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Science Translational Medicine  11 Jan 2017:
Vol. 9, Issue 372, eaal4991
DOI: 10.1126/scitranslmed.aal4991


Altered dopamine signaling in obesity might decrease physical activity without contributing to weight gain.

Here’s something no one wants to hear after the holidays: Lack of exercise exacerbates obesity’s adverse effects on health. A decrease in physical activity appears to correlate with weight gain, but the underlying mechanisms are muddled. Some reports suggest that dopamine signaling is altered in obesity, and we know that dopamine pathways, such as those disrupted in Parkinson’s disease, are crucial for motor control. Now, Friend and colleagues examine the effects of obesity on dopamine signaling in the forebrain and motor activity.

Midbrain dopamine neurons project to the forebrain, where they activate a subset of neurons via G protein–coupled dopamine-binding D1 receptors that, in turn, switch on activity but inhibit a second set of neurons via D2 receptors. If D2 receptors are reduced or neurons with D2 receptors are activated, then physical activity decreases. In the new work, the authors first confirmed the effects of obesity on activity. As mice fed a high-fat diet gained weight, they became less active and slower than lean mice. The high-fat diet also disrupted the activity of forebrain neurons, reducing the proportion and the firing rate of those associated with movement. However, although their forebrain dopamine levels and D1 receptor binding had not changed, the obese mice displayed reduced binding to forebrain D2 receptors. Because D2 receptors normally inhibit neuron firing, the group next examined whether restoring this inhibition could improve physical activity in obese mice. When activity in D2 receptor–expressing neurons was decreased, both lean and obese mice exhibited more movement. Last, the researchers assessed whether changes in D2 receptor signaling might contribute to diet-induced weight gain. They examined the effects, on weight gain, of (i) naturally occurring variations in the forebrain density of D2 receptors and (ii) reduced D2 receptor expression on forebrain neurons in the transgenic mice when placed on a high-fat diet. They found that as D2 receptor availability decreased, so too did the physical activity levels of the mice, but they were not more susceptible to diet-induced obesity.

These studies suggest that although obesity might reduce dopamine signaling in the forebrain, this does not contribute significantly to weight gain in mice. If dopamine circuits contribute to decreased activity in obese humans, then modulating these pathways might increase physical activity, which in turn could stem associated metabolic and cardiac diseases.

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