We May Finally Know Why People Gain Weight After Losing Weight

Researchers have identified a brain pathway in mice that may explain why people regain lost weight. Future therapies targeting this pathway may aid in weight maintenance after abstinence.

About half of obese people who participate in weight loss programs regain the lost weight within five years. The mechanism underlying this weight regain is unknown, but it may be related to cells located in the hypothalamus called AGRP neurons, which have previously been shown to play an important role in controlling appetite. “They are activated when the body is low on fuel, and when they are activated, they cause intense hunger,” says Brad Lowell at Beth Israel Deaconess Medical Center in Massachusetts.

Many different brain regions send signals to AgRP neurons through connections known as synapses. These connections can be strong or weak, changing the intensity of the signals traveling along them – the stronger the connection, the louder the message.

To see how weight loss affects these synapses, Lovell and his team measured activity in the post-mortem brains of nine rats, five of whom fasted for 16 hours before examining their brains. The researchers stimulated brain regions known to signal to AgRP neurons using optogenetics, a technique that activates cells using light. In response, the fasted rats had more activity in a part of the hypothalamus called the paraventricular hypothalamic nucleus (PVH) than the rats that did not. This brain region is known to be involved in metabolism and development.

The researchers silenced these PVH neurons in a separate group of mice that fasted, and then tracked how much food the mice consumed over 24 hours. On average, the rats ate about 33 percent less food than rats in a control group, and they lost weight over the course of seven days. Further experiments showed that once the rats lost weight from fasting, the amplified signaling from PVH neurons returned to normal.

Together, these findings suggest that weight gain results from a temporary increase in signaling from PVH neurons to AgRP neurons. “Too much hunger is a medical problem and too little hunger is a medical problem,” says Lowell. “If we’re going to try to figure out how to overcome these problems, we need to understand how hunger works.”

These findings are an important step in doing so. Future therapies that reduce signaling from PVH neurons, for example, could help people lose weight, he says. However, more research is needed to better understand the function of PVH neurons and the consequences of silencing them. “Can you do it without side effects? We don’t know that yet,” Lowell says.