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J Appl Physiol 105: 1687-1690, 2008; doi:10.1152/japplphysiol.zdg-8233-vpcomm.2008a
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LETTER TO THE EDITOR

Commentary on Viewpoint: Regulation of leptin by hypoxia

TO THE EDITOR: Leptin, as a major cytokine secreted from adipocytes, is a primary hormone in the control of food intake (2). 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 (4). At molecular level, expression of leptin is increased by insulin and decreased by β3-adrenergic receptor signal that activates cAMP signaling pathway (3). Insulin may be involved in regulation of leptin level by food intake, which induces insulin secretion in β-cells. The cAMP signal is likely contributing to leptin reduction in physical exercise. Leptin expression may be upregulated by hypoxia. In obesity, hypoxia exists in adipose tissue and associates with leptin elevation (6). Leptin was reported as a hypoxia response gene whose transcription is induced by transcription factor HIF-1{alpha} (hypoxia inducible factor -1{alpha}; Ref. 1). 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 (4).

REFERENCES

  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.[Abstract/Free Full Text]
  2. Benoit SC, Clegg DJ, Seeley RJ, Woods SC. Insulin, and leptin as adiposity signals. Recent Prog Horm Res 59: 267–285, 2004.[Abstract/Free Full Text]
  3. 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.[Abstract]
  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; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]
  5. Yasumasu T, Takahara K, Nakashima Y. Hypoxia inhibits leptin production by cultured rat adipocytes. Obes Res 10: 128, 2002.[Web of Science][Medline]
  6. 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 Endocrinol 293: E1118–E1128, 2007.[CrossRef]

Jianping Ye
 Professor
Pennington Biomedical Research Center
Louisiana State University System

 
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 β-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 appetite. 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, Watson PM. The β3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 137: 4054–4057, 1996.[Abstract]
  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.[Abstract/Free Full Text]
  3. Koto T, Takubo K, Ishida S, Shinoda H, Inoue M, Tsubota K, Okada Y, 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 170: 1389–1397, 2007.[Abstract/Free Full Text]
  4. Pan W, Kastin AJ. Adipokines and the blood-brain barrier. Peptides 28: 1317–1330. 2007.[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]

Levent Öztürk
 Associate Professor
Department of Physiology
Trakya University Faculty of Medicine

 
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 Sierra-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, because 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 regimens of hypoxia.

REFERENCES

  1. Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR, O'Donnell CP. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552: 253–264, 2003.[Abstract/Free Full Text]
  2. Qin L, Song Z, Wen SL, Jing R, Li C, Xiang Y, Qin XQ. [Effect of intermittent hypoxia on leptin and leptin receptor expression in obesity mice]. Sheng Li Xue Bao 59: 351–356, 2007.[Medline]
  3. 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, 2007; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]
  4. Tatsumi K, Kasahara Y, Kurosu K, Tanabe N, Takiguchi Y, Kuriyama T. Sleep oxygen desaturation and circulating leptin in obstructive sleep apnea-hypopnea syndrome. Chest 127: 716–721, 2005.[CrossRef][Web of Science][Medline]
  5. Yang R, Barouch LA. Leptin signaling and obesity: cardiovascular consequences. Circ Res 101: 545–559, 2007.[Abstract/Free Full Text]

Lei Xi
Rakesh C. Kukreja
 Division of Cardiology
Department of Internal Medicine
Virginia Commonwealth University

 
TO THE EDITOR: At high altitudes humans are exposed to multiple factors such as hypoxia, cold, and changes in lifestyle. Sierra-Johnson and colleagues (2) previously expressed the opinion that altitude increases serum leptin. 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, Sierra-Johnson et al. (3) 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 Fig. 1, Sierra-Johnson claim that living at 200 to 1,200 m above sea level involves genetic adaptation, which they suggest may be a confounding factor. If this were the case, one-half the human population would show such an adaptation. They also suggest (Fig. 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, Aguirre-Jaime A. Leptin concentration declines as altitude increases. Obes Res 13: 636–637, 2005.[CrossRef][Web of Science]
  2. Sierra-Johnson J, Snyder EM, Johnson BD. Altitude exposure should increase serum leptin levels in healthy adults. Obes Res 13: 635–636, 2005.[CrossRef][Web of Science][Medline]
  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; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]
  4. Tschop M, Strasburger CJ, Hartmann G, Biollaz J, Bartsch P. Raised leptin concentrations at high altitude associated with loss of appetite. Lancet 352: 1119–1120, 1998.[Medline]
  5. Woolcott OO, Castillo OA, Torres J, Damas L, Florentini E. Serum leptin levels in dwellers from high altitude lands. High Alt Med Biol 3: 245–246, 2002.[CrossRef][Medline]

Antonio Cabrera de Leon
 Hospital San Juan de Dios de Tenerife
Universidad de La Laguna

 
TO THE EDITOR: The Viewpoint of Sierra-Johnson et al. (5) 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-1{alpha}). In the field of obstructive sleep apnea (OSA) there is compelling evidence that leptin is elevated relative to weight-matched control subjects (6) and that leptin is reduced in OSA patients by treatment with continuous positive airway pressure (1). The intermittent hypoxia (IH) that characterizes OSA is a likely physiological mechanism since mice exposed to IH demonstrate increased circulating levels of leptin in association with elevated leptin mRNA expression in adipose tissue (6). As with the chronic hypoxia associated with altitude, HIF-1{alpha} may represent the cellular transduction signal through which IH stimulates leptin production. However, based on cell culture studies, the concept that IH activates HIF-1{alpha} is equivocal (4, 5). Nevertheless, a recent study by Li et al. (2) demonstrated a strong trend for a reduction in the magnitude of hyperleptinemia that occurs with IH exposure in HIF-1{alpha} heterozygous knockout mice that have a partial, but not complete, loss of HIF-1{alpha} function. Thus the chronic hypoxia from altitude and the intermittent hypoxia from OSA may act through HIF-1{alpha} to stimulate leptin production and secretion from adipocytes.

REFERENCES

  1. Chin K, Shimizu K, Nakamura T, Narai N, Masuzaki H, Ogawa Y, Mishima M, Nakao K, Ohi M. 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, 1999.[Abstract/Free Full Text]
  2. Li J, Bosch-Marce M, Nanayakkara A, Savransky V, Fried SK, Semenza GL, Polotsky VY. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Physiol Genomics 25: 450–457, 2006.[Abstract/Free Full Text]
  3. Polotsky VY, Li J, Punjabi NM, Rubin AE, Smith PL, Schwartz AR, O'Donnell CP. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 552: 253–264, 2003.[Abstract/Free Full Text]
  4. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 112: 2660–2667, 2005.[Abstract/Free Full Text]
  5. Sierra-Johnson J, Romero-Corral A, Somers V, Johnson B. 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]
  6. Vgontzas AN, Bixler EO, Papanicolaou D, Kales A, 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.
  7. Yuan G, Nanduri J, Bhasker CR, Semenza GL, Prabhakar NR. Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem 280: 4321–4328, 2005.[Abstract/Free Full Text]

Chris O'Donnell
 Department of Medicine
University of Pittsburgh

 
TO THE EDITOR: 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. (4) compared different published studies and hypothesized that altitude stimulates 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 (1). But it is also reported that HIF-1 expression increases during cold exposure (3). If HIF-1 is the only factor that regulates 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 decreases in cold exposure (2). Exercise, decrease in food intake, body weight, and body fat are the other factors that inhibit leptin release (5). This hypothesis is much focused on hypoxia and leptin gene expression in cell lines. But in actual altitude exposure cold, anorexia and decrease in body weight are the other factors that act on the system. And all these factors downregulate leptin gene expression. This indicates that HIF-1 is not the only factor responsible for leptin gene regulation at high altitude. In conclusion, the authors rightly concluded that other factors should also be considered while assessing the leptin-altitude relationship.

REFERENCES

  1. 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]
  2. Ricci MR, Fried SK, Mittleman KD. Acute cold exposure decrease plasma leptin in women. Metabolism 49: 421–423, 2000.[CrossRef][Web of Science][Medline]
  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 209: 994–1003, 2006.[Abstract/Free Full Text]
  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; first published February 14, 2008; doi:10.1152/japplphysiol.1284.2007.
  5. Vats P, Singh VK, Singh SN, Singh SB. High altitude induced anorexia: effect of change in leptin and oxidative stress levels. Nutr Neurosci 10: 243–249, 2007.[CrossRef][Web of Science][Medline]

Praveen Vats
 Defence Institute of Physiology and Allied Sciences
Delhi, India

 
TO THE EDITOR: 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 showed 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.

REFERENCES

  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.[Abstract/Free Full Text]
  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.[Abstract/Free Full Text]
  3. Grosfeld A, Zilberfarb V, Turban S, Andre J, Guerre-Millo M, Issad T. Effects of hypoxia on human P.AZ6 adipocytes. Diabetologia 45: 527–530, 2002.[CrossRef][Web of Science][Medline]
  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; first published February 14, 2008; doi:10.1152/japplphysiol.01284.2007.[Free Full Text]
  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.[Abstract/Free Full Text]

Michele Guerre-Millo
 Centre de Recherche des Cordeliers
Universite Pierre et Marie Curie
Paris, France

 
TO THE EDITOR: Many studies were aimed at examining 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. (3) is an interesting attempt to identify the confounding factors that might affect leptin levels.

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; Refs. 1, 2), oxygen availability can be considered as an important determinant of leptin mRNA upregulation 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 constitute 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.

REFERENCES

  1. Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. J Biol Chem 277: 34601–34609, 2002.[Abstract/Free Full Text]
  2. Grosfeld A, André J, Haugel-de Mouzon S, Berra E, Pouysségur J, 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, 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]
  4. 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, 2005.[CrossRef][Web of Science][Medline]

Xavier Bigard
 Professor
Nadine Simler
National Health Research Center for Defense-France





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