to. The biological impacts are recognized to focus on appetite, not on metabolism, where people who gain too much weight or struggle to retain normal weight feel hunger on a frequency scale not reflected by their naturally thin counterparts.

The appetite-dulling mutation, led by Dr. Farooqi and Nick Wareham, an epidemiologist at the University of Cambridge, drew on Dr. Farooqi's research into the gene MC4R which she has studied for the past two decades. Her study of the gene was primarily in an effort to parse why it is that some people are overweight, not the opposite; why some people are not.

Endowed with MC4R mutations people tend toward obesity. As many as 300 mutations are located in this gene; the most common single gene cause of obesity. Six percent of children suffering from severe obesity can trace the cause to this gene mutation.

Satiety -- the feeling of fullness following a meal -- is destroyed by the mutations. When people eat a meal, the gene is automatically switched on to signal people that they have consumed their nutritional needs for that meal. When people consequently feel that 'full' signal they stop eating, and the signal turns off.

Those people carrying a mutation in MC4R preventing the gene from doing its work are absent the signal of satiety. Consequently they always feel the need to eat, and as a result become overweight, with a risk of diabetes and heart disease 50 percent more elevated than those lacking the mutation.

In some people, according to the new study, the MC4R gene is always turned to 'on'; they feel full always. And 6 percent of the population is affected by that mutant gene.

As for the related study, Dr. Amit V. Khera, a cardiologist at Massachusetts General Hospital and fellow researchers were looking for a method to predict out of a huge collection of minuscule variations in DNA, who might be destined to struggle with weight gain. As a result, the scientists designed an obesity risk score based on DNA alternations, such that people with the highest score weighed 13 kilograms more on average than those with the lowest scores.

The very obese saw 60 percent scoring high. And since the  U.K. Biobank population data consisted of adults, the scientists made use of other genetic studies where at birth, babies with high scores weighed the same as babies with low scores. But by three-and-a-half, they were heavier and by age eight, they were obese. Late adolescence saw them weighing on average 13 kilograms more than children with low risk scores.

"Those eight years might be magical and give you a unique opportunity to make a difference", observed Dr. Joel Hirschhorn, a geneticist at Boston Children's Hospital.

Business Standard