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J Appl Physiol 105: 1686-1687, 2008; doi:10.1152/japplphysiol.zdg-8233-vpcomm.2008
8750-7587/08 $8.00
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LETTER TO THE EDITOR

Commentaries on Viewpoint: Effect of altitude on leptin levels, does it go up or down? Control of leptin with altitude exposure

TO THE EDITOR: The Viewpoint by Sierra-Johnson et al. (6) raises a number of interesting points about the control of leptin release in response to altitude exposure.

The authors correctly point out that "altitude" can comprise many stimuli to the endocrine system including hypoxia, cold exposure, anorexia, and exercise. In fact, it is likely that these factors interact to make assignment of a mechanism difficult. If one is truly interested in hypoxia per se, simulated altitude can be studied. Although one must always take into account species differences, we found a decrease in leptin in juvenile rats during exposure to normobaric hypoxia for 7 days (5). One of the studies cited by the authors as exposure to high altitude was actually in patients with obstructive sleep apnea at sea level (4). Another study cited as exposure to altitude was actually an in vitro study in which oxygen levels were not manipulated (3). Probably the best study cited did not find an increase in leptin with exposure to hypoxia, although leptin was higher when caloric intake was maintained (1).

Finally, it is a huge leap of faith to assume that hypoxia-inducible factors, which clearly are important in responses to low oxygen in vitro, have anything to do with specific organ responses to tolerable hypoxic exposures in vivo (2).

I can only conclude from the evidence in the literature that the jury is still out on the effect of altitude on leptin.

REFERENCES

  1. Barnholt KE, Hoffman AR, Rock PB, Muza SR, Fulco CS, Braun B, Holloway L, Mazzeo RS, Cymerman A, Friedlander AL. Endocrine responses to acute and chronic high-altitude exposure (4,300 meters): modulating effects of caloric restriction. Am J Physiol Endocrinol Metab 290: E1078–E1088, 2006.[Abstract/Free Full Text]
  2. Bruder ED, Lee JJ, Widmaier EP, Raff H. Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth. Physiol Genomics 29: 193–200, 2007.[Abstract/Free Full Text]
  3. Grosfeld A, Andre J, Hauguel-de Mouzon S, Berra E, Pouyssegur J, Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J Biol Chem 277: 42953–42957, 2002.[Abstract/Free Full Text]
  4. Ozturk L, Unal M, Tamer L, Celikoglu F. The association of the severity of obstructive sleep apnea with plasma leptin levels. Arch Otolaryngol Head Neck Surg 129: 538–540, 2003.[Abstract/Free Full Text]
  5. Raff H, Bruder ED, Jankowski BM. The effect of hypoxia on plasma leptin and insulin in newborn and juvenile rats. Endocrine 11: 37–39, 1999.[CrossRef][Web of Science][Medline]
  6. Sierra-Johnson J, Romero-Corral A, Somers VK, Johnson BD. Viewpoint: effect of altitude on leptin levels, does it go up or down? J Appl Physiol; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]

Hershel Raff
 Professor
Medical College of Wisconsin

 
TO THE EDITOR: Many investigators have shown that leptin levels are in a complex dynamic flux even without hypoxic exposure. Leptin levels change with a circadian rhythm; they are modulated by insulin (1, 5), cortisol (3), hypoxia (2), carbon monoxide, and melatonin (1); and have been associated with food intake, energy expenditure, and whole body energy balance (3). Leptin modulation of the endothelin system is important in pulmonary physiology. The fact leptin plays a regulatory role in immunity, inflammation, hematopoiesis (4), and proangiogenic activity (2) and that HIF-1{alpha} protein levels are reduced in wounds of leptin receptor-deficient diabetic mice, underscores leptin level regulation in the presence of hypoxia as compelling and significant. Evidence for the role of other hormones and growth factors important in leptin expression, regulation, and secretion is still emerging. Given this combinational complexity, it is easy to agree with Sierra-Johnson et al. (6) and conclude that to study the effect of altitude alone on leptin levels, confounding factors need to be controlled and considered. Factors, such as cold exposure, physical activity, diet, and genetic adaptations, as well as sleep, are sure to be important in leptin level regulation, especially given the variability of each in high-altitude exposure during a demanding activity such as mountaineering.

REFERENCES

  1. Alonso-Vale MI, Andreotti S, Peres SB, Anhe GF, das Neves C, Borges-Silva J, C Neto C, Lima FB. Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab Physiol 288: E805–E812, 2005.[Abstract/Free Full Text]
  2. Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 277: 34601–34609, 2002.[Abstract/Free Full Text]
  3. Houseknecht KL, Baile CA, Matteri RL, Spurlock ME. The biology of leptin: a review. J Anim Sci 76: 1405–1420, 1998.[Abstract/Free Full Text]
  4. Fantuzzi G, Faggioni R. Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol 68: 437–446, 2000.[Abstract/Free Full Text]
  5. Meissner U, Ostreicher I, Allabauer I, Rascher W, Dotsch J. Synergistic effects of hypoxia and insulin are regulated by different transcriptional elements of the human leptin promoter. Biochem Biophys Res Commun 303: 707–712, 2003.[CrossRef][Web of Science][Medline]
  6. Sierra-Johnson J, Romero-Corral A, Somers VK, Johnson BD. Viewpoint: Effect of altitude on leptin levels, does it go up or down? J Appl Physiol; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]

Robert Molthen
 Associate Professor
Medical College of Wisconsin

 
TO THE EDITOR: The Viewpoint by Sierra-Johnson et al. (5) summarizes and emphasizes the conflicting reports on plasma concentrations of leptin at high altitudes. This raises the issue of the pertinence of these measurements to the loss of appetite, increased energy expenditure, and weight loss associated with leptin and high altitude in this Viewpoint. Such effects are generally considered to be mediated by the central nervous system (CNS) and do not necessarily involve leptin. Many years ago we emphasized the lack of correlation of blood levels of peptides with their biological actions in the CNS (2). The question of the role of leptin in CNS symptoms at high altitude could be resolved by examination of the effects of altitude/hypoxia on the transport of leptin across the blood-brain barrier (BBB). It has been known for more than a decade that the blood-to-brain transport of leptin is a saturable process, susceptible to physiological and pathological processes (1). This saturable permeation is largely responsible for the "leptin resistance" of obesity and is subject to a diurnal rhythm. Unfortunately, the diurnal rhythm of leptin concentrations in blood does not correlate with the diurnal rhythm of leptin transport across the BBB into brain or spinal cord (4). The circadian rhythm of leptin entry into spinal cord, however, seems to correlate with that reported in this journal for another cytokine, tumor necrosis factor-{alpha} (3). The report by Sierra-Johnson et al. (5) should stimulate examination of the effects of hypoxia on leptin transport across the BBB.

REFERENCES

  1. Banks WA, Kastin AJ, Huang W, Jaspan JB, Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides 17: 305–311, 1996.[CrossRef][Web of Science][Medline]
  2. Kastin AJ, Zadina JE, Banks WA, Graf MV. Misleading concepts in the field of brain peptides. Peptides 5: 249–253, 1984.[CrossRef][Web of Science][Medline]
  3. Pan W, Cornelissen G, Halberg F, Kastin AJ. Circadian rhythm of tumor necrosis factor-{alpha} uptake into mouse spinal cord. J Appl Physiol 92: 1357–1362, 2002.[Abstract/Free Full Text]
  4. Pan W, Kastin AJ. Diurnal variation of leptin entry from blood to brain involving partial saturation of the transport system. Life Sci 68: 2705–2714, 2001.[CrossRef][Web of Science][Medline]
  5. Sierra-Johnson J, Romero-Corral A, Somers VK, Johnson BD. Viewpoint: effect of altitude on leptin levels, does it go up or down? J Appl Physiol; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]

Weihong Pan
Abba J. Kastin
 Pennington Biomedical Research Center
Baton Rouge, Louisiana




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J. Sierra-Johnson, A. Romero-Corral, V. K. Somers, and B. D. Johnson
Last Word on Viewpoint: Effect of altitude on leptin levels, does it go up or down?
J Appl Physiol, November 1, 2008; 105(5): 1691 - 1691.
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