Journal of Applied Physiology
Vol. 83, No. 1, pp. 3-4, July 1997

Invited Editorial on "Acute and chronic effects of exercise on leptin levels in humans"

Robert V. Considine

Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5111

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THE DISCOVERY of the ob gene only a little over 2 yr ago provided new insight into the mechanisms through which body weight and composition are regulated (14). Simply put, leptin, the product of the ob gene, is a hormone that communicates to the brain the amount of adipose tissue in the body. The more adipose tissue present, the more leptin is produced and released into the circulation. Neural networks in the hypothalamus then use this information to coordinate energy intake and expenditure to regulate body size and composition. Although serum leptin is proportional to the amount of adipose tissue in the body, production of this hormone has been demonstrated to be influenced by energy intake as well (3). It is, therefore, reasonable to hypothesize that serum leptin levels may also be regulated by energy expenditure, as investigated by Pérusse and colleagues (12) in this issue of the Journal. These investigators have examined the effect on leptin levels on the most variable component of the daily energy expenditure, i.e., exercise. They have chosen to investigate the influence of a short bout of exercise as well as the effect of a 20-wk training program on serum leptin in humans.

Ob/ob mice, which completely lack leptin as a result of mutations in the ob gene, are exceptionally obese (14). Administration of recombinant leptin to ob/ob mice results in a decrease in food consumption and an increase in body temperature and locomotor activity, ultimately resulting in weight loss (11). Normal-weight wild-type mice and diet-induced obese mice also lose weight with leptin administration, although with higher doses than needed in the ob/ob mice (2, 5, 11). These remarkable observations demonstrate the importance of leptin in the regulation of body weight.

In humans, leptin circulates in proportion to the amount of adipose tissue in the body. Obese humans (body mass index > 27 kg/m²) have on average four times more serum leptin than lean subjects (body mass index < 27 kg/m²; see Ref. 4). No defects in the ob gene in humans have been detected to date. Weight loss results in a reduction (4, 10, 13), and weight gain in an increase, in leptin levels (9). However, leptin production not only is determined by fat mass but also is influenced by gender, metabolic hormones, pharmacological agents, and current body energy requirements (3). Females have higher leptin levels than males with an equivalent fat mass. This effect appears to be at least partially due to reproductive hormones. Insulin and cortisol stimulate leptin production. In contrast, -adrenergic agonists and thiazolidinediones inhibit leptin production.

With respect to body energy requirements, serum leptin falls dramatically with short-term fasting (12 h) in the absence of appreciable weight loss (1, 8, 13). In contrast, 1 day of massive overfeeding (120 cal/kg over 12 h) was sufficient to raise serum leptin 40% in the absence of a weight gain (9). It is important to keep in mind, however, that leptin levels do not change after consumption of a normal meal (4). Taken together, these findings demonstrate that leptin can be regulated by energy intake but only by the extremes of fasting or massive overfeeding.

The fact that energy intake can influence leptin levels suggests that energy expenditure may also influence leptin levels. It has previously been noted in rats that ob mRNA levels were reduced immediately after an acute bout of exercise (15). In contrast, there was no effect on leptin of a 20-mile run by highly trained male athletes (6) nor of a 9-mo exercise program in older postmenopausal females (7). Pérusse and co-workers (12) have examined the effect of both a single acute bout of exercise and a 20-wk training program in sedentary adults. They found that leptin levels are unchanged after 10-12 min of exercise on a cycle ergometer. In contrast, endurance training for 20 wk resulted in a significant reduction in leptin in men, but not in women, in their study. This effect, however, was not independent of the reduction in fat mass. Therefore, all studies in humans to date find that energy expenditure through exercise does not alter leptin levels independently of its effects on the adipose tissue depot.

An important point that should be returned to in reference to the findings on exercise is whether the current protocols have tested the extremes of exercise. As noted above, energy intake, in the form of normal food consumption, does not alter leptin levels. However, the extremes of massive overfeeding or fasting do change leptin levels. It is, therefore, possible that extremes in energy expenditure may yet be shown to alter leptin levels, independently of effects on the adipose tissue mass.

How could changes in energy intake and/or expenditure alter leptin levels? At this point, it appears that most changes in leptin levels are mediated by changes in ob gene expression in the adipose tissue. Therefore, changes in energy intake/expenditure would most likely have to be detected by the adipocyte. A role for insulin, cortisol, and epinephrine could, therefore, be postulated. With respect to insulin and exercise, a training program that improves insulin sensitivity could alter leptin levels independently of the adipose tissue mass. This prospect has not been fully investigated to date. Fatty acids also fluctuate during fasting and exercise and, therefore, could provide a signal to the adipocyte. Alternatively, the clearance of leptin by the kidney may be altered during the extremes of fasting, overfeeding, or exercise.

In summary, leptin is an important contributor to the regulation of body weight and composition. Although serum leptin reflects the amount of adipose tissue mass in the body, the levels of this hormone are influenced by other factors. Despite the fact that leptin levels are altered by extremes in energy intake, an effect of exercise has yet to be demonstrated.

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