Sports Med 2003; 33 (7): 473-482 0112-1642/03/0007-0473/$30.00/0

LEADING ARTICLE

 Adis Data Information BV 2003. All rights reserved.

Plasma Leptin and Exercise Recent Findings Matthew W. Hulver1 and Joseph A. Houmard2 1 2

Department of Physiology, East Carolina University, Greenville, North Carolina, USA Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA

Abstract

It is established that plasma leptin is associated with satiety and that leptin stimulates lipid metabolism, and increases energy expenditure. These effects implicate leptin as a major regulator of energy homeostasis, which may serve to limit excess energy storage. As plasma leptin concentrations are tightly coupled with fat mass in humans, decreases in adipose mass with weight loss coincide with decreased concentrations of circulating leptin. However, due to many confounding factors, the effects of exercise on circulating leptin are less clear. The data from investigations examining single exercise bouts suggest that serum leptin concentrations are unaltered by short duration (41 minutes or less), non-exhaustive exercise, but may be affected by short duration, exhaustive exercise. More convincingly, studies investigating long duration exercise bouts indicate that serum leptin concentrations are reduced with exercise durations ranging from one to multiple hours. These findings raise speculation that exercise-associated reductions in leptin may be due to alterations in nutrient availability or nutrient flux at the level of the adipocytes, the primary site of leptin production and secretion. Thus, one purpose of this review is to discuss the effects of exercise on circulating leptin concentrations with special emphasis on studies that have examined single exercise bouts that are associated with high levels of energy expenditure and energy deficit. In addition, a ‘nutrient sensing pathway’ (the hexosamine biosynthetic pathway), which regulates leptin gene expression, will be discussed as a possible mechanism by which exercise-induced energy deficit may modulate serum leptin concentrations.

Since the cloning of the obese gene in 1994 by Zhang et al.,[1] much work has been devoted to elucidating the biology and physiological role of leptin. To date, it is known that plasma leptin concentrations are associated with satiety[2-5] and that leptin stimulates the oxidation of lipids[6-8] and increases energy expenditure.[9-13] These effects suggest that leptin plays a major role in energy homeostasis and serves to limit excessive energy storage in adipose tissue of mammals. Counter intuitive to these findings, human obesity is accompanied by

hyperleptinaemia,[14-18] which is indicative of either a state of reduced leptin clearance and/or excess leptin secretion with obesity. The cause of hyperleptinaemia with obesity in humans has yet to be clearly elucidated. In an attempt to treat hyperleptinaemia, interventions such as weight loss[19-22] and exercise[22-49] have been investigated. As plasma leptin concentrations are tightly coupled with fat mass in humans,[9,17,20,30,50] decreases in adipose mass with weight loss coincide with decreased concentrations of circulating leptin.[19-22] However, because of

474

many confounding factors, the effects of exercise on circulating leptin are less clear.

Hulver & Houmard

possible mechanism by which exercise-induced energy deficit may modulate serum leptin concentrations.

The effects of exercise on circulating leptin have been investigated cross-sectionally,[23,24] in response to short-[42] and long-term exercise training,[22,39,43-49] and following single bouts of exercise (maximal, submaximal, short duration and long duration).[25-41,51] Cross-sectional data have shown that plasma leptin concentrations are associated with fitness level; however, these relationships are not independent of body fat mass.[23,24] A short-term training study of 7 days did not influence fasting plasma leptin levels.[42] Long-term exercise training has resulted in decreases in circulating leptin levels, but these reductions are generally not independent of changes in body fat mass.[22,39,43-46] Several long-term training investigations have demonstrated reductions in plasma leptin independent of weight reduction;[47-49] however, it is unclear whether these changes were due to long-term exercise training or a result of the last exercise bout. Studies examining the leptin response to single bouts of exercise have produced equivocal results, but it appears that circulating leptin levels are only decreased by bouts of exercise with considerably high intensity[51] and long duration.[25,29,31,32,35,37]

Leptin is a product of the obese gene and circulates as a 16 kDa protein[1] either in a free or bound form. Expression and secretion of leptin occurs primarily in white adipose tissue;[56-59] however, there have been additional physiological locations that have been shown to be sites of production (stomach,[60] brain,[61,62] placenta,[63] skeletal muscle,[64] bone,[65] and arterial endothelium[66]). Leptin acts by activating specific leptin receptor isoforms (long and numerous short forms),[67] which are expressed in a variety of tissues.[56,68-74] The long receptor isoform (OB-Rb) is a member of the class I cytokine receptor family and is preferentially expressed in the hypothalamus and activates the Janus Kinase signal transducer and an activator of transcription (JAKSTAT) pathway.[56,75] Short forms of the leptin receptor, which include OB-Ra and OB-Re, are expressed in a number of peripheral tissues with OBRa being the most prevalent.[56,75]

Plasma leptin concentrations are modulated by energy balance,[18,52-54] as circulating leptin is decreased and increased in response to fasting and overfeeding, respectively. In a recent review discussing leptin and exercise, Hickey and Calsbeek[55] proposed that in order for exercise to alter serum leptin, a threshold of energy deficit must be achieved. Furthermore, it was also hypothesised that circulating leptin might be modulated by glucostatic factors at the level of the adipocyte. Support for both of these hypotheses has been reported in the literature. Thus, one purpose of this review is to discuss the effects of exercise on circulating leptin concentrations with special emphasis on studies that have examined single exercise bouts that are associated with high levels of energy expenditure and/or energy deficit. In addition, a ‘nutrient sensing pathway’ (the hexosamine biosynthetic pathway), which regulates leptin gene expression, will be discussed as a

Plasma leptin exhibits a clear circadian rhythm with the highest concentrations occurring near midnight and lowest concentrations occurring near midmorning.[56,76,77] This diurnal rhythm is hormonally influenced,[78,79] dependent on sex[80,81] and energy availability,[79,81-83] and may be altered by meal timing[84] and dietary composition.[85,86] Prolonged infusions of insulin or supraphysiological insulin levels markedly increase circulating leptin concentration.[87-96] Isoproterenol[97] and β3-adrenergic receptor agonists[98,99] reduce leptin messenger RNA (mRNA) expression and circulating levels. Glucocorticoids have been shown to increase leptin production in vitro,[89,100] and exogenously administered glucocorticoids resulted in a substantial increase in circulating leptin levels in humans.[101-103] Several cytokines, such as tumour necrosis factor-α, interleukin-1, and interleukin-6, also alter leptin mRNA expression and circulating levels.[104-108]

 Adis Data Information BV 2003. All rights reserved.

1. The Biology of Leptin

Sports Med 2003; 33 (7)

Leptin and Exercise

2. Plasma Leptin and Exercise Many studies have investigated the effects of a single bout of exercise on circulating leptin in humans.[25-41] These studies range from designs that employed short duration exercise at varying degrees of intensity to very long duration bouts of considerably high volume. Weltman et al.[28] examined the effects of short duration (30 minutes) treadmill exercise of varying intensity (intensities below, at, and above lactate threshold) on serum leptin levels in recreationally active men and reported no change in leptin concentrations irrespective of exercise intensity. Kraemer et al.[40] observed no change in serum leptin concentrations in untrained postmenopausal women in response to 30 minutes of treadmill exercise at ~80% of maximal oxygen consumption. Fisher et al.[38] investigated serum leptin in response to 41 minutes of cycle ergometry at 85% of maximal oxygen consumption in young, sedentary males, and observed no effect. Perusse et al.[39] reported no change in serum leptin in untrained subjects, consisting of 51 men and 46 women, following a 10- to 12-minute maximal exercise test on a cycle ergometer. In contrast, Elias et al.[51] reported a transient decrease in serum leptin following a treadmill exercise bout to exhaustion in seven sedentary males. It is important to note that leptin concentrations were assessed immediately following exercise in the study from Perusse et al. and 30 minutes post-exercise and later in the work of Elias et al. Decreases in plasma leptin following a single bout of exercise have manifested themselves as a late 24–48 hours post-exercise,[31,32] thus the time of blood sampling relative to the exercise bout may have been a contributing factor to these disparate results.[39,51] Studies employing exercise bouts of considerably high volume and substantial energy expenditure have resulted in decreases in circulating leptin. In 14 male runners, Landt et al.[31] demonstrated 32% and 16% reductions in plasma leptin immediately and 18–24 hours following a 101-mile (162.5km) run, respectively. Leal-Cerro et al.[25] reported a 10% reduction in plasma leptin immediately following a marathon run in 29 males compared with non-exer Adis Data Information BV 2003. All rights reserved.

475

cising controls. Following 3 hours of cycling, Koistinen et al.[29] observed 42% and 23% reductions in circulating leptin levels immediately following exercise in healthy and diabetic males, respectively. Two hours after a 3-hour run, Duclos et al.[37] detected a 30% decrease in plasma leptin in eight trained males. In nine trained males, Olive & Miller[32] reported 19% and 29% reductions in plasma leptin at 24 and 48 hours, respectively, following a 60-minute treadmill run. In the same study,[32] the effect of an incremental exercise stress test (12–15 minutes’ duration) on plasma leptin was also examined. The incremental exercise test resulted in energy expenditure of 200 kcal compared with ~870 kcal expended during the 60-minute run. The incremental exercise test had no effect on circulating leptin levels. These data provide support for the notion that exercise bouts with greater energy expenditure are more influential on circulating leptin levels. A report from Essig et al.[36] provides additional support as 800 and 1500 kcals of expenditure during treadmill running decreased leptin by 23% and 22% 48 hours post-exercise, respectively, in moderately trained males. The work from Essig et al.[36] also lends support to the hypothesis that a threshold of exercise-induced energy expenditure must be achieved in order to have influential effects on circulating leptin concentrations. Koistinen et al.[29] examined the alterations in circulating leptin in response to long-duration exercise with and without feeding by comparing changes in leptin in response to a marathon run with food intake to 3 hours of cycling in a fasted state. The marathon run with feeding resulted in no change in plasma leptin concentration. Furthermore, the decreased leptin levels following the 3 hours of cycling was independent of fasting effects as fasted non-exercising control groups experienced only a 12% decrease in leptin versus a mean decrease following cycling exercise of 32%. The data from investigations examining single exercise bouts suggest that serum leptin concentrations are unaltered by short duration (41 minutes or less), non-exhaustive exercise, but may be affected by short duration, exhaustive exercise. More conSports Med 2003; 33 (7)

476

vincingly, studies investigating long duration exercise bouts indicate that serum leptin concentrations are reduced with exercise durations ranging from one to multiple hours. These findings raise speculation that exercise-associated reductions in leptin may be due to alterations in nutrient availability or nutrient flux at the level of the adipocytes, the primary site of leptin production and secretion. 3. Regulation of Leptin Via the Hexosamine Biosynthetic Pathway The hexosamine biosynthetic pathway is thought to be a ‘nutrient-sensing pathway’ and is known to regulate leptin gene expression. The hexosamine biosynthetic pathway is a metabolic process that uses a small percentage of the glucose that enters the cell. In adipose and skeletal muscle cells, glucose is transported into the cell and subsequently phosphorylated to become glucose-6-phosphate. Glucose-6-phosphate is then converted to fructose-6-phosphate. Glucose-6-phosphate is primarily used in two major pathways: glycogen synthesis and glycolysis.[109,110] However, 1–3% of the glucose that is converted to fructose-6-phosphate enters the hexosamine biosynthetic pathway.[111] The end products of the hexosamine pathway are uridine 5′diphosphate (UDP)-N-acetylglucosamine and UDPN-acetylgalactosamine, which are produced in a 3 : 1 ratio, respectively. The hexosamine pathway has been hypothesised to be a measure of nutrient flux into the cell.[112] The hexosamine biosynthetic pathway has been implicated in the development of insulin resistance in skeletal muscle and adipose tissue,[109,113-122] and more recently in the regulation of leptin production in rodent[64,123] and human[124] adipocytes as well as rodent skeletal muscle.[64] Wang et al.[64] originally demonstrated that increased tissue concentrations of UDP-N-acetylglucosamine resulted in rapid and marked increases in leptin mRNA and protein levels in skeletal muscle and adipose tissue. These findings provided an important link between nutrient availability and leptin gene expression. McClain et al.,[123] using a transgenic mouse over-expressing the rate-limiting enzyme for hexosamine synthesis  Adis Data Information BV 2003. All rights reserved.

Hulver & Houmard

(glutamine : fructose-6-phosphate amidotransferase [GFAT]), observed increased levels of UDP-Nacetylglucosamine in adipose tissue of the transgenic mice, which coincided with 70% greater leptin mRNA compared with control mice. Emilsson et al.[125] demonstrated hexosamine-induced leptin and OB-Rb production in clonal β cells. This hexosamine-induced production of leptin and OB-Rb was corroborated in native islet cells treated with high glucose concentrations and excess free fatty acids. Moreover, the effect of high glucose concentrations was blocked by the inhibition of GFAT, the rate-limiting step in the hexosamine biosynthetic pathway. More recently, Zhang et al.[126] demonstrated that glucose and hexosamines regulate leptin production through transcriptional mechanisms localised to the proximal portion of the leptin gene promoter in 3T3-L1 adipocytes. Taken together, these findings[64,123,125,126] implicate the hexosamine biosynthetic pathway as a regulator of leptin gene expression at the whole body level. 4. Plasma Leptin, Energy Balance, and Exercise Hilton and Loucks[82] and van Aggel-Leijssen et recently published data from investigations, which were discussed in detail in a recent review from Hickey and Calsbeek.[55] These investigations were carefully designed in an effort to tease out the effects of exercise from those of energy balance on circulating leptin levels. Hilton and Loucks[82] concluded that the only influence of exercise on 24-hour mean and amplitude of leptin occurred via the impact of its energy cost on energy availability. van Aggel-Leijssen et al.[127] observed a decrease in 24-hour leptin levels in response to exercise-induced increases in 24-hour energy expenditure. In addition, 24-hour leptin concentrations tended to increase in response to overfeeding on a day of relatively high physical activity. Thus, the findings from these investigations[82,127] suggest that modulations in circulating leptin concentrations are regulated by changes in energy balance and not the stress of exercise. al.[127]

Sports Med 2003; 33 (7)

Leptin and Exercise

Reduced caloric intake has been shown to decrease glucose flux through the hexosamine biosynthetic pathway in rats.[128] Wetter et al.[129] observed significantly lower glucose-6-phosphate and fructose-6-phosphate concentrations in muscle from calorie-restricted rats compared with ad libitum fed controls. Fructose-6-phosphate is a substrate for GFAT, the initial and rate-limiting step in the hexosamine biosynthetic pathway. These findings led to the presumption that a negative energy balance may result in a reduced glucose flux through the hexosamine biosynthetic pathway. In an effort to conclusively discern the effects of calorie restriction on glucose flux through this pathway, Gazdag et al.[128] measured skeletal muscle concentrations of UDP-N-acteylhexosamine in calorie restricted and ad libitum fed rats. UDP-N-acteylhexosamine content was significantly lower in calorie-restricted rats compared with ad libitum fed controls. The authors speculated that this reduction of UDP-N-acetylhexosamine was a result of reduced glucose flux through the hexosamine biosynthetic pathway. In addition, the authors also stated that a decrease of glucose flux through this pathway does not require extreme hypoglycaemia, as UDP-Nacetylhexosamine concentrations were significantly reduced with only an 8% decrease (not statistically significant) in glucose concentrations in calorie restricted compared with ad libitum fed rats. The purpose of these investigations[128,129] was to examine mechanisms by which energy restriction improves skeletal muscle insulin sensitivity; thus, no measures of leptin gene expression or secretion were obtained. Nor were any measures of UDP-Nacetylhexosamine concentrations in adipocytes obtained. Nonetheless, compelling evidence exists that implicates the hexosamine biosynthetic pathway as a major regulator of leptin gene expression and secretion. This evidence combined with data suggesting that calorie restriction reduces glucose flux through this pathway, provides a basis for the hypothesis that exercise-induced energy deficit may modulate leptin secretion through the hexosamine biosynthetic pathway.  Adis Data Information BV 2003. All rights reserved.

477

To our knowledge, Nelson et al.[130] is the only study that has examined the effects of exercise on glucose flux through the hexosamine biosynthetic pathway. This study[130] was conducted using rats, and the purpose was to assess whether or not decreased glucose flux through the hexosamine biosynthetic pathway contributed to the enhanced insulin response of muscles after an acute bout of exercise. The authors stated that such an effect could occur if GFAT activity declined after vigorous exercise or if the availability of the rate limiting substrate, fructose-6-phosphate, decreased due to increased glucose flux via the major pathways, glycolysis and/or glycogen synthesis. The results did not support their hypothesis as exercise had no effect on GFAT activity and the concentrations of UDP-Nacteylhexosamine in skeletal muscle were unchanged. Once again, no measures of either leptin gene expression and/or secretion were obtained. Furthermore, UDP-N-acetylhexosamine concentrations were not determined in adipose tissue, which is the predominant site for leptin production. Whether or not glucose flux through the hexosamine biosynthetic pathway in adipocytes is altered during exercise has yet to be discerned. To date, there is no evidence directly linking the hexosamine biosynthetic pathway to long duration exercise-induced decreases in plasma leptin levels. Expression and secretion of leptin occurs primarily in white adipose tissue[56-59] and, as stated previously, the hexosamine biosynthetic pathway has been implicated in the regulation of leptin production in rodent[23,64] and human[124] adipocytes. The possibility exists that a slight decrease in plasma glucose concentrations during the course of a long duration exercise bout may result in reduced glucose uptake at the level of the adipocyte, which would in turn decrease glucose flux through the hexosamine biosynthetic pathway. Of the articles previously discussed in this review demonstrating reduced serum leptin concentrations with long duration exercise,[25,29,31,32,36,37] three of them reported plasma glucose concentrations before and after exercise.[29,32,36] Koistinen et al.[29] observed 16% and 33% reductions in circulating glucose concentraSports Med 2003; 33 (7)

478

Hulver & Houmard

tions in healthy and type I diabetic men, respectively, following 3 hours of cycle ergometry. These reductions in glucose concentrations occurred in concert with significant reductions in serum leptin. Olive and Miller[32] reported significant reductions in plasma leptin at 24 and 48 hours following a 60-minute treadmill run, which coincided with an ~8% decrease in plasma glucose concentrations compared with pre-exercise values. Essig et al.[36] observed significant reductions in serum leptin concentrations 48 hours following treadmill exercise bouts that induced 800 and 1500 kcals of energy expenditure; however, no changes in plasma glucose concentrations were observed. It is important to note, however, that 48 hours following exercise plasma insulin concentrations were reduced by 11%. Thus, it is possible that glucose uptake at the level of the adipocyte was reduced due to lower levels of circulating insulin. The hexosamine biosynthetic pathway is a cellular sensor of energy availability[109,118,119,131] and mediates the effects of glucose on the expression of several gene products[132-135] including leptin.[64,123-125] It is unclear at this time if this pathway is the mechanism by which long duration exercise mediates circulating leptin concentrations. However, based on the findings that energy restriction modulates glucose flux through the hexosamine biosynthetic pathway, this metabolic pathway may be a good candidate for a mechanistic explanation. Future research examining adipose tissue concentrations of UDP-N-acetylhexosamine in conjunction with measures of leptin expression/secretion before and after long duration exercise would provide valuable insight to this mechanistic question. 5. Conclusions Data from investigations examining single exercise bouts suggest that serum leptin concentrations are unaltered by short duration (41 minutes or less), non-exhaustive exercise, but may be affected by short duration, exhaustive exercise. Studies investigating long duration exercise bouts indicate that serum leptin concentrations are reduced with exercise durations ranging from one to multiple hours.  Adis Data Information BV 2003. All rights reserved.

These findings raise speculation that exercise-associated reductions in leptin may be due to alterations in nutrient availability or nutrient flux at the level of the adipocytes, the primary site of leptin production and secretion. The hexosamine biosynthetic pathway is a cellular sensor of energy availability and mediates leptin expression. Future research is warranted on the effects of long duration exercise bouts on glucose flux through the hexosamine biosynthetic pathway and the concomitant effects, if any, on leptin expression and secretion. The clinical relevance of the effects of exercise on circulating leptin concentrations has yet to be established. Although, based on the findings of this review, it appears that weight loss interventions may be a better treatment for hyperleptinaemia than exercise. Hyperleptinaemia typically accompanies obesity and very long duration exercise bouts (i.e. 1–3 hours) are not practical for this population. Acknowledgements Funding support came from a National Research Service Award from the National Institutes of Health (grant # F32DK6260501) awarded to Matthew W. Hulver.

References 1. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372 (6505): 425-32 2. Heini AF, Lara-Castro C, Kirk KA, et al. Association of leptin and hunger-satiety ratings in obese women. Int J Obes Relat Metab Disord 1998; 22 (11): 1084-7 3. Stratton RJ, Stubbs RJ, Elia M. Interrelationship between circulating leptin concentrations, hunger, and energy intake in healthy subjects receiving tube feeding. JPEN J Parenter Enteral Nutr 1998; 22 (6): 335-9 4. Keim NL, Stern JS, Havel PJ. Relation between circulating leptin concentrations and appetite during a prolonged, moderate energy deficit in women. Am J Clin Nutr 1998; 68 (4): 794-801 5. Meister B. Control of food intake via leptin receptors in the hypothalamus. Vitam Horm 2000; 59: 265-304 6. Bryson JM, Phuyal JL, Swan V, et al. Leptin has acute effects on glucose and lipid metabolism in both lean and gold thioglucose-obese mice. Am J Physiol 1999; 277 (3 Pt 1): E417-22 7. Muoio DM, Dohm GL, Tapscott EB, et al. Leptin opposes insulin’s effects on fatty acid partitioning in muscles isolated from obese ob/ob mice. Am J Physiol 1999; 276 (5 Pt 1): E913-21 8. Muoio DM, Dohm GL, Fiedorek Jr FT, et al. Leptin directly alters lipid partitioning in skeletal muscle. Diabetes 1997; 46 (8): 1360-3

Sports Med 2003; 33 (7)

Leptin and Exercise

9. Baile CA, Della-Fera MA, Martin RJ. Regulation of metabolism and body fat mass by leptin. Annu Rev Nutr 2000; 20: 105-27 10. Halaas JL, Gajiwala KS, Maffei M, et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 1995; 269 (5223): 543-6 11. Salbe AD, Nicolson M, Ravussin E. Total energy expenditure and the level of physical activity correlate with plasma leptin concentrations in five-year-old children. J Clin Invest 1997; 99 (4): 592-5 12. Trayhurn P, Hoggard N, Mercer JG, et al. Hormonal and neuroendocrine regulation of energy balance: the role of leptin. Arch Tierernahr 1998; 51 (2-3): 177-85 13. van Dijk G. The role of leptin in the regulation of energy balance and adiposity. J Neuroendocrinol 2001; 13 (10): 913-21 14. Lee JH, Reed DR, Price RA. Leptin resistance is associated with extreme obesity and aggregates in families. Int J Obes Relat Metab Disord 2001; 25 (10): 1471-3 15. Hamann A, Matthaei S. Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes 1996; 104 (4): 293-300 16. Rohner-Jeanrenaud F, Jeanrenaud B. Obesity, leptin, and the brain. N Engl J Med 1996; 334 (5): 324-5 17. Ronnemaa T, Karonen SL, Rissanen A, et al. Relation between plasma leptin levels and measures of body fat in identical twins discordant for obesity. Ann Intern Med 1997; 126 (1): 26-31 18. Tritos NA, Mantzoros CS. Leptin: its role in obesity and beyond. Diabetologia 1997; 40 (12): 1371-9 19. Carantoni M, Abbasi F, Azhar S, et al. Can changes in plasma insulin concentration explain the variability in leptin response to weight loss in obese women with normal glucose tolerance? J Clin Endocrinol Metab 1999; 84 (3): 869-72 20. Eriksson J, Valle T, Lindstrom J, et al. Leptin concentrations and their relation to body fat distribution and weight loss: a prospective study in individuals with impaired glucose tolerance. DPS-study group. Horm Metab Res 1999; 31 (11): 616-9 21. Heymsfield SB, Greenberg AS, Fujioka K, et al. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA 1999; 282 (16): 1568-75 22. Thong FS, Hudson R, Ross R, et al. Plasma leptin in moderately obese men: independent effects of weight loss and aerobic exercise. Am J Physiol Endocrinol Metab 2000; 279 (2): E307-13 23. Hickey MS, Israel RG, Gardiner SN, et al. Gender differences in serum leptin levels in humans. Biochem Mol Med 1996; 59 (1): 1-6 24. Gippini A, Mato A, Peino R, et al. Effect of resistance exercise (body building) training on serum leptin levels in young men: implications for relationship between body mass index and serum leptin. J Endocrinol Invest 1999; 22 (11): 824-8 25. Leal-Cerro A, Garcia-Luna PP, Astorga R, et al. Serum leptin levels in male marathon athletes before and after the marathon run. J Clin Endocrinol Metab 1998; 83 (7): 2376-9 26. Racette SB, Coppack SW, Landt M, et al. Leptin production during moderate-intensity aerobic exercise. J Clin Endocrinol Metab 1997; 82 (7): 2275-7 27. Torjman MC, Zafeiridis A, Paolone AM, et al. Serum leptin during recovery following maximal incremental and prolonged exercise. Int J Sports Med 1999; 20 (7): 444-50 28. Weltman A, Pritzlaff CJ, Wideman L, et al. Intensity of acute exercise does not affect serum leptin concentrations in young men. Med Sci Sports Exerc 2000; 32 (9): 1556-61

 Adis Data Information BV 2003. All rights reserved.

479

29. Koistinen HA, Tuominen JA, Ebeling P, et al. The effect of exercise on leptin concentration in healthy men and in type 1 diabetic patients. Med Sci Sports Exerc 1998; 30 (6): 805-10 30. Hickey MS, Considine RV, Israel RG, et al. Leptin is related to body fat content in male distance runners. Am J Physiol 1996; 271 (5 Pt 1): E938-40 31. Landt M, Lawson GM, Helgeson JM, et al. Prolonged exercise decreases serum leptin concentrations. Metabolism 1997; 46 (10): 1109-12 32. Olive JL, Miller GD. Differential effects of maximal and moderate-intensity runs on plasma leptin in healthy trained subjects. Nutrition 2001; 17 (5): 365-9 33. Kanaley JA, Fenicchia LM, Miller CS, et al. Resting leptin responses to acute and chronic resistance training in type 2 diabetic men and women. Int J Obes Relat Metab Disord 2001; 25 (10): 1474-80 34. Nindl BC, Kraemer WJ, Arciero PJ, et al. Leptin concentrations experience a delayed reduction after resistance exercise in men. Med Sci Sports Exerc 2002; 34 (4): 608-13 35. Zaccaria M, Ermolao A, Roi S, et al. Leptin reduction after endurance races differing in duration and energy expenditure. Eur J Appl Physiol 2002; 87 (2): 108-11 36. Essig DA, Alderson NL, Ferguson MA, et al. Delayed effects of exercise on the plasma leptin concentration. Metabolism 2000; 49 (3): 395-9 37. Duclos M, Corcuff JB, Ruffie A, et al. Rapid leptin decrease in immediate post-exercise recovery. Clin Endocrinol (Oxf) 1999; 50 (3): 337-42 38. Fisher JS, Van Pelt RE, Zinder O, et al. Acute exercise effect on postabsorptive serum leptin. J Appl Physiol 2001; 91 (2): 680-6 39. Perusse L, Collier G, Gagnon J, et al. Acute and chronic effects of exercise on leptin levels in humans. J Appl Physiol 1997; 83 (1): 5-10 40. Kraemer RR, Johnson LG, Haltom R, et al. Serum leptin concentrations in response to acute exercise in postmenopausal women with and without hormone replacement therapy. Proc Soc Exp Biol Med 1999; 221 (3): 171-7 41. Sliwowski Z, Lorens K, Konturek SJ, et al. Leptin, gastrointestinal and stress hormones in response to exercise in fasted or fed subjects and before or after blood donation. J Physiol Pharmacol 2001; 52 (1): 53-70 42. Houmard JA, Cox JH, MacLean PS, et al. Effect of short-term exercise training on leptin and insulin action. Metabolism 2000; 49 (7): 858-61 43. Christensen JO, Svendsen OL, Hassager C, et al. Leptin in overweight postmenopausal women: no relationship with metabolic syndrome X or effect of exercise in addition to diet. Int J Obes Relat Metab Disord 1998; 22 (3): 195-9 44. Okazaki T, Himeno E, Nanri H, et al. Effects of mild aerobic exercise and a mild hypocaloric diet on plasma leptin in sedentary women. Clin Exp Pharmacol Physiol 1999; 26 (5-6): 415-20 45. Kohrt WM, Landt M, Birge Jr SJ. Serum leptin levels are reduced in response to exercise training, but not hormone replacement therapy, in older women. J Clin Endocrinol Metab 1996; 81 (11): 3980-5 46. Reseland JE, Anderssen SA, Solvoll K, et al. Effect of longterm changes in diet and exercise on plasma leptin concentrations. Am J Clin Nutr 2001; 73 (2): 240-5 47. Pasman WJ, Westerterp-Plantenga MS, Saris WH. The effect of exercise training on leptin levels in obese males. Am J Physiol 1998; 274 (2 Pt 1): E280-6

Sports Med 2003; 33 (7)

480

48. Hickey MS, Houmard JA, Considine RV, et al. Gender-dependent effects of exercise training on serum leptin levels in humans. Am J Physiol 1997; 272 (4 Pt 1): E562-6 49. Ishii T, Yamakita T, Yamagami K, et al. Effect of exercise training on serum leptin levels in type 2 diabetic patients. Metabolism 2001; 50 (10): 1136-40 50. Momose Y, Kaetsu A, Ishii T, et al. Serum leptin level among non-obese students: relationship to body fat, blood pressure, serum lipids, physical activity, and eating habits. Nippon Eiseigaku Zasshi 1999; 54 (2): 474-80 51. Elias AN, Pandian MR, Wang L, et al. Leptin and IGF-I levels in unconditioned male volunteers after short- term exercise. Psychoneuroendocrinology 2000; 25 (5): 453-61 52. Flier JS. Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci U S A 1997; 94 (9): 4242-5 53. Kolaczynski JW, Considine RV, Ohannesian J, et al. Responses of leptin to short-term fasting and refeeding in humans: a link with ketogenesis but not ketones themselves. Diabetes 1996; 45 (11): 1511-5 54. Kolaczynski JW, Ohannesian JP, Considine RV, et al. Response of leptin to short-term and prolonged overfeeding in humans. J Clin Endocrinol Metab 1996; 81 (11): 4162-5 55. Hickey MS, Calsbeek DJ. Plasma leptin and exercise: recent findings. Sports Med 2001; 31 (8): 583-9 56. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395 (6704): 763-70 57. Gong DW, Bi S, Pratley RE, et al. Genomic structure and promoter analysis of the human obese gene. J Biol Chem 1996; 271 (8): 3971-4 58. Cinti S, Frederich RC, Zingaretti MC, et al. Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 1997; 138 (2): 797-804 59. Klein S, Coppack SW, Mohamed-Ali V, et al. Adipose tissue leptin production and plasma leptin kinetics in humans. Diabetes 1996; 45 (7): 984-7 60. Bado A, Levasseur S, Attoub S, et al. The stomach is a source of leptin. Nature 1998; 394 (6695): 790-3 61. Esler M, Vaz M, Collier G, et al. Leptin in human plasma is derived in part from the brain, and cleared by the kidneys. Lancet 1998; 351 (9106): 879 62. Wiesner G, Vaz M, Collier G, et al. Leptin is released from the human brain: influence of adiposity and gender. J Clin Endocrinol Metab 1999; 84 (7): 2270-4 63. Lepercq J, Cauzac M, Lahlou N, et al. Overexpression of placental leptin in diabetic pregnancy: a critical role for insulin. Diabetes 1998; 47 (5): 847-50 64. Wang J, Liu R, Hawkins M, et al. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 1998; 393 (6686): 684-8 65. Reseland JE, Syversen U, Bakke I, et al. Leptin is expressed in and secreted from primary cultures of human osteoblasts and promotes bone mineralization. J Bone Miner Res 2001; 16 (8): 1426-33 66. Parhami F, Tintut Y, Ballard A, et al. Leptin enhances the calcification of vascular cells: artery wall as a target of leptin. Circ Res 2001; 88 (9): 954-60 67. Tartaglia LA. The leptin receptor. J Biol Chem 1997; 272 (10): 6093-6 68. Tartaglia LA, Dembski M, Weng X, et al. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995; 83 (7): 1263-71

 Adis Data Information BV 2003. All rights reserved.

Hulver & Houmard

69. Huang KC, Chuang LM, Chen CY, et al. Serum leptin and leptin receptor isoforms in omental adipose tissue of nondiabetic women undergoing gynecologic surgery for benign disease. J Formos Med Assoc 2000; 99 (11): 839-43 70. Kielar D, Clark JS, Ciechanowicz A, et al. Leptin receptor isoforms expressed in human adipose tissue. Metabolism 1998; 47 (7): 844-7 71. Mix H, Widjaja A, Jandl O, et al. Expression of leptin and leptin receptor isoforms in the human stomach. Gut 2000; 47 (4): 481-6 72. Ebenbichler CF, Kaser S, Laimer M, et al. Polar expression and phosphorylation of human leptin receptor isoforms in paired, syncytial, microvillous and basal membranes from human term placenta. Placenta 2002; 23 (6): 516-21 73. White DW, Tartaglia LA. Leptin and OB-R: body weight regulation by a cytokine receptor. Cytokine Growth Factor Rev 1996; 7 (4): 303-9 74. Tsiotra PC, Pappa V, Raptis SA, et al. Expression of the long and short leptin receptor isoforms in peripheral blood mononuclear cells: implications for leptin’s actions. Metabolism 2000; 49 (12): 1537-41 75. Friedman JM. Leptin, leptin receptors, and the control of body weight. Nutr Rev 1998; 56 (2 Pt 2): s38-46; discussion s54-75 76. Casanueva FF, Dieguez C. Neuroendocrine regulation and actions of leptin. Front Neuroendocrinol 1999; 20 (4): 317-63 77. Kanabrocki EL, Hermida RC, Wright M, et al. Circadian variation of serum leptin in healthy and diabetic men. Chronobiol Int 2001; 18 (2): 273-83 78. Ahmad AM, Guzder R, Wallace AM, et al. Circadian and ultradian rhythm and leptin pulsatility in adult GH deficiency: effects of GH replacement. J Clin Endocrinol Metab 2001; 86 (8): 3499-506 79. Wagner R, Oberste-Berghaus C, Herpertz S, et al. Time relationship between circadian variation of serum levels of leptin, insulin and cortisol in healthy subjects. Horm Res 2000; 54 (4): 174-80 80. Saad MF, Riad-Gabriel MG, Khan A, et al. Diurnal and ultradian rhythmicity of plasma leptin: effects of gender and adiposity. J Clin Endocrinol Metab 1998; 83 (2): 453-9 81. Ahren B. Diurnal variation in circulating leptin is dependent on gender, food intake and circulating insulin in mice. Acta Physiol Scand 2000; 169 (4): 325-31 82. Hilton LK, Loucks AB. Low energy availability, not exercise stress, suppresses the diurnal rhythm of leptin in healthy young women. Am J Physiol Endocrinol Metab 2000; 278 (1): E43-9 83. Dallongeville J, Hecquet B, Lebel P, et al. Short term response of circulating leptin to feeding and fasting in man: influence of circadian cycle. Int J Obes Relat Metab Disord 1998; 22 (8): 728-33 84. Schoeller DA, Cella LK, Sinha MK, et al. Entrainment of the diurnal rhythm of plasma leptin to meal timing. J Clin Invest 1997; 100 (7): 1882-7 85. Herrmann TS, Bean ML, Black TM, et al. High glycemic index carbohydrate diet alters the diurnal rhythm of leptin but not insulin concentrations. Exp Biol Med (Maywood) 2001; 226 (11): 1037-44 86. Cha MC, Chou CJ, Boozer CN. High-fat diet feeding reduces the diurnal variation of plasma leptin concentration in rats. Metabolism 2000; 49 (4): 503-7 87. Caro JF, Sinha MK, Kolaczynski JW, et al. Leptin: the tale of an obesity gene. Diabetes 1996; 45 (11): 1455-62 88. Rentsch J, Chiesi M. Regulation of ob gene mRNA levels in cultured adipocytes. FEBS Lett 1996; 379 (1): 55-9

Sports Med 2003; 33 (7)

Leptin and Exercise

89. Wabitsch M, Jensen PB, Blum WF, et al. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996; 45 (10): 1435-8 90. Kolaczynski JW, Nyce MR, Considine RV, et al. Acute and chronic effects of insulin on leptin production in humans: Studies in vivo and in vitro. Diabetes 1996; 45 (5): 699-701 91. Utriainen T, Malmstrom R, Makimattila S, et al. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4h in normal subjects. Diabetes 1996; 45 (10): 1364-6 92. Ryan AS, Elahi D. The effects of acute hyperglycemia and hyperinsulinemia on plasma leptin levels: its relationships with body fat, visceral adiposity, and age in women. J Clin Endocrinol Metab 1996; 81 (12): 4433-8 93. Malmstrom R, Taskinen MR, Karonen SL, et al. Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia 1996; 39 (8): 993-6 94. Remesar X, Rafecas I, Fernandez-Lopez JA, et al. Is leptin an insulin counter-regulatory hormone? FEBS Lett 1997; 402 (1): 9-11 95. Haffner SM, Miettinen H, Mykkanen L, et al. Leptin concentrations and insulin sensitivity in normoglycemic men. Int J Obes Relat Metab Disord 1997; 21 (5): 393-9 96. Mantzoros CS, Liolios AD, Tritos NA, et al. Circulating insulin concentrations, smoking, and alcohol intake are important independent predictors of leptin in young healthy men. Obes Res 1998; 6 (3): 179-86 97. Donahoo WT, Jensen DR, Yost TJ, et al. Isoproterenol and somatostatin decrease plasma leptin in humans: a novel mechanism regulating leptin secretion. J Clin Endocrinol Metab 1997; 82 (12): 4139-43 98. Couillard C, Mauriege P, Prud’homme D, et al. Plasma leptin response to an epinephrine infusion in lean and obese women. Obes Res 2002; 10 (1): 6-13 99. Mantzoros CS, Qu D, Frederich RC, et al. Activation of beta (3) adrenergic receptors suppresses leptin expression and mediates a leptin-independent inhibition of food intake in mice. Diabetes 1996; 45 (7): 909-14 100. Slieker LJ, Sloop KW, Surface PL, et al. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP. J Biol Chem 1996; 271 (10): 5301-4 101. Miell JP, Englaro P, Blum WF. Dexamethasone induces an acute and sustained rise in circulating leptin levels in normal human subjects. Horm Metab Res 1996; 28 (12): 704-7 102. Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women. J Clin Endocrinol Metab 1996; 81 (12): 4428-32 103. Papaspyrou-Rao S, Schneider SH, Petersen RN, et al. Dexamethasone increases leptin expression in humans in vivo. J Clin Endocrinol Metab 1997; 82 (5): 1635-7 104. Mantzoros CS, Moschos S, Avramopoulos I, et al. Leptin concentrations in relation to body mass index and the tumor necrosis factor-alpha system in humans. J Clin Endocrinol Metab 1997; 82 (10): 3408-13 105. Zumbach MS, Boehme MW, Wahl P, et al. Tumor necrosis factor increases serum leptin levels in humans. J Clin Endocrinol Metab 1997; 82 (12): 4080-2 106. Grunfeld C, Zhao C, Fuller J, et al. Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters. J Clin Invest 1996; 97 (9): 2152-7

 Adis Data Information BV 2003. All rights reserved.

481

107. Sarraf P, Frederich RC, Turner EM, et al. Multiple cytokines and acute inflammation raise mouse leptin levels: potential role in inflammatory anorexia. J Exp Med 1997; 185 (1): 171-5 108. Janik JE, Curti BD, Considine RV, et al. Interleukin 1 alpha increases serum leptin concentrations in humans. J Clin Endocrinol Metab 1997; 82 (9): 3084-6 109. Marshall S, Bacote V, Traxinger RR. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system: role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem 1991; 266 (8): 4706-12 110. Rossetti L, Giaccari A. Relative contribution of glycogen synthesis and glycolysis to insulin- mediated glucose uptake: a dose-response euglycemic clamp study in normal and diabetic rats. J Clin Invest 1990; 85 (6): 1785-92 111. Rossetti L. Perspective: hexosamines and nutrient sensing. Endocrinology 2000; 141 (6): 1922-5 112. Marshall S, Garvey WT, Traxinger RR. New insights into the metabolic regulation of insulin action and insulin resistance: role of glucose and amino acids. FASEB J 1991; 5 (15): 3031-6 113. McClain DA, Crook ED. Hexosamines and insulin resistance. Diabetes 1996; 45 (8): 1003-9 114. Ciaraldi TP, Carter L, Nikoulina S, et al. Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects. Endocrinology 1999; 140 (9): 3971-80 115. Chen H, Ing BL, Robinson KA, et al. Effects of overexpression of glutamine: fructose-6-phosphate amidotransferase (GFAT) and glucosamine treatment on translocation of GLUT4 in rat adipose cells. Mol Cell Endocrinol 1997; 135 (1): 67-77 116. Baron AD, Zhu JS, Zhu JH, et al. Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle: implications for glucose toxicity. J Clin Invest 1995; 96 (6): 2792-801 117. Hawkins M, Barzilai N, Chen W, et al. Increased hexosamine availability similarly impairs the action of insulin and IGF-1 on glucose disposal. Diabetes 1996; 45 (12): 1734-43 118. Hawkins M, Angelov I, Liu R, et al. The tissue concentration of UDP-N-acetylglucosamine modulates the stimulatory effect of insulin on skeletal muscle glucose uptake. J Biol Chem 1997; 272 (8): 4889-95 119. Rossetti L, Hawkins M, Chen W, et al. In vivo glucosamine infusion induces insulin resistance in normoglycemic but not in hyperglycemic conscious rats. J Clin Invest 1995; 96 (1): 132-40 120. Hebert Jr LF, Daniels MC, Zhou J, et al. Overexpression of glutamine: fructose-6-phosphate amidotransferase in transgenic mice leads to insulin resistance. J Clin Invest 1996; 98 (4): 930-6 121. Patti ME, Virkamaki A, Landaker EJ, et al. Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle. Diabetes 1999; 48 (8): 1562-71 122. Robinson KA, Sens DA, Buse MG. Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles: study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Diabetes 1993; 42 (9): 1333-46 123. McClain DA, Alexander T, Cooksey RC, et al. Hexosamines stimulate leptin production in transgenic mice. Endocrinology 2000; 141 (6): 1999-2002

Sports Med 2003; 33 (7)

482

124. Considine RV, Cooksey RC, Williams LB, et al. Hexosamines regulate leptin production in human subcutaneous adipocytes. J Clin Endocrinol Metab 2000; 85 (10): 3551-6 125. Emilsson V, O’Dowd J, Nolan AL, et al. Hexosamines and nutrient excess induce leptin production and leptin receptor activation in pancreatic islets and clonal beta-cells. Endocrinology 2001; 142 (10): 4414-9 126. Zhang P, Klenk ES, Lazzaro MA, et al. Hexosamines regulate leptin production in 3T3-L1 adipocytes through transcriptional mechanisms. Endocrinology 2002; 143 (1): 99-106 127. van Aggel-Leijssen DP, van Baak MA, Tenenbaum R, et al. Regulation of average 24h human plasma leptin level; the influence of exercise and physiological changes in energy balance. Int J Obes Relat Metab Disord 1999; 23 (2): 151-8 128. Gazdag AC, Wetter TJ, Davidson RT, et al. Lower calorie intake enhances muscle insulin action and reduces hexosamine levels. Am J Physiol Regul Integr Comp Physiol 2000; 278 (2): R504-12 129. Wetter TJ, Gazdag AC, Dean DJ, et al. Effect of calorie restriction on in vivo glucose metabolism by individual tissues in rats. Am J Physiol 1999; 276 (4 Pt 1): E728-38 130. Nelson BA, Robinson KA, Koning JS, et al. Effects of exercise and feeding on the hexosamine biosynthetic pathway in rat skeletal muscle. Am J Physiol 1997; 272 (5 Pt 1): E848-55 131. Hawkins M, Barzilai N, Liu R, et al. Role of the glucosamine pathway in fat-induced insulin resistance. J Clin Invest 1997; 99 (9): 2173-82

 Adis Data Information BV 2003. All rights reserved.

Hulver & Houmard

132. Sayeski PP, Kudlow JE. Glucose metabolism to glucosamine is necessary for glucose stimulation of transforming growth factor-alpha gene transcription. J Biol Chem 1996; 271 (25): 15237-43 133. Daniels MC, Kansal P, Smith TM, et al. Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway. Mol Endocrinol 1993; 7 (8): 1041-8 134. McClain DA, Paterson AJ, Roos MD, et al.

Glucose and

glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci U S A 1992; 89 (17): 8150-4 135. Han I, Kudlow JE. Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol Cell Biol 1997; 17 (5): 2550-8

Correspondence and offprints: Dr Matthew W. Hulver, Department of Physiology, The Brody School of Medicine, East Carolina University, Greenville, NC 27858-4354, USA. E-mail: [email protected]

Sports Med 2003; 33 (7)