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Longitudinally Sampled Human Plasma Leptin and Cortisol Concentrations Are Inversely Correlated

Clinical Neuroendocrinology Branch NIMH, NIH Bethesda, MD 20892

Haffner et al. (1) reported that leptin concentrations were not significantly related to cortisol. In that study the authors measured fasting levels of cortisol and leptin at one time point in 87 normoglycemic men.

It has long been known that plasma cortisol concentrations exhibit clinically relevant ultradian and circadian fluctuations that can be altered in disease states such as major depression (2). More recently, our group (3) and others (4, 5) have shown that plasma concentrations of leptin have pulsatility and diurnal variation, which seem to be of biological relevance: Matkovic et al. (6) have shown that a blunted nocturnal rise in leptin levels correlates with weight gain. Because both cortisol and leptin exhibit statistically significant ultradian and diurnal fluctuation that are clinically relevant, it is inadequate to rely on single fasting measurements to assess a relationship between these hormones. In our own studies we have shown a highly significant inverse relationship between the variability of simultaneous 1,242 measurements of cortisol and leptin in 6 normoglycemic men who were sampled every 7 min for 24 h (Pearson correlation: r = 0.764; P < 10^-9) (3). These data are consistent with the findings of Ahima et al. (7), that in rodents leptin administration blunts fasting-induced increases in cortisol levels, and with the findings of Bornstein et al. (8), that leptin acts directly in the adrenal gland to suppress cortisol production.

The effects of leptin on hypothalamic-pituitary-adrenal function indicate a mechanism by which a pulsatile peripheral signal of nutritional status may regulate stress-related endocrine function and behavior. Because the levels of leptin, adrenocorticotropic hormone, and cortisol are highly pulsatile, frequently-sampled longitudinal measurements are required for the study of relations between leptin and cortisol. Therefore, Haffner et al.’s conclusion that leptin levels in healthy men are not significantly related to cortisol is most likely erroneous, and reflects insufficient sampling.

Footnotes

Address correspondence to: Julio Licinio, Clinical Neuroendocrinology Branch, NIMH, NIH, Bldg. 10/2D46, 10 Center Drive, MSC 1284, Bethesda, Maryland 20892-1284.

Received July 25, 1997.

References

1. Haffner SM, Miettinen H, Karhapaa P, Mykkanen L, Laakso M. 1997 Leptin concentrations, sex hormones, and cortisol in nondiabetic men. J Clin Endocrinol Metab. 82:1807–1809.[Abstract/Free Full Text]
2. Sachar EJ, Hellman L, Fukushima DK, Gallagher TF. 1970 Cortisol production in depressive illness: a clinical and biochemical clarification. Arch Gen Psychiatry. 23:289–298.[Abstract/Free Full Text]
3. Licinio J, Mantzoros C, Negrão AB, et al. 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med. 3:575–579.[CrossRef][Medline]
4. Sinha MK, Ohannesian JP, Heiman ML, et al. 1996 Nocturnal rise of leptin in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J Clin Invest. 97:1344–1347.[Medline]
5. Sinha MK, Sturis J, Ohannesian J, et al. 1996 Ultradian oscillations of leptin secretion in humans. Biochem Biophys Res Commun. 228:733–738.[CrossRef][Medline]
6. Matkovic V, Ilich JZ, Badenhop NE, et al. 1997 Gain in body fat is inversely related to the nocturnal rise in serum leptin level in young females. J Clin Endocrinol Metab. 82:1368–1372.[Abstract/Free Full Text]
7. Ahima RS, Prabakaran D, Mantzoros C, et al. 1996 Role of leptin in the neuroendocrine response to fasting. Nature. 382:250–252.[CrossRef][Medline]
8. Bornstein SR, Uhlmann K, Haidan A, Ehrhart BM, Scherbaum WA. 1997 Evidence for a novel peripheral action of leptin as a metabolic signal to the adrenal gland: leptin inhibits cortisol release directly. Diabetes. 46:1235–1238.[Abstract]

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