Genetics of Obesity

Jeffrey Friedman discusses the influence of leptin and the genetic factors that influence how we eat and why we eat.

Genetic factors and specifically the influence of leptin may just be critical targets for the future study of obesity, according to Jeffrey Friedman, MD, whose presentation “Genetics of Obesity” explained the evolutionary process of food consumption from a human standpoint.

For years, health professionals dedicated to solving the weight management issue have stated that obesity and overeating may result from an individual’s “lack of will power,” “life-style/environment,” and “biology/genes.”

All three are key components and some are more critical in individual cases than others, he said. In focusing on the genetic factors, it is important to take a look at twin studies. What has been found is that among the two most common genetic traits demonstrated in monozygotic twins are obesity (.80-.90) and height (.90), with schizophrenia coming in third (.68).

“Why study the genetics,” he asked? There are two main reasons:

-identifying causal genes can provide entry points for understanding the pathogenesis

-studying the genetics can help improve diagnostic information to stratify disease

Friedman’s own lab studied the genetic factors related to obesity in mice in the 1980s. In 1994, it was revealed that genes associated with leptin in mice were responsible for food intake and energy levels. Furthermore, not only was leptin a factor, but research uncovered that there was a force that acted when levels of food intake were increased or decreased to return the body to a perceived balanced level.

The reason behind this force could be the result of two phenomena that helped shape the biological processes related to food intake:

-Leaness increased the risk of starvation

-Obesity increased the risk of predation (or being eaten by a predator).

As a result, the body came to design mechanisms that would keep the individual at a stable level between the two extremes for optimal functioning. However, this process can be interrupted or becoming abnormal. Friedman highlighted a case study of a four-year-old child that became morbidly obese eating meals that were 2000 caoriesl each and living with an insatiable appetite.

It was discovered that the child’s biological process was perpetually stuck in starvation mode, so he kept eating although he was way beyond the point of normal satiety. His levels of leptin were low and once treated with leptin the symptoms were eradicated.

Those with low leptin levels may also present with:

-Reduced thyroid function

-Reduced immune function

-Reduced reproductive function

-Reducead insulin signaling

The conditions that might create low leptin levels are lypodystrophy and hypothalamic amenorrhea.

These cases are small, however, and when it comes to most overweight or obese patients the leptin levels are usually high, he said. The problem with these patients is that there is leptin resistance. Adequate leptin is being produced but resistance takes place, which effects its appropriate use in the body. In this state, it is important to identify responder subsets, he said. As a monotherapy, treatment with leptin for this group has not been very effective consistently but as a combination therapy with Amalyin, effective results have been seen. While there are not many specific drugs approved for weight loss, currently, all of the drugs in the works do act on leptin circuits, he said.

The question that needs to be answered next is where the signals that regulate eating satiety are propagated to influence eating, he said.

Friedman’s advice for physicians dealing with obese or overweight patients was the following:

-focus on improving health

-tell patients to exercise and eat a heart healthy diet

-tell patients to do their best to lose weight

-tell patients not to berate themselves if they are having difficulty to lose weight.

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