Findings suggest neurological basis of obesity

As the world gravitates toward the two polar extremes of body weight — obesity and anorexia — scientists struggle to determine the underlying biological causes, hoping to find effective treatments to combat these disorders.

Bradford Lowell, physician scientist and professor of medicine at the Beth Israel Deaconess Medical Center (BIDMC), recently published novel findings on the neurological mechanisms regulating energy expenditure and fat-burning.

In the United States alone, approximately 37.5 percent of the adult population is obese. While there are many sociocultural factors influencing the development of these disorders, psychological and physiological factors are often the forefront considerations when determining treatment plans.

Biologically, it has been well established that the human body maintains homeostasis via precise internal processes. Our bodies are frequently compared to a thermostat, which activates either the cooling or the heating system depending on the direction of deviation from the preset temperature.

Likewise, the human body has specific set points for various properties, including the availability of blood sugar for energy. When we eat, the food is broken down into small molecules that our cells can use. Carbohydrates, for instance, are broken down to glucose and then converted to ATPs.

Depending on how much glucose we have available to convert to ATPs and whether this is enough to fuel our energy requirements, the body then uses various hormones to regulate our intake. This gives us the sensations of hunger and fullness.

Leptin, for instance, is a hormone produced by adipose cells in proportion to the amount of body fat we have. It is a satiety signal that tells us to stop eating. Similarly, other physiological signals are used to control our caloric intake so that we have enough energy to fuel normal body functions.

The hypothalamus is an essential neural region that regulates many functions in the body, including energy balance and food intake. This region integrates external inputs, internal motivations, and the body’s physiological needs to control our appetite.

If homeostasis is so tightly maintained, what’s is the purpose of storing fat?

“We were [once] hunters and gatherers, and our meals were infrequent. Our body has evolved… this really efficient ability to store the nutrients and have them on reserve,” Farah Madison, a professor of behavioral biology at Hopkins, said.

Originally, this was an extremely adaptive mechanism, but coupled with the easy accessibility of high calorie foods, many have unfortunately stored too much fat, leading to obesity.

“These mechanisms were not originally designed for food levels we have now,” Madison said.

To better understand how the brain controls appetite and weight management, Lowell and colleagues focused in their study on the neurons in the arcuate nucleus of the hypothalamus.

The research team engineered mice with a defect in the arcuate nucleus neurons, preventing them from releasing GABA, an inhibitory neurotransmitter. Experiments showed that these mice were significantly obese, despite normal food intake.

From their results, Lowell conclude that GABA neurons in the arcuate nucleus likely play a key role in regulating energy expense, not intake.

Moreover, a follow-up study suggested that these GABA neurons play a key role in mediating energy expenditure in brown fat.

There are two types of adipose tissue: white fat and brown fat. While the main function of white fat is to store energy, the primary purpose of brown fat is to generate heat in a process called thermogenesis. The function of brown fat in adults is not well understood, thereby rendering results from this study a crucial advance.

For future studies, Lowell emphasizes the importance of gaining a more complete understanding of the neural pathway underlying energy expenditure.

Lowell hopes that these results will help develop methods that can effectively treat obesity. While our neural circuits may be evolutionarily predisposed to stock up on our fat reserve, scientific advances show promise in overcoming this outdated mechanism.