Fat Rats: Exercise in Childhood May Protect Against Later Obesity

Almost everyone tries to lose weight at some point, but we are remarkably bad at it; most people quickly return to their original weight after cessation of exercise or resumption of a normal diet. A review article by Patterson & Levin elucidates the pathways for this effect, and in the process finds a special role for juvenile exercise in guarding against obesity throughout the lifespan.

Patterson & Levin review several reasons for why it's so difficult to lose weight. First, caloric restriction is associated with subsequent "compensatory" increases in food intake, in both humans and rats, probably due to a strong mammalian tendency to preserve energy stores. Two hormones, leptin and insulin, are key players here: when an animal's net energy intake is negative (i.e., they're expending more energy than they're consuming), blood saturation of these hormones falls, which may activate the anabolic system (via arcuate nucleus neuropeptide Y/agouti related peptide) and deactivate the catabolic system (via arcuate nucleus pro-opiomelanocortin). The end result is a decrease in the resting rate of energy metabolism - thus softening the impact of caloric restriction on weight.

But exercise does something special: exercising rats bred for a genetic predisposition to obesity (showing excessive hunger, insulin and leptin resistance, high blood pressure and fatness of the skin, all exacerbated by high-energy diets) leads those rats to increase their energy intake, in contrast with rats bred for obesity-resistance; likewise, they fail to decrease their energy intake when put on a high-energy diet, in contrast with rats bred for obesity-resistance. And when exercise and caloric restriction are combined, obese rats will run less than their obesity-resistant cousins (though this decrease is not enough to outstrip the benefits of combined exercise & dieting).

There appears to be a biological mechanism for maintaining a certain level of obesity, and this level can be altered through exercise. While caloric restriction will lower resting metabolic rate (through the dual anabolic/catabolic pathway mentioned above), exercise only lowers leptin levels without affecting resting metabolic rate - leading to more effective weight loss.

The catch: in adult rats, the weight loss occurs for only as long as rats are exercising; afterwards they regain their original obesity. However, young rats don't show this rebound effect; for them, exercise soon after birth leads to an apparently permanent lowering in the level of obesity which is internally protected, suggesting that hypothalamic development continues after birth.

What mechanisms may mediate this effect? Patterson & Levin review how a variety of factors (such as CRF, 5-HT, BDNF, anabolic norepinephrine, and aminobutyric acid) influence obesity; for example, exercising rats show an increase in CRF in the dorsomedial nucleus of the hypothalamus, perhaps inhibiting compensation in energy intake. Similarly, leptin-induced BDNF expression in ventromedial hypothalamus may also play a role.

Another paper by Patterson, Dunn-Meynell & Levin demonstrates this differing effect of early-onset exercise - and that early caloric restriction can actually be harmful in later regulation of obesity!

In a first experiment, the authors raised rats selectively bred to be obesity-prone or obesity-resistant on healthy Purina rat food for the first 28 days of life, and then at day 36 half were provided with a running wheel (which itself had no effect on food intake). The obesity-prone rats were heavier at day 36, and those with running wheels ran less than obesity-resistant rats.

In a second experiment, obesity-prone rats were fed the high-energy diet and separated into five groups: 1) a sedentary group, 2) an exercising group, 3) rats first allowed to exercise (for 6 weeks) and were thereafter sedentary, 4) sedentary rats whose caloric intake was limited, and 5) rats who were initially limited in their caloric intake but thereafter unlimited. Exercising rats showed less weight gain than sedentary rats, they showed higher temperatures even when not physically active, lower insulin and leptin levels, and yet they did not increase their food intake to compensate for the energy lost through exercise. Even those rats who were only initially allowed to exercise showed these effects, albeit to a lesser extent, including somewhat lower weight and lower insulin levels. This contrasts starkly with calorically restricted rats, who, despite showing initially lower insulin and leptin levels, eventually gained more weight and higher insulin/leptin levels than exercising rats; those rats who were only initially restricted ultimately gained even more weight than rats who were sedentary and never calorically restricted!

In a third experiment, Patterson et al showed that rats exercised for 3, but not 2 weeks were able to maintain a lowered body weight for the following 10 weeks (relative to sedentary rats) even while consuming a high-energy diet. This difference was not due to differences in the amount of food eaten.

Finally, the authors also analyzed a variety of biological markers of exercise and changes in energy metabolism.

Rats with 3 weeks of exercise had lower mRNA expression of ARC MC3R, and lower NPY1 & SOCS3 expression in the dorsomedial nucleus of the hypothalamus. Lower NPY1 is the opposite of what would have been expected, since weight loss is typically associated with lower leptin levels. This would be expected to increase NPY1, and thereby increase the metabolic drive for hunger. The same time period of caloric restriction was associated with lower MC3R, SOCS3, and BDNF expression (but not NPY1, again suggesting that this may be involved in the hunger drive and contribute to the tendency for those rats to ultimately exceed sedentary rats in weight.)

In comparison to sedentary rats, those who were only temporarily exercised also showed increases in both ARC POMC and VMN melanocortin-3 receptor mRNA expression, while those with permanent access to exercise showed an increase in DMN NPY. The calorically restricted rats didn't show the normal increase in ARC NPY and decrease in POMC, but rather increased POMC relative to rats temporarily exercised, and the reduction in leptin didnt predict ARC expression of leptin receptor B, despite reduced VMN MC3R, MC4R, leptin receptor B, and DMN NPY relative to sedentary rats.

In summary, there may be a "critical period" for exercise to affect developing hypothalamic pathways which regulate the level of obesity that is defended against. Early exercise seems to lower the weight "set point" towards which hunger and the resting metabolic rate drive the animal. Similar mechanisms may exist in humans, and future therapies may specifically target the molecular mechanisms for setting this defended level of obesity.