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Nutritional Neuroscience, October/December 2007; 10(5/6): 243–249

High altitude induced anorexia: Effect of changes in leptin and
oxidative stress levels

PRAVEEN VATS, VIJAY KUMAR SINGH, SOM NATH SINGH, & SHASHI BALA SINGH
Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India
(Received 25 June 2007; revised 23 September 2007; accepted 2 October 2007)

Abstract
High altitude (HA) exposure usually leads to a significant weight loss in non-acclimatized humans. Anorexia is believed to be
the main cause of this body weight loss. Appetite regulatory peptides, i.e. leptin and neuropeptide Y play a key role in food
intake and energy homeostasis. Recent studies suggests increased oxidative stress during HA exposure. In present study effect
of HA exposure on levels of leptin and NPY was evaluated along with N-acetyl cysteine (NAC) and vitamin E
supplementation in relation to food intake and body weight changes. The study was conducted on 30 healthy male volunteers
(age 19 – 29 years). Subjects were divided randomly into three groups of 10 each. Group 1 (placebo) supplemented with
400 mg of calcium gluconate, group 2 and 3 were supplemented with 400 mg of NAC and 400 mg vitamin E, respectively per
day. The study was conducted at low altitude (320 m, Phase I), at HA 3600 m (Phase II) and at an altitude of 4580 m
(Phase III). On HA exposure significant reduction in plasma leptin levels was observed in all the groups on day 2 (Phase II)
along with decrease in food intake and reduction in body weight. Statistically significant increase in blood malondialdehyde
(MDA) levels was seen in all the groups on HA exposure (Phase II, Day 2), but the maximum increase was in case of placebo
group (65.1%) on day 2 (Phase II) in comparison to low altitude values. The decrease in energy intake was almost same in all
the groups indicating that antioxidant supplementation did not provide any protection against HA anorexia. From the study, it
may be concluded that leptin and oxidative stress possibly are not the key players for HA anorexia.

Keywords: Anorexia, high altitude, leptin, N-acetyl cysteine, neuropeptide Y, vitamin E, weight loss

Introduction
Exposure to inhospitable environmental conditions of
high altitude (HA) usually leads to significant weight
loss along with other HA maladies in non-acclimatized
humans. Anorexia is believed to be the main cause of
this body weight loss. Loss of appetite is more
pronounced during the early phase of exposure.
Weight loss at HA is mainly caused by malnutrition
due to hypoxia-related satiety, which is independent of
acute mountain sickness (AMS) (Westerterp-Plantenga 1999; Westerterp-Plantenga et al. 1999).
Calorie consumption can get reduced by 40%,
which can results in negative nitrogen balance. A
number of studies have shown that subjects lose
significant amount of body mass, body fat mass and

lean body mass during climbing or stay at HA
(Zachariah et al. 1987; Kayser et al. 1992).
Leptin, a product of the ob gene, considered a
powerful satiety factor due to its marked effect on food
intake and energy expenditure. Circulating leptin
inform the brain about adipocyte mass, thereby
controlling appetite and body weight homeostasis
(Halaas et al. 1995; Pelleymounter et al. 1995). It has
been reported that injected exogenous leptin inhibits
food intake and reduces body weight by activating
specific brain receptors (Tartaglia et al. 1995; Lee et al.
1996; Heymsfield et al. 1999). Neuropeptide Y
(NPY), a 36 amino acid peptide, is also believed to
be important in the hypothalamic mediation of energy
balance in many species (Vettor et al. 1994; Frankish

Correspondence: Dr P. Vats, Defence Institute of Physiology and Allied Sciences, Lucknow Road, Timarpur, Delhi 110 054, India.
Tel: 91 11 23831180. Fax: 91 11 23914790. E-mail: vatsp2001@rediffmail.com
ISSN 1028-415X print/ISSN 1476-8305 online q 2007 Informa UK Ltd.
DOI: 10.1080/10284150701722299

1998). Group 1 was considered as placebo control and supplemented with 400 mg of calcium gluconate. Physical characteristic of the volunteers. (2000) demonstrated increase in cholecystokinin concentration in plasma on HA exposure and suggested that this may be the cause of hypophagia and weight loss at HA. subjects ascended to an altitude of 4580 m (Phase III.8 ^ 3. At HA increase in leptin levels have been reported (Tschop et al. Hansen et al. Subjects abstained from drinking alcoholic drinks throughout the study. and samples were stored in aliquots at 2 208C until assayed. seca corporation. approved by the Institute’s Ethics Committee. ambient temperature T ¼ 28 –358C). Plasma leptin and NPY were estimated using EIA kits by dbcDiagnostic Biochem Canada. initially blood samples were collected at low altitude seven days after the supplementation started. seca 770. on day 7 at 3600 m and on day 2 at 4580 m. 2001. Therefore. et al. Canada and Peninsula .9 ^ 2. 1995. 1998. Beltowski et al.3 ^ 4. 2004). USA. and it was speculated that this increase in leptin levels might be responsible for loss of body weight at HA (Tschop et al. role of oxidative stress in regulation of eating behavior is also not clear. Blood glucose was estimated using a kit supplied by Monozyme India Ltd. Free radicals modulate expression of some specific cytokines those can suppress feeding via activation of hypothalamic. Written consent for participating in the study was obtained from the volunteers after providing detailed information of the protocol. Plasma insulin was measured using ELISA kit supplied by Diagnostic System Laboratory. In another study.244 P. Magalhaes et al. Schmidt et al.1 ^ 6. Vats et al. Table I. the present study was undertaken with the objective to see the effect of HA exposure on leptin. 2001. 2004. Similarly. Vit E ¼ Vitamin E.9 22. T ¼ 2 5– 78C) by walking. Subjects were divided randomly into three groups of 10 each. The arcuate-paraventicularneuropeptide Y (ARC-PVN-NPY) pathway is activated in response to starvation and body weight loss (Kalra 1997. 3600 m. They had never been to HA before. camp maintenance. 2004). T ¼ 2 2 – 158C) by air.0 ^ 1. initially at low altitude (Phase I. Leptin and NPY is key regulator in energy homeostasis but results available so far are not consistent about their role in HA induced anorexia. along with evaluation of effect of the antioxidant supplementation. NPY and oxidative stress levels in relation to food intake and body weight changes. Bailey et al. Plasma was separated by centrifugation at 1000 g for 10 min. Biochemical estimations Blood samples were collected in heparinized tubes at 0800 –0845 h from an antecubital vein after 12 h fasting. After a week of stay at this altitude. Energy intake was computed by 24 h dietary recall method at low altitude. Assessment of body composition and calorie intake Body mass (using electronic platform balance. (2002) found a lower level of serum leptin in HA natives in comparison to sea level residents. Raposinho et al. 2004). Increase in oxidative stress on HA exposure is well documented (Ilavazhagan et al.3 172. then the subjects taken to HA (Phase II.6 22. It is also reported that leptin increases oxidative stress in animals (Balasubramaniyan et al.6.5 21. Reduction in endogenous NPY leads to a decrease in food intake.0 ^ 2.9 169.4 20. Supplementation was started seven days before the first blood sample was drawn and continued through the study period.8 ^ 3. Materials and methods The study was conducted on 30 healthy male volunteers of the age group of 19 – 29 (22. The study was conducted in three phases. on day 7 at 3600 m and on day 2 at 4580 m. and on day 2 at 4580 m. 1998). 1998).5 173. Jefferson et al.4 ^ 1.1 21. Age (years) mean ^ SD Height (cm) mean ^ SD BMI mean ^ SD 23. Mean ^ SD) years.5 ^ 1. It took about four hours to reach at 4580 m.4 Placebo (calcium gluconate) NAC supplemented Vit E supplemented NAC ¼ N-acetyl cysteine. they found that antioxidant supplementation caused increase in calorie intake at HA and speculated that decrease in satiety may be due to oxidative stress (Bailey and Davies 2001). metabolic and endocrine dependent mechanism (Plata-Salaman 1998). 2004). 2003. Woods et al. galley duty and classroom teaching beside their routine work. 320 m. 2002. thereafter at 3600 m after 48 h of reaching at that altitude (day 2) and on day 7. Heinrichs et al. India. All the groups were on same activity pattern and training during the study period. However in subsequent study they decline the involvement of free radicals in eating behavior at HA (Bailey et al. During the study subjects were involved in daily morning PT. respectively per day (as antioxidants) at the time of breakfast in form of identical capsules.3 ^ 1. Whereas Woolcott et al. Group 2 and 3 were supplemented 400 mg of N-acetyl cysteine (NAC) and 400 mg vitamin E. USA) and heights were recorded after voiding the bladder in minimum clothing early in the morning at low altitude.

NAC and vitamin E supplemented groups. Whereas. The percentage decrease in energy intake was almost same in all the groups showing that antioxidant supplementation did not provide any protection against HA anorexia (Table III).9 ^ 4.6% in vitamin E supplemented group) as compared to the placebo group (4. Vit E ¼ Vitamin E. Day 7 (Phase II) vs. Significant decrease in body weights was observed in all the groups ( p . Values are in Kg.9* (21. Day 2 (Phase III). Values are mean ^ SD.1) 61.3%) on day 7 of Phase II. Placebo (calcium gluconate) NAC supplemented Vit E supplemented Phase I SL Phase II HA-Day 7 (3600 m) (D) Phase III HA-Day 2 (4580 m) (D) 61. . Malondialdehyde (MDA) in whole blood as a measure of lipid peroxidation was assayed by the method of Utley et al. Inc.8) 60. but the levels of all the three groups were almost same on day 2 at 4580 m (Phase III) (Table IV). 0. respectively. HA ¼ High altitude.4* (23. * p . N ¼ 30 (n ¼ 10 in each group). 69. However.9% in NAC supplemented and 2.6* (22.0* (21. Changes in body weights in control and supplemented groups in different phases. On exposure to HA significant increase in blood MDA levels was seen in all the groups.7 ^ 4. A further decrease in body weight was observed on day 2 of Phase III but the change was not significant as compared to day 7 of Phase II (Table II). But in vitamin E supplemented group the leptin levels reduced further on day 7 (Phase II) and improve only on day 2 (Phase III) (Figure 1).3) 59. On exposure to HA statistically significant reduction in leptin levels were observed in all the groups on day 2 (Phase II) in comparison to low altitude values.Changes in leptin at high altitude 245 Table II. 0. (1967). (D) ¼ Change in weight at compared to initial weight in respective group. Table III.1*† (22.6) 58. Statistical analysis To compare the changes in different phases data were analyzed statistically using one way analysis of variance (ANOVA) with repeated measures and post hoc testing with Tukey’s multiple comparison test. USA.7) 62.3% in placebo. HA ¼ High altitude. The reduction was 70. On further ascent to higher altitude (Phase III) placebo and NAC supplemented groups maintained their blood glucose levels.1%. HA exposed.0 ^ 4. † p .0 61. respectively.001) in all the groups but the increase in vitamin E supplemented group was less as compared to placebo and NAC supplemented groups on day 2 at 3600 m (Phase II). statistically significant increase in vitamin E supplemented group was observed on day 2 (Phase III). 0.8* (22.01. In NAC supplemented group the increase was 42. SL ¼ Sea level.001. On exposure to HA. In NAC and vitamin E supplemented groups slight increase was observed on day 2 (Phase II). Values are mean ^ SD.8 ^ 5. A non-significant increase in plasma insulin levels was observed on day 2 and 7 at 3600 m (Phase II) in the placebo group. but the increase was highest in placebo treated group (65. 0. N ¼ 30 (n ¼ 10 in each group).1) NAC ¼ N-acetyl cysteine.6 and 44. in supplemented groups statistically significant increase was observed on day 7 at 3600 m (NAC supplemented group) and on day 2 at 4580 m (vitamin E supplemented group) (Table V). HA exposure increased the fasting blood glucose levels ( p .001. Vit E ¼ Vitamin E. the percent decreases in body weights were less in supplemented groups (2. Slight improvement was observed in placebo and NAC supplemented group on day 7 (Phase II) in comparison to day 2 (Phase II). Sea level vs. whereas. Laboratories.2 ^ 5. Values are expressed in kcal.05 was considered significant.6 ^ 3. Non-significant increase in plasma NPY levels was observed in placebo group after HA exposure in comparison to low altitude values. Results Subject’s age and BMI were similar in all the three groups (Table I).1%) on day 2 (Phase II) in comparison to low altitude values. Changes in calorie intake in control and supplemented groups in different phases. **p . Placebo (calcium gluconate) NAC supplemented Vit E supplemented Phase I SL Phase II HA-Day 7 (3600 m) Phase III HA-Day 2 (4580 m) 2955 ^ 461 3006 ^ 393 2593 ^ 502 2023 ^ 394** 2036 ^ 581** 1731 ^ 517* 2228 ^ 380 ** 2231 ^ 600** 1900 ^ 126* NAC ¼ N-acetyl cysteine. HA exposed.1 ^ 3. a significant decrease in energy intake was observed in all the groups. Sea level vs. but on day 2 (Phase III) the increase was statistically significant in both the groups in comparison to low altitude and day 7 (Phase II) (Table VI). 0.9.6 ^ 4. *p . 0.1 59. SL ¼ Sea level.7 ^ 5.9 63. and p value .05. 0.001).

1996.89 7.43 4. Values are mean ^ SD. Phase I SL Phase II HA-Day 2 (3600 m) Phase II HA-Day 7 (3600 m) Phase III HA-Day 2 (4580 m) 5.42 7. Placebo (calcium gluconate) NAC supplemented Vit E supplemented performed. or sex of the volunteers. 1992). 1980.7 ^ 4.7 ^ 4. † p .3* 119.5* 111. 0.5 89. But this body water loss is in proportion to the decrease in body weight (Jain et al.89 5.63 ^ 2. 0.05.4 ^ 8.14 13. where we observed increased blood glucose along with liver glycogen in initial days of hypoxic exposure. 1986). 1986) along with increased insulin circulation at HA is also reported earlier by several workers (Sawhney et al. Values are mean ^ SD. HA exposed. Day 2 (Phase III). Vit E ¼ Vitamin E. In the present study. Guilland and Klepping 1985.8 ^ 7. Singh et al. 1990). 1988. Day 2 (Phase II) vs. the total weight loss in different groups range from 228 to 378 g/day at 3600 m. Rose et al.52 ^ 2.2 ^ 10.05. Weight losses reported in different studies at 2400 – 6000 m were in range of 61 –474 g/day with an average of 200 g/day (Butterfield 1996). Since subjects were taking food ad libitum and were on wellcontrolled activity schedule. † p .1*† NAC ¼ N-acetyl cysteine. Sawhney et al. Westerterp et al. Changes in blood glucose levels in control and supplemented groups in different phases. Sea level vs.51 ^ 2.32 ^ 3.99 ^ 5.53 10. which tends to recover toward low altitude values following stay at that altitude.01. 0. N ¼ 30 (n ¼ 10 in each group). Values are expressed as mU/ml. 0. Table IV. energy expenditure of the subjects could not be determined. Decrease in food intake is more pronounced during the initial stage of acclimatization and causes a drastic reduction in lean body mass (Guilland and Klepping 1985. This is in agreement with our earlier study on animals exposed to simulated hypobaric hypoxia (Singh et al.95 5. At HA.14 ^ 3. Increase in fasting blood glucose levels with increase in circulating insulin on HA exposure was observed in the present study. 1994). SL ¼ Sea level. Day 2 (Phase II) vs. SL ¼ Sea level.19*† 8. The decrease in food intake and loss in body mass in the present study is similar as reported earlier by several other workers.8 82. N ¼ 30 (n ¼ 10 in each group).33 4. * p . Discussion Exposure of humans to HA induces various physiological and biochemical changes.5% of total body water decreases during first 3 days of HA (3500 m) exposure.9 ^ 6. Placebo (calcium gluconate) NAC supplemented Vit E supplemented Phase I SL Phase II HA-Day 2 (3600 m) Phase III HA-Day 2 (4580 m) 83. whereas in vitamin E supplemented group the enhancement was only 33. It is reported that about 3. Decrease in MDA levels was observed on day 7 at 3600 m in all the groups as compared to day 2 (Phase II). A substantial portion of this initial weight loss comprises of body water. Day 7 (Phase II). Kayser et al. HA ¼ High altitude. hypoxia and cold are the main identifiable factors that may act on human physiology and psychology during climbing and prolonged sojourn. Sea level vs. energy intake should match the total energy expenditure. HA exposure usually leads to anorexia along with weight loss and other HA maladies in sojourners (Boyer and Blume 1984. but it was tried to maintain a fixed activity schedule throughout the study period.6* 118. 1999). Values are expressed as mg/dl.246 P. Day 2 (Phase II) vs. This increase in glucose and insulin circulating levels suggests that there is a glucoinsulinar axis operating at a higher level at HA (Sawhney et al. Butterfield et al. * p . 1973.17 ^ 2. HA exposed.001.1* 109. Impaired glucose tolerance (Brahmachari et al.19 ^ 2. whereas vitamin E supplemented group maintained its MDA level as on day 7.0 ^ 5. Butterfield (1996) reported a decrease of 756 KJ in energy intake at HA in comparison to sea level and this relationship seems to hold regardless of altitude attained. Srivastava et al.14 15. Day 2 (Phase III). activity Table V. To maintain body weight. 0.92‡ NAC ¼ N-acetyl cysteine. the loss in body weight clearly indicates negative energy balance on HA exposure. which is in the same range as reported by different workers earlier (Butterfield 1996). 1991).05. Vit E ¼ Vitamin E. Phase II (Table VII). 1975.32 8. Which may be due to the decrease in food intake.96 ^ 8. But on further ascend to 4580 m MDA levels increased further in placebo and NAC supplemented groups.4 ^ 7.64 ^ 15.75 ^ 10. 1992.6 115. Vats et al.92 ^ 3.5 ^ 12. ‡ p . The increase in blood glucose levels at HA may be the result of increased hepatic glycogenolysis and glucose release due to activation of the sympatho-adrenomedullary and adrenocortical Changes in insulin levels in control and supplemented groups in different phases. Vats et al. In the present study. .3% on day 2 (Phase II).3* 113. HA ¼ High altitude.

Day 2 (Phase III). Maffei et al. N ¼ 30 (n ¼ 10 in each group).01. 0.183 0. In the present study also there was a non-significant increase in NPY levels on day 2 (Phase II) and significant increase on day 2 (Phase III) in supplemented groups. 0. Day 7 (Phase II). 0. Cold exposure also inhibits leptin secretion and circulating levels (MacDougald et al. 0. HA ¼ High altitude. in the present study. This was contrary to the study of Tschop et al. 2004) and by Zaccaria et al. SL ¼ Sea level. § p .123 0. Day 7 (Phase II) vs. Food restriction or starvation results in suppression of circulating leptin (Frederich et al. The changes observed in leptin and NPY levels. Day 2 (Phase II) vs. Over-expression of hypothalamic NPY is observed in animals that are either deficient in leptin or resistant to leptin. *p .467 ^ 0. † p .567 ^ 0. Environmental temperature at HA in the present study was probably sufficiently low to alter leptin secretion. Hardie et al.067 0. Placebo (calcium gluconate) NAC supplemented Vit E supplemented Phase I SL Phase II HA-Day 2 (3600 m) Phase II HA-Day 7 (3600 m) Phase III HA-Day 2 (4580 m) 0. 1995. Day 2 (Phase III). But in the present study we observed a decrease in leptin levels along with a decrease in food intake on HA exposure. NAC ¼ N-acetyl cysteine.604 ^ 0. Changes in plasma leptin levels in control and supplemented groups in different phases. Day 7 (Phase II) vs. Leptin inhibits the activity of orexigenic NPY neurons and reduces expression of NPY in the hypothalamus.561 ^ 0.390 ^ 0. 1996).537 ^ 0. Day 2 (Phase II) vs.001. . 0.159 0.129{ 0. Values are expressed as % of initial levels. 1995. 1980). Low leptin concentrations signals energy deficit to the hypothalamus-pituitary axes (Chang and Mantzoros 2005). (1998). (2004) on HA exposure. Changes in plasma NPY levels in control and supplemented groups in different phases. which can be reversed by refeeding. 0. along with decrease in food intake put the role of leptin in HA induced anorexia in remote and indicates the involvement of other factors in regulation of energy homeostasis at HA that leads to anorexia and loss of body mass. ‡ p . 2004). Norese et al.111 0.Changes in leptin at high altitude 247 Figure 1.597 ^ 0. D ¼ Day.475 ^ 0. (2002) have reported decreased leptin levels in mice exposed to simulated altitude of 4560 m and conclude that at least in case of rodents leptin is probably not causally implicated in the energy imbalance observed at HA.118 0. Other workers also reported lower levels of circulating leptin on HA exposure. in the present study. Values are expressed as ng/ml. * p . Sea level vs.307 ^ 0.114 0. cold and decrease in energy stores due to anorexia. 1995).185*†‡ 0.110 0. 2002. 1995.190*§ NAC ¼ N-acetyl cysteine.05. Sea level vs.001. Vit E ¼ Vitamin E.05. HA exposed. The changes seen in leptin levels might be the result of combined effects of hypoxia.558 ^ 0. Decrease in circulating leptin levels was also reported by this laboratory (Vats et al.01. Cabrera de Leon et al.486 ^ 0. Circulating leptin levels reflect both energy stores and acute energy balance. Table VI.175 0. system. A significant decrease in circulatory leptin level along with a decrease in food intake was observed in all the groups. They speculate that the decrease in food intake at HA may be the effect of raised circulating leptin levels. But this increase in NPY levels may not be to that extent which can stop HA induced anorexia. { p . on HA exposure.725 ^ 0. HA exposed. Values are mean ^ SD. Vit E ¼ Vitamin E. Trayhurn et al. in which they observed an increase in circulating leptin levels on HA exposure. Lower levels of circulating leptin were observed in HA natives as compared to sea level residents (Woolcott et al. or to the direct effect of hypoxia on glucose metabolism by increasing the rate limiting enzymes such as pyruvate kinase and pyruvate phosphotransferase (Hance et al. Day 2 (Phase III). N ¼ 30 (n ¼ 10 in each group).

Sutton JR. Gajiwala KS. editors. Bailey DM. the hypothalamus. Carlson SJ. Ainslie PN. Blume FD.47** 2. Hunt T. Fujioka K.94 ^ 0. Napolitano-Rosen A. Flier JS. Jordinson M. Hunt P. Herzenberg LA. 1998. 2001. Increase in MDA levels was less in the supplemented groups as compared to placebo group.96 ^ 0. Patane J. Simon LM. 0. Theodore J.28 ^ 0. Beltowski J. Changes in blood MDA levels in control and supplemented groups in different phases. Richards M. Butterfield GE. Day 2 (Phase II) vs. 0. Day 2 (Phase III). 1984. This could be attributed to the increased level of lipid peroxidation as a consequence of free radical generation under oxidative stress. The measurement of blood MDA. 1995. Hance AJ. Elevated plasma cholecystokinin at high altitude: Metabolic implications for the anorexia of acute mountain sickness. Eur J Appl Physiol Occup Physiol 54:517–523. Williams SRP. J Appl Physiol 57:1580–1585.31 ^ 0. J Clin Invest 66:1258 –1264. 1973. J Appl Physiol 72:1741–1748. Sharma SK. 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