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March 22/29, 2000

Chronobiology of Recombinant Leptin Therapy

Author Affiliations

Phil B.FontanarosaMD, Deputy EditorIndividualAuthorStephen J.LurieMD, PhD, Fishbein FellowIndividualAuthor

JAMA. 2000;283(12):1567-1568. doi:10.1001/jama.283.12.1563

To the Editor: Dr Heymsfield and colleagues1 documented the effect of exogenous leptin administration on body weight and showed that only patients in the highest dose groups had significant weight loss compared with those taking placebo. We suggest that the physiological characteristics of leptin may be relevant to its pharmacokinetics.

Diurnal and ultradian oscillations are essential characteristics of hormone secretion. Leptin is characterized by nyctohemeral rhythms, with serum leptin concentrations being highest around midnight.2 This pattern closely resembles the circadian rhythmicity of other hormones, such as thyrotropin and prolactin, and precedes the peak concentrations of cortisol and growth hormone. To what extent the nocturnal increase in leptin is related to biological activity remains to be clarified. In humans, the nocturnal increase in leptin secretion seems to be entrained to meal timing and most likely is related to the cumulative hyperinsulinemia from food ingestion during the entire waking period.

Superimposed on the circadian rhythm, total circulating leptin levels exhibit a pattern indicative of pulsatile release with a pulse duration of approximately 30 minutes and are inversely related to rapid fluctuations in plasma cortisol and adrenocorticotropic hormone levels.3 Pulsatility is crucial for the attainment of biological effects in several endocrine systems (eg, luteinizing hormone-releasing hormone and growth hormone). Thus, for maximal biological leptin effectiveness, pulsatility may be an important requirement. In this sense, it is interesting that a high dosage need for nonpulsatile administration of leptin has been reported. Initial animal studies showed that a single daily leptin injection resulted in a small but significant body weight reduction, whereas twice-daily injections yielded better results.4,5 Interestingly, constant leptin infusion at a low dose through subcutaneously implanted minipumps resulted in maximal weight loss.4

Due to its peptide nature, leptin had to be administered subcutaneously, which produced significant injection site reactions.1 These adverse effects explain the rationale for a single daily administration. However, taking into account the rhythmicity and pulsatility of leptin, it might have been more effective to administer leptin in the evening. Even better results might have been obtained by using subcutaneously implanted minipumps, which could simulate a more physiological release. The beneficial effects of exogenous leptin treatment in a leptin-deficient child using a similar single morning administration6 may be explained by a possible leptin receptor overexpression in congenital leptin deficiency.

In our opinion, the findings of Heymsfield et al need to be interpreted with caution until the clinical significance of the optimal method for leptin administration is defined.

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