Correspondence
Serum Leptin in Normal-Weight and Obese Humans
N Engl J Med 1996; 334:1544June 6, 1996
- Article
To the Editor:
Considine and coworkers (Feb. 1 issue)1 report that obese subjects have elevated serum leptin concentrations that decrease during weight reduction. The authors conclude that “most obese persons are insensitive to endogenous leptin production.” We do not believe that this conclusion necessarily follows from the results of their study.
Body weight is regulated by complex mechanisms involving numerous afferent metabolic and hormonal signals informing the brain about the body's energy status. insulin, cholecystokinin, and cortisol are just a few examples of these signals.2 Abnormal production or action of any of the afferent messengers may lead to weight gain. A subsequent increase in leptin production may reflect the body's attempt to counterbalance the increase in body fat stores. Weight gain evokes an increase in the basal metabolic rate, which is significantly related to fat mass (as is the serum leptin concentration).3 This increase is supposedly meant to return energy stores to their previous, regulated level. Assuming that the metabolic effects of leptin in humans are similar to those in rodents, it is possible that the increase in serum leptin concentrations in obese persons is primarily involved in the pathophysiology of this phenomenon. The fact that increased serum leptin concentrations do not lead to weight loss may well be related to defects in other systems regulating body weight. This notion is supported by the fact that increased serum leptin concentrations in mice with diet-induced obesity do not cause weight loss,4 although some loss does occur when these mice are given leptin exogenously.5 We believe that in most obese persons, increased serum leptin concentrations will prove to be merely a reflection of the body's attempts to reduce increased body fat stores, rather than a reflection of the decreased action of leptin in the brain.
5 ReferencesHanno Pijl, M.D., Ph.D.
Arnoud C. Toornvliet, M.D.
A. Edo Meinders, M.D.
Leiden University Hospital, 2300 RC Leiden, the Netherlands1
Considine RV ,Sinha MK ,Heiman ML , et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292-295
Full Text | Web of Science | Medline2
Leibowitz SF . Neurochemical-neuroendocrine systems in the brain controlling macronutrient intake and metabolism. Trends Neurosci 1992;15:491-497
CrossRef | Web of Science | Medline3
Leibel RL ,Rosenbaum M ,Hirsch J . Changes in energy expenditure resulting from altered body weight. N Engl J Med 1995;332:621-628[Erratum, N Engl J Med 1995;333:399.]
Full Text | Web of Science | Medline4
Maffei M ,Halaas J ,Ravussin E , et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155-1161
CrossRef | Web of Science | Medline5
Campfield LA ,Smith FJ ,Guisez Y ,Devos R ,Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-549
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In our study, serum leptin concentrations were up to four times higher in obese subjects than in normal-weight subjects. In mice, leptin reduces appetite and increases energy expenditure, resulting in weight loss.1,2 If the actions of leptin in humans are similar, appetite should decrease and energy expenditure increase in obese subjects. Our finding of increased serum leptin concentrations in obese subjects suggests a decreased sensitivity or resistance to leptin. As Pijl et al. correctly point out, body weight is regulated by complex mechanisms, a defect in any of which may lead to obesity. Morbidly obese db/db mice have reduced energy expenditure and hyperphagia.3 A defect in the hypothalamic leptin receptor, which is believed to block the ability of leptin to reduce intake and increase energy expenditure, has recently been described in these mice.4 Although the receptor and effector mechanisms for leptin in humans have not yet been elucidated, obese persons may have a defect similar to that in db/db mice. Even if the leptin receptor is functional in obese persons, however, it is apparent that they do not have a reduction in food intake or an increase in the metabolic rate in response to a high serum leptin concentration. It is likely that the lack of this response to leptin leads to the increase in the serum leptin concentration. We think that mice with diet-induced obesity are a good example of partial leptin resistance. They are less sensitive to endogenous leptin, but weight loss can be achieved with high doses of exogenous leptin.4 The administration of leptin in humans may also result in weight loss by overcoming resistance to the hormone, at whatever step it occurs.
4 ReferencesRobert V. Considine, Ph.D.
José F. Caro, M.D.
Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA 191071
Halaas JL ,Gajiwala KS ,Maffei M , et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995;269:543-546
CrossRef | Web of Science | Medline2
Campfield LA ,Smith FJ ,Guisez Y ,Devos R ,Burn P . Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks. Science 1995;269:546-549
CrossRef | Web of Science | Medline3
Coleman DL . Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 1978;14:141-148
CrossRef | Web of Science | Medline4
Chen H ,Charlat O ,Tartaglia LA , et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996;84:491-495
CrossRef | Web of Science | Medline
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