We may finally know why people tend to regain weight after losing it

Researchers have identified a brain pathway in mice that may explain why people tend to regain lost weight. Future therapies targeting this pathway could help with weight maintenance after dieting.

Nearly half of people with obesity who participate in weight loss programmes regain the lost weight within five years. The mechanism driving 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 regulating hunger. “They are activated when a body is low on fuel, and when they are active, 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 strengthen or weaken, altering the intensity of the signals that travel along them – the stronger the connection, the louder the message.

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

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

Together, these findings suggest that weight regain is driven by a temporary increase in signalling 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 are going to try to figure out how to address these problems, we need to understand how hunger works.”

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

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