Does Leptin Reduce the Reward Response to Exercise?

In my conversations with skinny runners, they often cannot stop telling me how much satisfaction and enjoyment they get from their “runner’s high”. No wonder, they so often seem “addicted” to their runs (or other workouts).

In contrast, a “runner’s high” seldom comes up when any of my patients living with obesity talk about their exercise experiences (yes, many people with obesity exercise regularly).

Now, work by Maria Fernandes and colleagues from the University of Montreal, published in Cell Metabolism, reports findings in rats, which, if applicable to humans,  may provide a biological explanation for this observation.

Building on previous studies showing that leptin modulates multiple components of brain reward circuitry, particularly in dopamine (DA) neurons of the ventral tegmental area (VTA), an area of the brain allegedly responsible for the “runner’s high”.

Using an elegant set of experiments, the researchers showed that leptin markedly reduces mice’s willingness to work for access to a running wheel or show other signs of seeking out exercise-induced reward.

In contrast, mice with a deletion of the signal transducer and activator of transcription-3 (STAT3), involved in leptin signalling in dopamine neurons of the VTA, showed greater interest in voluntary running.

In other words, STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner.

Together these findings strongly suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone.

Or, in other words, higher levels of leptin (as seen in people living with obesity) directly inhibit the rewarding nature of running, making it less likely to experience a runner’s high, than in someone with low leptin levels (as seen in people with low fat mass).

As to why this may be the case, the authors offer the following explanation:

“We speculate that in conditions of restricted food availability the mesolimbic DA system engages motivational processes concerned with obtaining food and more readily responds to leptin to decrease appetitive physical activity. On the other hand, during fed states, the actions of leptin may be biased toward hypothalamic processes that could increase physical activity as a means to maintain energy homeostasis.”

“While heightened physical activity during food restriction seems paradoxical to the maintenance of energy reserves, it is considered an expression of increased food acquisition behaviors. The capacity for endurance running in cursorial mammals is considered to enable food attainment when it is distant or requires pursuit. Correspondingly, the runner’s high may have evolved to encourage stamina and thereby increase the probability of return on this energetic investment.”

As the authors note, this line of reasoning is supported by the recent observation that exercise addiction in men is associated with low, fat-adjusted leptin levels.

In light of these findings, I also wonder if the “increase in energy levels”, which is rather consistently reported by my patients when they lose weight, may simply be reflective of their often dramatic reduction in leptin levels.

@DrSharma
Edmonton, AB