Nature Medicine | Spoonful of Medicine

Thin and happy

A lot has been said about the link between calorie restriction and aging — eat less, live longer. But if that wasn’t enough, there seems to be a new reason to do away with snacking: calorie restriction has an anti-depressant effect in mice, which depends on orexin-mediated signaling.

Michael Lutter and his colleagues tested mice in two animal models of depression — forced swim (a “depressed” animal will stop trying to escape from the water and will therefore cease to swim) and social defeat (a mouse that has been bullied will express its “depression” by reduced social interactions with other mice). The authors found that, if the mice were on calorie restriction, both their latency to stop swimming and their likelihood to engage in social interactions increased. In other words, the restricted mice did not show signs of depression.

But if the mice lacked orexin, calorie restriction had no effect. Orexin’s claim to fame is its relationship to narcolepsy — people (and some dog breeds) without orexin fall asleep without warning. But orexin has also been linked to the regulation of food and drug reward, pointing to a role for orexin in emotional processes. Lutter et al. further strengthen the link of orexin with depression by showing that mice in the social-defeat model have epigenetic modifications in the orexin promoter, which lead to decreased expression of the orexin gene in the “depressed” mice.

Clearly, the mechanistic link between depression, orexin and calorie restriction could do with some additional tightening. Similarly, the existing animal models of depression and their relevance to human depression are consistently criticized by the community. One also wonders about the behavioral (or “psychological”, if you will) effects of calorie restriction per se on an animal that is undergoing a stressful situation like the one the mice experience in the forced-swim and social-defeat tests. In other words, is the increased latency to show depression a true anti-depressant effect, or is it that the mouse’s hunger causes it to be more anxious in the context of the behavioural testing it is exposed to?

All of that said, other effects of calorie restriction that were originally met with scepticism now enjoy widespread acceptance. Maybe the same will turn out to occur in this fascinating case.



  1. Report this comment

    Sergio Stagnaro MD said:

    I do not like mice at all, and at the same time I do not know mice biology.At my best knowledge, mice may be ALL equal. On the contrary, I have studied men for 52 years, and I state that beside EBM there exists really Single Patient Based Medicine, according to one observes THIN persons depressed, as well as overwheight persons happy.

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    Megan said:

    Dr. Stagnaro, as an MD, you know that not all thin people are calorie deprived. The relationship observed here is between calorie deprivation and happiness mediated by the production of orexin. There is need for more studies, such as the relationship between calorie restriction and measure of orexin production, but the hypothesis here is plausible.

    Furthermore, it seems poignant to point to this data as a possible physiological relationship responsible for the experience of hightened spiritual experienced by those who fast for spiritual reasons and emotional highs of anorexics and their addiction to the high that ,in part, perpetuates their disease.