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Dexamethasone, OB Gene, and Leptin in Humans: Effect of Exogenous Hyperinsulinemia—Author’s Response^b

Division of Endocrinology, Diabetes and Metabolic Diseases Thomas Jefferson University Hospital and Jefferson Medical College Philadelphia, PA 19107

In their correspondence above, D. J. Torpy et al. point to the existing discrepancy between effects of exogenous chronic hypercortisolemia (e.g. of Cushing’s syndrome) and of administered exogenous glucocorticoids, on circulating leptin response in humans. They suggest that the observed elevation of leptin after exogenous steroid administration may have no physiological relevance. The observed effect is a "pharmacological" one because current evidence suggests a negative feedback inhibition of HPA axis by leptin acting in the hypothalamus and in the adrenals.

We agree with Drs. Torpy et al. that the issue requires further investigation. We suggest, however, that stress should be placed on finding the physiological meaning of this pharmacological phenomenon. In pursuits of this kind we suggest the following:

1. Revitalizing our knowledge about the acute metabolic effects of glucocotricoids. The most familiar one is the steroid-induced insulin resistance but perhaps the most physiologically important is the steroid-induced rise in hepatic glycogen (1, 2). 2. Challenging the current standing on the interaction between HPA axis and leptin. The recent report documented a highly significant inverse correlation between rapid pulsations in leptin and ACTH and the reciprocity of their diurnal profiles in humans (3). We find it very hard to understand how it is possible that the different adipose tissue depots can be coordinated by a humoral factor to produce a synchronous leptin release resulting in detectable pulsations every several minutes. 3. Expanding our understanding on duality of circulating leptin regulation, i.e. fat mass-dependent and fat mass-independent. The most remarkable phenomenon here is fat-mass independent down-regulation of the circulating leptin in response to short-term fasting (4).
   
2. The figureillustrates relative changes in hepatic glycogen and leptin levels during fasting extrapolated from our study (relative leptin change; ref. 4) and from the data of Rothman et al. (relative hepatic glycogen change; ref. 5). Does this remarkable similarity in responses resemble a causal relationship? Is the leptin elevation, in response to the acute stress of illness or to the "stress" doses of exogenous glucocorticoids, a reflection of acute elevation in hepatic glycogen? If so, how is the system likely to operate, and what is its physiological meaning?
   
3. The personal concept of one of us (J.W.K.) is that if fat in adipose tissue and hepatic glycogen are viewed as the body reserves of exportable fuels (fatty acids and glucose), a cross-talk between these depots would be a logical scenario. Perhaps, the fat mass-independent changes in the circulating leptin levels are just a reflection of it. Interestingly, in humans, this fat mass-independent regulation of leptin production appears to be regulated at the post-transcriptional level (4, 6). The proposed cross-talk between the liver, central nervous system, and adipose tissue is probably brought about by a combination of neural (autonomic nervous system) and humoral (leptin and other unknown) factors.
   
4. In summary, neither study cited by the Authors of the submitted correspondence should be neglected or labeled "pharmacological" or physiological. We hope that concepts presented in points 1–3 will provide some direction on how to solve the puzzle.
   

View larger version (28K): [in this window] [in a new window]   Figure 1.

Address correspondence to: Jerzy Kolaczynski, M.D., Ph.D., Division of Endocrinology, Diabetes and Metabolic Diseases, Thomas Jefferson University Hospital and Jefferson Medical College, 211 South 9th Street, Suite 600, Philadelphia, Pennsylvania 19107.

Received February 2, 1998.

References

1. Margolis RN, Curnow RT. 1984 Effects of dexamethasone administration on hepatic glycogen synthesis and accumulation in adrenalectomized rats. Endocrinology. 115:625–629.[Abstract/Free Full Text]
2. Iancu TC, Shiloh H, Dembo I. 1986 Hepatomegaly following short-term high dose steroid therapy. J Pediat Gastroent Nutr. 5:41–46.
3. Licinio J, Mantzoros C, Negrao AB, et al. 1997 Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nature Med 3:575–579.
4. Kolaczynski JW, Considine RV, Ohannesian J., et al. 1996 Responses of leptin to short-term fasting and refeeding in humans: A link with ketogenesis but not ketones themselves. Diabetes. 45:1455–1462.[Medline]
5. Rothman DL, Magnusson I, Katz DL, Shulman RG, Shulman GI. 1991 Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science. 254:573–576.[Abstract/Free Full Text]
6. Kolaczynski JW, Goldstein BJ, Considine RV. 1997 Dexamethasone, OB gene, and leptin in humans: effects of exogenous hyperinsulinemia. J Clin Endocrinol Metab. 82:3895–3897.[Abstract/Free Full Text]

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