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Effect of altitude on leptin levels, does it go up or down?

2008; American Physiological Society; Volume: 105; Issue: 5 Linguagem: Inglês

10.1152/japplphysiol.01284.2007

8750-7587

Justo Sierra‐Johnson, Abel Romero‐Corral, Virend K. Somers, Bruce D. Johnson,

High Altitude and Hypoxia

VIEWPOINTEffect of altitude on leptin levels, does it go up or down?Justo Sierra-Johnson, Abel Romero-Corral, Virend K. Somers, and Bruce D. JohnsonJusto Sierra-Johnson, Abel Romero-Corral, Virend K. Somers, and Bruce D. JohnsonPublished Online:01 Nov 2008https://doi.org/10.1152/japplphysiol.01284.2007This is the final version - click for previous versionMoreSectionsPDF (40 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat reports of a relationship between altitude and circulating levels of leptin suggest a possible role of hypoxia in leptin regulation. However, studies on the changes in plasma leptin levels at altitude are controversial, with some showing an increase and others suggesting no change or a fall in these levels. Exposure to hypoxia has been shown to stimulate hypoxia-inducible factor 1 (HIF-1), which appears to be an important regulator for the expression of the leptin gene. However, there are a number of other variables that may influence the altitude-leptin relationship that could explain these divergent findings, such as cold exposure, physical activity, and diet, among others. Some of the studies presented suggest that hypoxia directly stimulates leptin release under controlled experimental conditions, whereas leptin levels may paradoxically decrease in response to certain physiological conditions associated with altitude. In conclusion, all confounding factors associated with altitude should be considered when assessing the leptin-altitude relationship.Introduction.Leptin is a protein (∼16 kDa in mass) hormone produced by adipose tissue with regulatory effects on metabolism and body weight. It is encoded by the obese (ob) gene and circulates to the brain and interacts with receptors in the hypothalamus to inhibit eating (14, 15). Recently, there has been some controversy regarding the role of leptin in high-altitude studies. Basically, there are two opposite positions. The first supports that leptin levels increase with exposure to high altitude (4, 9, 15, 17) and the second supports that leptin levels decrease with exposure to high altitude (2, 16, 20).Given the altitude effects on circulating levels of leptin and the controversy created by the effect of high altitude on leptin, we would like to demonstrate the link between hypoxia and leptin and suggest a possible explanation for the ongoing controversy.Evidence of increased or unchanged leptin levels with altitude.In a prospective study of 20 healthy males, Tschop and colleagues (15) reported elevated plasma leptin levels in human subjects at high altitude, leading to loss of appetite, increased energy expenditure, and weight loss. In a recent study, Shukla and colleagues (11) reported elevated plasma levels of leptin and weight loss after exposure to hypoxic conditions for 7 days in a group of 30 lowlanders who had never visited high altitudes before. In a cross-sectional study of 55 healthy men, Woolcott and colleagues (17) reported no statistical difference between plasma leptin levels in three different populations of dwellers from sea level and two places in the Peruvian Andes. In an intervention study, Barnholt and colleagues (1) reported that leptin concentrations did not change after exposure to hypoxia regardless of energy intake. Other studies have suggested elevations in leptin levels in patient populations that may be associated with chronic hypoxia or intermittent hypoxia, such as sleep apnea (4, 9; see Table 1).Table 1. Summary of studies reporting leptin concentrations after hypoxia exposureFirst Author/YearLeptinDegree of HypoxiaDuration of Exposure/nWeight ChangeAgePossible Confounding FactorsTschop (15)/1998Increase4,559 mts1–2 days/20Weight loss19–42Cold exposure, physical activityShukla (11)/2005Increase3,600–4,550 mts7 days/30Weight loss20–25Woolcott (17)/2002No change3,250–4,550 mtsChronic, cross sectional/5520–30Genetically adaptedBarnholt (1)/2006No change4,300 mts21 days/26Not reported18–35Cold exposure, physical activity, dietCabrera de Leon (2)/2004Decrease200–1,200 mtsChronic, Cross sectional study/88918–70Genetically adapted, low altitude exposureVats (16)/2004Decrease3,600–4,580 mts7 days/10Weight loss19–29Cold exposure, physical activity, dietZaccaria (20)/2004Decrease5,050 mts15–20 days/12Weight loss26–47Cold exposure, physical activity, dietEvidence of decreased leptin levels with altitude.In a prospective study of 10 healthy males, Vats and colleagues (16) reported that leptin levels decrease significantly after 7 days of acute exposure to high altitudes (3,600 and 4,580 m) compared with their baseline leptin measurements at sea level. Recently, in a prospective study of 12 healthy males, Zaccaria and colleagues reported that subjects exposed 15–20 days to high altitude (5,050 m) decreased their plasma leptin levels compared with their baseline leptin measurements at sea level (20). Also recently, Cabrera de Leon and colleagues (2) reported that serum leptin levels decrease when altitude increases in a cross-sectional cohort of 889 subjects in the Canary Islands, Spain, at a relatively low altitude (200–1,020 m; Ref. 2).Hypothesis.On the basis of these observations, we therefore hypothesize that altitude stimulates leptin release through hypoxia-sensitive mechanisms. However, there are many factors that can alter this relationship.Mechanistic considerations.Regarding the evidence that altitude increases levels of leptin, there is one hypothesis that might explain this. HIF-1 is a transcription factor of major importance in the cellular response to oxygen deficiency such as the one experienced at high altitude. It is important that this critical transcription factor be tightly regulated for cells to respond to a wide range of oxygen concentrations. Exposure to hypoxia has been shown to stimulate HIF-1, which appears to be an important regulator for the expression of the leptin gene (4). Furthermore, hypoxia appears to upregulate leptin expression depending on the degree of obesity, as a recent animal study reported that despite no different hematologic responses to hypoxia in lean and obese rats, activation of two hypoxia target genes in the adipose tissue was only seen in the obese. Showing perhaps a hypoxic sensitivity genotype in the obese produced by hypertrophy of the adipose tissue or perhaps it is a counterregulation in the lean that impedes leptin gene stimulation (13, 19).The results of the two cross-sectional studies (1, 17) that did not report changes in leptin levels could be due to the fact that these subjects were genetically adapted to live at high altitudes. Furthermore, recent animal studies have shown that hypoxia in adipose tissues underlies the dysregulated production of adipocytokines and metabolic syndrome in obesity (6, 18). Hence, leptin expression induced by hypoxia appears to be heavily influenced by genetic and obesity factors.As for the evidence that circulating leptin decreases with altitude, there are many confounders that have not been adequately addressed in the negative studies presented, which may alter the altitude-leptin relationship (12). Cold exposure and weight loss have been related with decreased leptin production, creating a "starvation signal" to the body. This might help explain why in acute exposure to hypoxia and extreme cold, the levels of leptin are diminished. Subjects in these studies were exposed to both hypobaric hypoxia and the cold environment of high altitude, and the changes seen in leptin levels might be a combined effect of hypoxia and cold. Other factors that can affect leptin levels are physical activity and diet. Many of the studies that reported decreased leptin levels failed to adequately control for these and other factors. Also, the inhalation of carbon monoxide (CO) can have a negative effect on leptin gene expression and translation, and reduced levels of leptin have been reported in smokers (7). Hypoxia also leads to an increase in neural sympathetic activity, in particular catecholamines, which in turn inhibit leptin gene expression through the β-adrenergic receptors (3). It is interesting to note that in obese rats, the response of fat cells to catecholamines is impaired (8). Finally, circulating leptin levels show diurnal variation with a particular nocturnal rise increasing in the morning (10).All these potential confounders alone or in combination could clearly alter the effects that hypoxia may have on leptin expression. Exposure to altitude is usually accompanied by increased activity levels, weight loss, altered hydration, cold exposure, sympathetic activation, and altered sleep patterns, all of which are potential modulators of leptin.Conclusion.Some of the studies presented suggest that hypoxia directly stimulates leptin release under controlled experimental conditions, whereas leptin levels may paradoxically decrease in response to certain physiological conditions associated with altitude. Therefore, all confounding factors associated with altitude should be considered when assessing the leptin-altitude relationship.REFERENCES1 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.Link | ISI | Google Scholar2 Cabrera de Leon A, Almeida Gonzalez D, Perez Mendez LI, Aguirre-Jaime A, Rodriguez Perez del C M, Dominguez Coello S, Carballo Trujillo I. Leptin and altitude in the cardiovascular diseases. Obes Res 12: 1492–1498, 2004.Crossref | Google Scholar3 Gettys TW, Harkness PJ, Watson PM. The β3-adrenergic receptor inhibits insulin-stimulated leptin secretion from isolated rat adipocytes. Endocrinology 137: 4054–4057, 1996.Crossref | PubMed | ISI | Google Scholar4 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.Crossref | PubMed | ISI | Google Scholar5 Grosfeld A, Turban S, Andre J, Cauzac M, Challier JC, Hauguel-de Mouzon S, Guerre-Millo M. Transcriptional effect of hypoxia on placental leptin. FEBS Lett 502: 122–126, 2001.Crossref | PubMed | ISI | Google Scholar6 Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, Furukawa S, Tochino Y, Komuro R, Matsuda M, Shimomura I. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes 56: 901–911, 2007.Crossref | PubMed | ISI | Google Scholar7 Meissner U, Hanisch C, Knerr I, Hofbauer KH, Blum WF, Allabauer I, Rascher W, Dotsch J. Differential regulation of leptin synthesis in rats during short-term hypoxia and short-term carbon monoxide inhalation. Endocrinology 146: 215–220, 2005.Crossref | PubMed | ISI | Google Scholar8 Mory G, Wiel M, Adli H, Diot-Dupuy F, Ferre P, Bazin R. Impaired beta-adrenergic signalling pathway in white adipocytes of suckling fa/fa Zucker rats: a defect in receptor coupling. Int J Obes Relat Metab Disord 25: 1592–1598, 2001.Crossref | PubMed | ISI | Google Scholar9 Ozturk L, Unal M, Tamer L, Celikoglu F. The association of the severity of obstructive sleep apnea with plasma leptin levels. Otolaryngol Head Neck Surg 129: 538–540, 2003.Crossref | ISI | Google Scholar10 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 | PubMed | ISI | Google Scholar11 Shukla V, Singh SN, Vats P, Singh VK, Singh SB, Banerjee PK. Ghrelin and leptin levels of sojourners and acclimatized lowlanders at high altitude. Nutr Neurosci 8: 161–165, 2005.Crossref | PubMed | ISI | Google Scholar12 Sierra-Johnson J, Snyder EM, Johnson BD. Altitude exposure should increase serum leptin levels in healthy adults. Obes Res 13: 635–636, 2005.Crossref | Google Scholar13 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.Link | ISI | Google Scholar14 Sweeney G. Leptin signalling. Cell Signal 14: 655–663, 2002.Crossref | PubMed | ISI | Google Scholar15 Tschöp M, Strasburger CJ, Töpfer M, Hautmann H, Riepl R, Fischer R, Hartmann G, Morrison K, Appenzeller M, Hildebrandt W, Biollaz J, Bärtsch P. Influence of hypobaric hypoxia on leptin levels in men. Int J Obes Relat Metab Disord 24, Suppl 2: S151, 2000.Crossref | PubMed | ISI | Google Scholar16 Vats P, Singh SN, Shyam R, Singh VK, Singh SB, Banerjee PK, Selvamurthy W. Leptin may not be responsible for high altitude anorexia. High Alt Med Biol 5: 90–92, 2004.Crossref | PubMed | ISI | Google Scholar17 Wo0lcott 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 | ISI | Google Scholar18 Ye J, Gao Z, Yin J, He Q. 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.Link | ISI | Google Scholar19 Yingzhong Y, Droma Y, Rili G, Kubo K. Regulation of body weight by leptin, with special reference to hypoxia-induced regulation. Intern Med 45: 941–946, 2006.Crossref | ISI | Google Scholar20 Zaccaria M, Ermolao A, Bonvicini P, Travain G, Varnier M. Decreased serum leptin levels during prolonged high altitude exposure. Eur J Appl Physiol 92: 249–253, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: B. D. Johnson, Division of Cardiovascular Diseases, 200 First St. SW- Gonda 5-369, Mayo Clinic, Rochester, Minnesota 55905 (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByThe association between living altitude and serum leptin concentrations in native women22 February 2023 | Frontiers in Endocrinology, Vol. 14Blood pressure levels among Indigenous children living at different altitudesApplied Physiology, Nutrition, and Metabolism, Vol. 44, No. 6Ernährung beim Bergwandern und BergsteigenVitamin D Levels and Cardiometabolic Markers in Indigenous Argentinean Children Living at Different Altitudes8 January 2019 | Global Pediatric Health, Vol. 6Prevalence of hypertension in argentinean indigenous children living at high altitudes versus US children2 February 2018 | Clinical and Experimental Hypertension, Vol. 40, No. 8Appetite Suppression and Altered Food Preferences Coincide with Changes in Appetite-Mediating Hormones During Energy Deficit at High Altitude, But Are Not Affected by Protein IntakeHigh Altitude Medicine & Biology, Vol. 19, No. 2Activity of the antioxidant enzyme paraoxonase in Argentinean children living at high altitude30 August 2017 | Redox Report, Vol. 23, No. 1Type 2 diabetes markers in indigenous Argentinean children living at different altitudes Running title: Type 2 diabetes markers in children at different altitudes AIMS Public Health, Vol. 5, No. 4Hypoxia-Related Hormonal Appetite Modulation in Humans during Rest and Exercise: Mini Review30 May 2017 | Frontiers in Physiology, Vol. 8Effects of prolonged hypoxia and bed rest on appetite and appetite-related hormonesAppetite, Vol. 107Hypoxic Living and Exercise Training Alter Adipose Tissue Leptin/Leptin Receptor in Rats23 November 2016 | Frontiers in Physiology, Vol. 7Living at Higher Altitude and Incidence of Overweight/Obesity: Prospective Analysis of the SUN Cohort3 November 2016 | PLOS ONE, Vol. 11, No. 11Resveratrol ameliorates chronic high altitude exposure‐induced oxidative stress and suppresses lipid metabolism alteration in rats22 June 2015 | European Journal of Lipid Science and Technology, Vol. 118, No. 4Comparison Between HDL-C Levels in Argentine Indigenous Children Living at High Altitudes and U.S. ChildrenDiabetes Technology & Therapeutics, Vol. 18, No. 4Waist Circumference Percentiles in Indigenous Argentinean School Children Living at High AltitudesChildhood Obesity, Vol. 12, No. 1Cardiometabolic risk factors in native populations living at high altitudes17 November 2015 | International Journal of Clinical Practice, Vol. 70, No. 2Ernährung beim Bergwandern und Bergsteigen20 May 2015Oxygen sensing and metabolic homeostasisMolecular and Cellular Endocrinology, Vol. 397, No. 1-2Plasma and Liver Lipid Profiles in Rats Exposed to Chronic Hypobaric Hypoxia: Changes in Metabolic PathwaysHigh Altitude Medicine & Biology, Vol. 15, No. 3Exercise Training during Normobaric Hypoxic Confinement Does Not Alter Hormonal Appetite Regulation2 June 2014 | PLoS ONE, Vol. 9, No. 6Lower Obesity Rate during Residence at High Altitude among a Military Population with Frequent Migration: A Quasi Experimental Model for Investigating Spatial Causation16 April 2014 | PLoS ONE, Vol. 9, No. 4Ascent to altitude as a weight loss method: The good and bad of hypoxia inducible factor activation15 October 2013 | Obesity, Vol. 22, No. 2Endocrine Function9 November 2013Plasma leptin and vascular endothelial growth factor (VEGF) in normal subjects at high altitude (5050 m)17 July 2013 | Archives of Physiology and Biochemistry, Vol. 119, No. 5Association of elevation, urbanization and ambient temperature with obesity prevalence in the United States29 January 2013 | International Journal of Obesity, Vol. 37, No. 10Effects of High Altitude on Sleep and Respiratory System and Theirs AdaptationsThe Scientific World Journal, Vol. 2013Physiology and Pathophysiology With Ascent to AltitudeThe American Journal of the Medical Sciences, Vol. 340, No. 1Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humansMetabolism, Vol. 59, No. 2Obstructive sleep apnea, immuno-inflammation, and atherosclerosis29 April 2009 | Seminars in Immunopathology, Vol. 31, No. 1Short Hypoxia Does not Affect Plasma Leptin in Healthy Men under Euglycemic Clamp ConditionsInternational Journal of Endocrinology, Vol. 2009Last Word on Viewpoint: Effect of altitude on leptin levels, does it go up or down?Justo Sierra-Johnson, Abel Romero-Corral, Virend K. Somers, and Bruce D. Johnson1 November 2008 | Journal of Applied Physiology, Vol. 105, No. 5Commentaries on Viewpoint: Effect of altitude on leptin levels, does it go up or down? Control of leptin with altitude exposureHershel Raff1 November 2008 | Journal of Applied Physiology, Vol. 105, No. 5Commentary on Viewpoint: Regulation of leptin by hypoxiaJianping Ye1 November 2008 | Journal of Applied Physiology, Vol. 105, No. 5 More from this issue > Volume 105Issue 5November 2008Pages 1684-1685 Copyright & PermissionsCopyright © 2008 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01284.2007PubMed18276896History Published online 1 November 2008 Published in print 1 November 2008 Metrics