Mouse Study: Inactivity in Obesity May be Tied to Dopamine Receptors, Not Excess Weight

Just in time for New Year’s resolutions, a new study has revealed why so many of us seem to have a hard time sticking to a workout routine — and it’s not just about extra weight. The findings, published in the journal Cell Metabolism, show that in obese mice, physical inactivity results from altered dopamine receptors rather than excess body fat.

“We know that physical activity is linked to overall good health, but not much is known about why people or animals with obesity are less active,” said the study’s senior author, Dr. Alexxai V. Kravitz, an investigator in the Diabetes, Endocrinology, and Obesity Branch at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

“There’s a common belief that obese animals don’t move as much because carrying extra body weight is physically disabling. But our findings suggest that assumption doesn’t explain the whole story.”

Kravitz, who has a background in studying Parkinson’s disease, began conducting obesity research a few years ago. He was struck by similarities in behavior between obese mice and Parkinsonian mice. Based on these observations, he questioned whether obese mice were inactive due to a dysfunction in their dopamine systems.

“Other studies have connected dopamine signaling defects to obesity, but most of them have looked at reward processing — how animals feel when they eat different foods,” Kravitz said.

“We looked at something simpler: dopamine is critical for movement, and obesity is associated with a lack of movement. Can problems with dopamine signaling alone explain the inactivity?”

For the study, mice were given either a standard diet or an unhealthy, high-fat diet for 18 weeks. Beginning in the second week, the mice on the unhealthy diet had higher body weight. By the fourth week, these mice spent less time moving and got around much more slowly when they did move.

However, an important finding was that the mice on the high-fat diet moved less before they gained the majority of the weight, suggesting that the excess weight alone was not responsible for the lack of movement.

The scientists analyzed six different components in the dopamine signaling pathway and discovered that the obese, inactive mice had deficits in the D2 dopamine receptor.

“There are probably other factors involved as well, but the deficit in D2 is sufficient to explain the lack of activity,” said Dr. Danielle Friend, first author and former postdoctoral fellow at NIDDK.

The researchers also looked at the link between inactivity and weight gain, to determine whether it was causative. By studying lean mice that were engineered to have the same defect in the D2 receptor, they found that those mice did not gain weight more readily on a high-fat diet, despite their lack of inactivity, suggesting that weight gain was compounded once the mice start moving less.

“In many cases, willpower is invoked as a way to modify behavior,” Kravitz said. “But if we don’t understand the underlying physical basis for that behavior, it’s difficult to say that willpower alone can solve it.”

Uncovering the physiological reasons for why people with obesity are less active can help reduce some of the stigma they face, said Kravitz. His upcoming research will focus on how unhealthy eating affects dopamine signaling. The researchers also want to determine how quickly mice recover to normal activity levels once they begin to eat a healthy diet and lose weight.

Source: Cell Press