| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
Electronic Letters to:
|
|
Electronic letters published:
![[Read eLetter]](/icons/misc/sectionDOWN.gif){kind=icon}
Control of Leptin with Altitude Exposure
Comments on: Viewpoint: Effect of altitude on leptin levels; Does it go up or down?
Comments on: Viewpoint: Effect of altitude on leptin levels; Does it go up or down?
Regulation of Leptin by Hypoxia
Commentary on Viewpoint: Effect of altitude on leptin levels, does it go up or down?
Comment on Viewpoint: Effects of altitude on leptin levels: Does it go up or down?
Comment on Viewpoint: "Effect of altitude on leptin levels"
Comment on Viewpoint: "Effect of altitude on leptin levels"
Comment on Viewpoint: "Effect of altitude on leptin levels"
Comment on Viewpoint: "Effect of altitude on leptin levels"
Comment on Viewpoint: Effect of altitude on leptin levels, does it go up or down ?
|
|
|||
|
Hershel Raff, Professor Medical College of Wisconsin
Send letter to journal:
hraff{at}mcw.edu Hershel Raff
|
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 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. 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 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. 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 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 (February 14, 2008). Doi:10.1152/japplphysiol.01284.2007 |
|||
|
|
|||
|
Robert Molthen, Associate Professor Medical College of Wisconsin
Send letter to journal:
rmolthen{at}mcw.edu Robert Molthen
|
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, 2) , cortisol(3), hypoxia(4), carbon monoxide, and melatonin(2), 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(5), and proangiogenic activity(4) and that Hif -1alpha 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 in order 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. 1. Meissner, U., I. Ostreicher, I. Allabauer, W. Rascher, and J. Dotsch, Synergistic effects of hypoxia and insulin are regulated by different transcriptional elements of the human leptin promoter. Biochem Biophys Res Commun, 2003. 303(2): p. 707-12. 2. Alonso-Vale, M.I., S. Andreotti, S.B. Peres, G.F. Anhe, C. das Neves Borges-Silva, J.C. Neto, and F.B. Lima, Melatonin enhances leptin expression by rat adipocytes in the presence of insulin. Am J Physiol Endocrinol Metab, 2005. 288(4): p. E805-12. 3. Houseknecht, K.L., C.A. Baile, R.L. Matteri, and M.E. Spurlock, The biology of leptin: a review. J Anim Sci, 1998. 76(5): p. 1405-20. 4. Ambrosini, G., A.K. Nath, M.R. Sierra-Honigmann, and J. Flores-Riveros, Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem, 2002. 277(37): p. 34601-9. 5. Fantuzzi, G. and R. Faggioni, Leptin in the regulation of immunity, inflammation, and hematopoiesis. J Leukoc Biol, 2000. 68(4): p. 437-46. 6. Sierra-Johnson, J., A. Romero-Corral, V.K. Somers, and B.D. Johnson, Viewpoint: Effect of Altitude on Leptin Levels; does it go up or down? J Appl Physiol, 2008. |
|||
|
|
|||
|
Weihong Pan Pennington Biomedical Research Center, Baton Rouge, LA, Abba J. Kastin
Send letter to journal:
Abba.Kastin{at}pbrc.edu Weihong Pan, et al.
|
The paper 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-á (3). The report by Sierra-Johnson et al. (5) should stimulate examination of the effects of hypoxia on leptin transport across the BBB. Reference List 1. Banks WA, Kastin AJ, Huang W, Jaspan JB and Maness LM. Leptin enters the brain by a saturable system independent of insulin. Peptides 17: 305-311, 1996. 2. Kastin AJ, Zadina JE, Banks WA and Graf MV. Misleading concepts in the field of brain peptides. Peptides 5: 249-253, 1984. 3. Pan W, Cornelissen G, Halberg F and Kastin AJ. Circadian rhythm of tumor necrosis factor-alpha uptake into mouse spinal cord. J Appl Physiol 92: 1357-1362, 2002. 4. Pan W and Kastin AJ. Diurnal variation of leptin entry from blood to brain involving partial saturation of the transport system. Life Sci 68: 2705-2714, 2001. 5. Sierra-Johnson, J., Romero-Corral, A., Somers, V. K., and Johnson, B. D. Viewpoint: Effect of Altitude on Leptin Levels; does it go up or down? J Appl Physiol , 2008, in press. |
|||
|
|
|||
|
Jianping Ye, Professor Pennington Biomedical Research Center, Louisiana State University System
Send letter to journal:
yej{at}pbrc.edu Jianping Ye, et al.
|
Leptin, as a major cytokine secreted from adipocytes, is a primary hormone in the control of food intake (1). Expression of leptin from adipocytes is regulated by body weight (or adiposity), food intake, other hormones and hypoxia (1-3). At whole body level, loss of adiposity from an increase in energy expenditure (such as physical exercise) or decrease in energy intake (such as caloric restriction) will lead to a reduction in leptin expression in adipose tissue. This may explain leptin reduction in some studies of high altitude effects on leptin level (6). At molecular level, expression of leptin is increased by insulin, and decreased by beta 3-adrenergic receptor signal that activates cAMP signaling pathway (2). Insulin may be involved in regulation of leptin level by food intake, which induces insulin secretion in beta-cells. The cAMP signal is likely contributing to leptin reduction in physical exercise. Leptin expression may be up-regulated by hypoxia. In obesity, hypoxia exists in adipose tissue and associates with leptin elevation (4). Leptin was reported as a hypoxia response gene whose transcription is induced by transcription factor HIF-1a (hypoxia inducible factor 1 alpha) (3). However, this regulation was not confirmed in a later study where classical hypoxia response genes were induced in adipocytes (5). Therefore, it remains controversial about the role of hypoxia in the regulation of leptin expression. In response to high altitude, changes in body weight, food intake, oxygen level, body stress, and cold response may influence leptin level (6). Reference: 1. Benoit SC, Clegg DJ, Seeley RJ, Woods SC: Insulin and leptin as adiposity signals. Recent Prog Horm Res 59:267-285, 2004 2. Gettys TW, Harkness PJ, Watson PM: The beta 3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 137:4054-4057, 1996 3. 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 4. Ye J, Gao Z, Yin J, He H: Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293:E1118-E1128, 2007 5. Yasumasu T, Takahara K, Nakashima Y: Hypoxia inhibits leptin production by cultured rat adipocytes. Obes Res 10:128, 2002 6. Sierra-Johnson J, Romero-Corral A, Somers VK, Johnson BD. Viewpoint: Effect of altitude on leptin levels; Does it go up or down? JAPPL, in press, 2008. |
|||
|
|
|||
|
Levent Öztürk, Assoc. Prof. Department of Physiology Trakya University Faculty of Medicine
Send letter to journal:
leventozturk{at}trakya.edu.tr Levent Öztürk
|
To the Editor: Sierra-Johnson et al. (5) hypothesized that altitude stimulates leptin release through hypoxia sensitive mechanisms. Besides peripheral mechanisms such as hypoxia-inducible factor 1 transactivation of leptin gene promoter (2) or catecholamine inhibition of leptin gene expression through beta adrenergic receptors (1), central mechanisms may also be involved in altering circulating leptin levels. Blood brain barrier (BBB) is a potential regulatory site for leptin transport into brain and leptin resistance. The transport system, with the transporting receptor ObRa for leptin to permeate the BBB, has limited capacity and is saturable (4). ObRa has a high level of expression in microvessels. The barrier function of neural vasculature is not static and is regulated dynamically in response to changes in the surrounding environment, such as changes in tissue oxygen concentration (3). Recently, it has been shown that hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5, a key molecule in the tight junction assembly, in endothelial cells (3). Taken together, acute hypoxia of high altitude may alter transport of leptin into brain by disrupting BBB and may be responsible for several symptoms of acute mountain sickness such as loss of apetite. Furthermore, during chronic exposure to high altitude hypoxia, barrier properties of neural blood vessel may be reconstituted. In conclusion, central response to leptin may modulate circulating leptin levels under the circumstances of high altitude hypoxia in a time-dependent manner. References 1. Gettys TW, Harkness PJ, and Watson PM. The beta 3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 1996;137:4054-7. 2. 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 2002;277:42953-7. 3. Koto T, Takubo K, Ishida S, Shinoda H, Inoue M, Tsubota K, Okada Y, and Ikeda E. Hypoxia disrupts the barrier function of neural blood vessels through changes in the expression of claudin-5 in endothelial cells. Am J Pathol 2007;170:1389-97. 4. Pan W, and Kastin AJ. Adipokines and the blood-brain barrier. Peptides 2007;28:1317-30. 5. Sierra-Johnson J, Romero-Corral A, Somers VK, and Johnson BD. Viewpoint: Effect of altitude on leptin levels, does it go up or down? J Appl Physiol 2008 (article in press; doi:10.1152/japplphysiol.01284.2007) |
|||
|
|
|||
|
Lei Xi, Division of Cardiology, Department of Internal Medicine Virginia Commonwealth University, Rakesh C. Kukreja
Send letter to journal:
rakesh{at}vcu.edu Lei Xi, et al.
|
To the Editor: As leptin is an adipocytokine that plays a key role for maintenance of body weight and energy homeostasis, recent research focuses on its regulatory and signaling functions in obesity-related pathological changes including cardiovascular consequences (5). The Viewpoint of Johnson and colleagues (3) timely addressed an important issue on leptin response to physiological stressors at high altitude. In general, we would support their central hypothesis and conclusion that hypobaric hypoxia associated with the elevated altitude should directly stimulate adipocytes to increase leptin production and its release to circulating blood, possibly through the hypoxia inducible factor 1 dependent pathway. To explain the divergent findings of serum leptin levels following high altitude exposure, these authors thoroughly described numerous confounding factors (3), among which we found that body weight loss and cold stress may not be the primary reasons for the opposing leptin response observed in the different studies. We believe that the difference in physical/psychological activities that may lead to variable degree of sympathetic activation and catecholamine release could be the determinant for the deviating leptin results. A delicate feedback loop may adjust the balance of leptin secretion and sympathetic activation, since leptin is known to centrally activate the sympathetic nervous system and catecholamine release (5) and hypoxia also causes sympathetic activation. The enhanced circulating catecholamines can in turn inhibit leptin production (3). Conversely, leptin is consistently upregulated by intermittent hypoxia in humans (4) and rodents (1; 2). Future studies are needed to uncover how leptin is regulated by different regime of hypoxia. REFERENCES 1. Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR and O'Donnell CP. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552: 253-264, 2003. 2. Qin L, Song Z, Wen SL, Jing R, Li C, Xiang Y and Qin XQ. Effect of intermittent hypoxia on leptin and leptin receptor expression in obesity mice. Sheng Li Xue Bao 59: 351-356, 2007. (In Chinese) 3. Sierra-Johnson J, Romero-Corral A, Somers VK and Johnson BD. Viewpoint: Effect of Altitude on Leptin Levels; does it go up or down? J Appl Physiol 2008. 4. Tatsumi K, Kasahara Y, Kurosu K, Tanabe N, Takiguchi Y and Kuriyama T. Sleep oxygen desaturation and circulating leptin in obstructive sleep apnea-hypopnea syndrome. Chest 127: 716-721, 2005. 5. Yang R and Barouch LA. Leptin signaling and obesity: cardiovascular consequences. Circ Res 101: 545-559, 2007. |
|||
|
|
|||
|
Antonio Cabrera de Leon, MD, PhD, Hospital San Juan de Dios de Tenerife Universidad de La Laguna
Send letter to journal:
antonio.cabreradeleon{at}gobiernodecanarias.org Antonio Cabrera de Leon, MD, PhD
|
At high altitudes humans are exposed to multiple factors such as hypoxia, cold, and changes in lifestyle. Sierra-Johnson and colleagues previously expressed the opinion that altitude increases serum leptin (2). In this issue (3) they cite an article as supporting their view (4) despite its biases, and attribute to another article (5) conclusions that are contrary to those actually reported. These errors have been brought to the attention of Sierra-Johnson before (1). In their opening paragraph (3) Sierra-Johnson cite four references they claim to support increased leptin levels in persons exposed to high altitudes. However, none of these studies proves that leptin increases. One documented the effect of hypoxia on a putative promoter of the leptin gene, but said nothing about altitude and serum leptin. Another studied patients with sleep apnea, which is not equivalent to high altitude. The third study (4) was clearly biased, and in the fourth (5) leptin actually decreased with altitude. With reference to their Table 1, Sierra-Johnson claim that living at 200 to 1200 meters above sea level involves genetic adaptation, which they suggest may be a confounding factor. If this were the case half the human population would show such an adaptation. They also suggest (Table 1) that exposure to low altitudes is a confounding factor, but overlook the fact that this was the independent variable and main factor of exposure in the study they criticize. Finally, Sierra-Johnson fails to cite several articles whose conclusions are contrary to their opinions. All in all, their view can hardly be considered impartial. References 1. Cabrera de León A, Almeida González D, Rodríguez Pérez MC, Brito Díaz B, Pérez Méndez LI, and Aguirre-Jaime A. Leptin Concentration Declines as Altitude Increases. Obes Res 2005; 13: 636-37. 2. Sierra-Johnson J, Snyder EM, Johnson BD. Altitude Exposure Should Increase Serum Leptin Levels in Healthy Adults. Obes Res. 2005; 13: 635- 36. 3. Sierra-Johnson J, Romero-Corral A, Somers VK, Johnson BD. Effect of Altitude on Leptin Levels, does it go up or down? J Appl Physiol. 2008; doi:10.1152/japplphysiol.01284.2007 4. Tschop M, Strasburger CJ, Hartmann G, Biollaz J, Bartsch P. Raised leptin concentrations at high altitude associated with loss of appetite. Lancet. 1998; 352: 1119-20. 5. Woolcott OO, Castillo OA, Torres J, Damas L, Florentini E. Serum leptin levels in dwellers from high altitude lands. High Alt Med Biol. 2002; 3: 245-46. |
|||
|
|
|||
|
Chris O'Donnell, Department of Medicine University of Pittsburgh
Send letter to journal:
odonnellcp{at}upmc.edu Chris O'Donnell
|
The viewpoint of Sierra-Johnson et al. addresses the interesting question of the ‘Effect of altitude on leptin levels, does it go up or down?’ Despite a number of conflicting studies in the area, they conclude that the hypoxia associated with altitude increases leptin and that various confounding factors associated with altitude, including cold exposure and weight loss, can attenuate or even reverse the hyperleptinemia. Moreover, they propose a plausible mechanism for hypoxia to cause hyperleptinemia through activation of hypoxia-inducible factor (HIF-1α). In the field of obstructive sleep apnea (OSA) there is compelling evidence that leptin is elevated relative to weight-matched control subjects(2) and that leptin is reduced in OSA patients by treatment with continuous positive airway pressure(3). The intermittent hypoxia (IH) that characterizes OSA is a likely physiologic mechanism since mice exposed to IH demonstrate increased circulating levels of leptin in association with elevated leptin mRNA expression in adipose tissue(4). As with the chronic hypoxia associated with altitude, HIF-1α may represent the cellular transduction signal through which IH stimulates leptin production. However, based on cell culture studies, the concept that IH activates HIF-1α is equivocal(5,6). Nevertheless, a recent study by Li et al.(7) demonstrated a strong trend for a reduction in the magnitude of hyperleptinemia that occurs with IH exposure in HIF-1α heterozygous knockout mice that have a partial, but not complete, loss of HIF-1α function. Thus, the chronic hypoxia from altitude and the intermittent hypoxia from OSA may act through HIF-1α to stimulate leptin production and secretion from adipocytes.
Reference List 1. Sierra-Johnson J, Romero-Corral A, Somers V, and Johnson B. “Viewpoint: Effect of altitude on leptin levels; Does it go up or down?” Journal of Applied Physiology, in press, 2008. 2. Vgontzas, AN, Bixler, EO, Papanicolaou, D, Kales, A, and Chrousos, GP. Plasma concentrations of tumor necrosis factor alpha (TNF), interleukin-6 (IL-6) and leptin are elevated in sleep apnea independent of obesity. Sleep 22, S331. 1999.
3. Chin, K., K. Shimizu, T. Nakamura, N. Narai, H. Masuzaki, Y. Ogawa, M. Mishima, K. Nakao, and M. Ohi. 1999. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 100:706-712. 4. Polotsky, V. Y., J. Li, N. M. Punjabi, A. E. Rubin, P. L. Smith, A. R. Schwartz, and C. P. O'Donnell. 2003. Intermittent hypoxia increases insulin resistance in genetically obese mice. J.Physiol 552:253-264. 5. Ryan, S., C. T. Taylor, and W. T. McNicholas. 2005. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112:2660-2667. 6. Yuan, G., J. Nanduri, C. R. Bhasker, G. L. Semenza, and N. R. Prabhakar. 2005. Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J.Biol.Chem. 280:4321-4328. 7. Li, J., M. Bosch-Marce, A. Nanayakkara, V. Savransky, S. K. Fried, G. L. Semenza, and V. Y. Polotsky. 2006. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Physiol Genomics 25:450-457.
|
|||
|
|
|||
|
Dr. Praveen Vats, Defence Institute of Physiology and Allied Sciences Delhi, India
Send letter to journal:
vatsp2001{at}rediffmail.com Dr. Praveen Vats
|
Leptin is a protein hormone produced primarily by adipose tissue with regulatory effects on metabolism and body weight. In the article “Viewpoint: Effect of altitude on leptin levels, does it go up or down?” Sierra-Johnson et al. (1) compared different published studies and hypothesized that altitude stimulate leptin release through hypoxia sensitive mechanism. This hypothesis is based on Hypoxia Inducible Factor- 1 (HIF-1), which stimulates on exposure to hypoxia and is also an important regulator for leptin gene expression (2). But it is also reported that HIF-1 expression increase during cold exposure (3). If HIF-1 is the only factor which regulate leptin gene expression its level should also increase during cold exposure, but this is not the case. It is well documented that leptin gene expression decrease in cold exposure (4). Exercise, decrease in food intake, body weight and body fat are the other factors which inhibit leptin release (5). This hypothesis is much focused on hypoxia and leptin gene expression in cell line. But in actual altitude exposure cold, anorexia and decrease in body weight are the other factors which act on the system. And all these factors down regulate leptin gene expression. This indicate that HIF-1 is not the only factor responsible for leptin gene regulation at high altitude. In the conclusion authors rightly concluded that other factors should also be considered while assessing the leptin–altitude relationship. References: 1. 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. 2008 Feb 14. 2. 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. 2002; 277:42953-7. 3. Rissanes E, Tranberg HK, Sollid J, Nilsson GE, Nikinmaa M. Temperature regulates hypoxia-inducible factor-1 (HIF-1) in a poikilothermic vertebrate, crucian carp (Carassius carassius). J Exp Biol. 2006;209:994- 1003. 4. Ricci MR, Fried SK, Mittleman KD. Acute cold exposure decrease plasma leptin in women. Metabolism. 2000; 49:421-3. 5. Vats P, Singh VK, Singh SN, Singh SB. High altitude induced anorexia: effect of change in leptin and oxidative stress levels. Nutr Neurosci. 2007:; 10:243-9. Dr. Praveen Vats Defence Institute of Physiology and Allied Sciences Lucknow Road, Timarpur Delhi - 110 054, India E Mail- vatsp2001@rediffmail.com |
|||
|
|
|||
|
Michele Guerre-Millo, Centre de Recherche des Cordeliers Universite Pierre et Marie Curie, Paris, France
Send letter to journal:
michele.guerre-millo{at}crc.jussieu.fr Michele Guerre-Millo
|
Cell studies by us and others have unequivocally demonstrated that the human leptin gene is induced by hypoxia in various cell types (1-3). However, as described in Johnson et al (4), it has been reported that exposure to high altitude increases, does not change or even decreases serum leptin in humans. Despite differences in the population studied, the discrepancy between in vitro and in vivo observations strongly argues for the implication of factors other than hypoxia, in leptin gene regulation with altitude. A question remains pending: does increased leptin signaling account for the well-known altitude-induced alteration of food intake? In an attempt to resolve this issue, we have exposed leptin receptor deficient (Leprfa/Leprfa) obese rats to low barometric pressure in hypobaric chambers (5). First, this allowed showing that serum leptin and adipose tissue leptin gene expression did not increase in lean control rats, but were both elevated in hypoxic obese rats. This experimental setting could help to define the counter-regulatory factors or pathways, which preclude the hypoxic stimulation of the leptin gene in lean rats and are inefficient or disrupted in the obese rats. Second, contrary to our initial hypothesis, the obese rats showed a closely similar pattern of food intake reduction as lean animals in response to hypobaric hypoxia. Thus, this animal model establishes that altitude-induced anorexia occurs in the absence of functional anorexic signaling triggered by leptin. The complex mechanisms implicated in the regulation of food intake and their alteration with high altitude exposure remain to be fully deciphered. Reference List 1. 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 2. 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 3. Grosfeld A, Zilberfarb V, Turban S, Andre J, Guerre-Millo M, Issad T: Effects of hypoxia on human PAZ6 adipocytes. Diabetologia 45:527- 530, 2002 4. 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. 2008 Feb 14. 5. Simler N, Grosfeld A, Peinnequin A, Guerre-Millo M, Bigard AX: Leptin receptor-deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia. Am J Physiol Endocrinol Metab. 290:E591- E597, 2006 |
|||
|
|
|||
|
Xavier Bigard, Professor National Health Research Center for Defense - France, Nadine Simler
Send letter to journal:
nsimler{at}crssa.net Xavier Bigard, et al.
|
Many studies were aimed at examine the responses of the main metabolic and hormonal signals involved in the control of food intake during altitude exposure, including leptin. The viewpoint by Sierra- Johnson et al. is an interesting attempt to identify the confounding factors that might affect leptin levels (3). Because a series of observations in cellular systems showed a stimulatory effect of hypoxia on the leptin gene expression and leptin secretion through the transcription factor hypoxia inducible factor-1 (HIF -1) (1,2), oxygen availability can be considered as an important determinant of leptin mRNA up-regulation in the adipose tissue during altitude exposure. However, whether altitude leads to cellular hypoxia and stabilization of the subunit HIF-1 alpha in vivo, remains to be carefully determined according to altitude levels and duration of exposure, especially regarding the adaptive responses to ambient hypoxia. Another important issue concerns the physiological role played by alterations in leptin production. Increased circulating leptin levels constitutes a satiety signal that would explain the altitude-induced reduction in food intake, except that it has been suggested that altitude- induced anorexia cannot be ascribed to enhanced leptin production (4). Moreover, no change or a decrease in circulating leptin argue against its putative role in the altitude-induced hypophagia. It is thus likely that during altitude exposure leptin might contribute to other regulations than the control of energy intake. Although leptin is induced by hypoxic stimuli in cellular models, no clear-cut conclusion can be drawn from in vivo observations on whether leptin contributes to adaptive responses to altitude. Reference 1. Ambrosini G, Nath AK, Sierra-Honigmann MR, and Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. J. Biol. Chem. 277: 34601-34609, 2002. 2. Grosfeld A, André J, Haugel-de Mouzon S, Berra E, Pouysségur J, and Guerre-Millo M. Hypoxia-inducible factor 1 transactivates the human leptin gene promoter. J. Biol. Chem. 45: 42953-42957, 2002. 3. Sierra-Johnson J, Romero-Corral A, Somers VK, and Johnson BD. Viewpoint: Effect of Altitude on Leptin Levels, does it go up or down? J Appl Physiol, 2008 (in press), doi:10.1152/japplphysiol.01284.2007. 4. Simler N, Grosfeld A, Peinnequin A, Guerre-Millo M, and Bigard AX. Leptin receptor deficient obese Zucker rats reduce their food intake in response to hypobaric hypoxia. Am. J. Physiol. 290: E591-E597, 2005. |
|||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
eLetters: