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

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Plasma Leptin and ExerciseRecent Findings

Matthew W. Hulver1 and Joseph A. Houmard2

1 Department of Physiology, East Carolina University, Greenville, North Carolina, USA2 Human Performance Laboratory, East Carolina University, Greenville, North Carolina, USA

It is established that plasma leptin is associated with satiety and that leptinAbstractstimulates lipid metabolism, and increases energy expenditure. These effectsimplicate leptin as a major regulator of energy homeostasis, which may serve tolimit excess energy storage. As plasma leptin concentrations are tightly coupledwith fat mass in humans, decreases in adipose mass with weight loss coincide withdecreased concentrations of circulating leptin. However, due to many con-founding factors, the effects of exercise on circulating leptin are less clear. Thedata from investigations examining single exercise bouts suggest that serum leptinconcentrations are unaltered by short duration (41 minutes or less), non-exhaus-tive exercise, but may be affected by short duration, exhaustive exercise. Moreconvincingly, studies investigating long duration exercise bouts indicate thatserum leptin concentrations are reduced with exercise durations ranging from oneto multiple hours. These findings raise speculation that exercise-associated reduc-tions in leptin may be due to alterations in nutrient availability or nutrient flux atthe 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 circulatingleptin concentrations with special emphasis on studies that have examined singleexercise bouts that are associated with high levels of energy expenditure andenergy deficit. In addition, a ‘nutrient sensing pathway’ (the hexosamine biosyn-thetic pathway), which regulates leptin gene expression, will be discussed as apossible mechanism by which exercise-induced energy deficit may modulateserum leptin concentrations.

Since the cloning of the obese gene in 1994 by hyperleptinaemia,[14-18] which is indicative of eitherZhang et al.,[1] much work has been devoted to a state of reduced leptin clearance and/or excesselucidating the biology and physiological role of leptin secretion with obesity. The cause of hyperlep-leptin. To date, it is known that plasma leptin con- tinaemia with obesity in humans has yet to be clearlycentrations are associated with satiety[2-5] and that elucidated. In an attempt to treat hyperleptinaemia,leptin stimulates the oxidation of lipids[6-8] and in- interventions such as weight loss[19-22] and exer-creases energy expenditure.[9-13] These effects sug- cise[22-49] have been investigated. As plasma leptingest that leptin plays a major role in energy homeo- concentrations are tightly coupled with fat mass instasis and serves to limit excessive energy storage in humans,[9,17,20,30,50] decreases in adipose mass withadipose tissue of mammals. Counter intuitive to weight loss coincide with decreased concentrationsthese findings, human obesity is accompanied by of circulating leptin.[19-22] However, because of

474 Hulver & Houmard

many confounding factors, the effects of exercise on possible mechanism by which exercise-induced en-circulating leptin are less clear. ergy deficit may modulate serum leptin concentra-

tions.The effects of exercise on circulating leptin havebeen investigated cross-sectionally,[23,24] in responseto short-[42] and long-term exercise train- 1. The Biology of Leptining,[22,39,43-49] and following single bouts of exercise(maximal, submaximal, short duration and long du-

Leptin is a product of the obese gene and circu-ration).[25-41,51] Cross-sectional data have shown thatlates as a 16 kDa protein[1] either in a free or boundplasma leptin concentrations are associated withform. Expression and secretion of leptin occurs pri-fitness level; however, these relationships are notmarily in white adipose tissue;[56-59] however, thereindependent of body fat mass.[23,24] A short-termhave been additional physiological locations thattraining study of 7 days did not influence fastinghave been shown to be sites of production (stom-plasma leptin levels.[42] Long-term exercise trainingach,[60] brain,[61,62] placenta,[63] skeletal muscle,[64]has resulted in decreases in circulating leptin levels,bone,[65] and arterial endothelium[66]). Leptin acts bybut these reductions are generally not independentactivating specific leptin receptor isoforms (longof changes in body fat mass.[22,39,43-46] Several long-and numerous short forms),[67] which are expressed-term training investigations have demonstrated re-in a variety of tissues.[56,68-74] The long receptorductions in plasma leptin independent of weightisoform (OB-Rb) is a member of the class I cytokinereduction;[47-49] however, it is unclear whether thesereceptor family and is preferentially expressed in thechanges were due to long-term exercise training or ahypothalamus and activates the Janus Kinase signalresult of the last exercise bout. Studies examiningtransducer and an activator of transcription (JAK-the leptin response to single bouts of exercise haveSTAT) pathway.[56,75] Short forms of the leptin re-produced equivocal results, but it appears that circu-ceptor, which include OB-Ra and OB-Re, are ex-lating leptin levels are only decreased by bouts ofpressed in a number of peripheral tissues with OB-exercise with considerably high intensity[51] andRa being the most prevalent.[56,75]long duration.[25,29,31,32,35,37]

Plasma leptin exhibits a clear circadian rhythmPlasma leptin concentrations are modulated bywith the highest concentrations occurring near mid-energy balance,[18,52-54] as circulating leptin is de-night and lowest concentrations occurring nearcreased and increased in response to fasting andmidmorning.[56,76,77] This diurnal rhythm is hormon-overfeeding, respectively. In a recent review dis-ally influenced,[78,79] dependent on sex[80,81] and en-cussing leptin and exercise, Hickey and Calsbeek[55]

ergy availability,[79,81-83] and may be altered by mealproposed that in order for exercise to alter serumtiming[84] and dietary composition.[85,86] Prolongedleptin, a threshold of energy deficit must beinfusions of insulin or supraphysiological insulinachieved. Furthermore, it was also hypothesised thatlevels markedly increase circulating leptin concen-circulating leptin might be modulated by glucostatictration.[87-96] Isoproterenol[97] and β3-adrenergic re-factors at the level of the adipocyte. Support for bothceptor agonists[98,99] reduce leptin messenger RNAof these hypotheses has been reported in the litera-(mRNA) expression and circulating levels.ture. Thus, one purpose of this review is to discussGlucocorticoids have been shown to increase leptinthe effects of exercise on circulating leptin concen-production in vitro,[89,100] and exogenously adminis-trations with special emphasis on studies that havetered glucocorticoids resulted in a substantial in-examined single exercise bouts that are associatedcrease in circulating leptin levels in humans.[101-103]with high levels of energy expenditure and/or ener-Several cytokines, such as tumour necrosis factor-α,gy deficit. In addition, a ‘nutrient sensing pathway’interleukin-1, and interleukin-6, also alter leptin(the hexosamine biosynthetic pathway), which regu-mRNA expression and circulating levels.[104-108]lates leptin gene expression, will be discussed as a

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Leptin and Exercise 475

2. Plasma Leptin and Exercise cising controls. Following 3 hours of cycling, Kois-tinen et al.[29] observed 42% and 23% reductions in

Many studies have investigated the effects of a circulating leptin levels immediately following ex-single bout of exercise on circulating leptin in ercise in healthy and diabetic males, respectively.humans.[25-41] These studies range from designs that Two hours after a 3-hour run, Duclos et al.[37] de-employed short duration exercise at varying degrees tected a 30% decrease in plasma leptin in eightof intensity to very long duration bouts of considera- trained males. In nine trained males, Olive & Mill-bly high volume. Weltman et al.[28] examined the er[32] reported 19% and 29% reductions in plasmaeffects of short duration (30 minutes) treadmill exer- leptin at 24 and 48 hours, respectively, following acise of varying intensity (intensities below, at, and 60-minute treadmill run. In the same study,[32] theabove lactate threshold) on serum leptin levels in effect of an incremental exercise stress test (12–15recreationally active men and reported no change in minutes’ duration) on plasma leptin was also exam-leptin concentrations irrespective of exercise inten- ined. The incremental exercise test resulted in ener-sity. Kraemer et al.[40] observed no change in serum gy expenditure of 200 kcal compared with ~870 kcalleptin concentrations in untrained postmenopausal expended during the 60-minute run. The incremen-women in response to 30 minutes of treadmill exer- tal exercise test had no effect on circulating leptincise at ~80% of maximal oxygen consumption. Fish- levels. These data provide support for the notion thater et al.[38] investigated serum leptin in response to exercise bouts with greater energy expenditure are41 minutes of cycle ergometry at 85% of maximal more influential on circulating leptin levels.oxygen consumption in young, sedentary males, and

A report from Essig et al.[36] provides additionalobserved no effect.support as 800 and 1500 kcals of expenditure duringPerusse et al.[39] reported no change in serumtreadmill running decreased leptin by 23% and 22%leptin in untrained subjects, consisting of 51 men48 hours post-exercise, respectively, in moderatelyand 46 women, following a 10- to 12-minute maxi-trained males. The work from Essig et al.[36] alsomal exercise test on a cycle ergometer. In contrast,lends support to the hypothesis that a threshold ofElias et al.[51] reported a transient decrease in serumexercise-induced energy expenditure must beleptin following a treadmill exercise bout to exhaus-achieved in order to have influential effects on cir-tion in seven sedentary males. It is important to noteculating leptin concentrations. Koistinen et al.[29]

that leptin concentrations were assessed immediate-examined the alterations in circulating leptin in re-ly following exercise in the study from Perusse et al.sponse to long-duration exercise with and withoutand 30 minutes post-exercise and later in the work offeeding by comparing changes in leptin in responseElias et al. Decreases in plasma leptin following ato a marathon run with food intake to 3 hours ofsingle bout of exercise have manifested themselvescycling in a fasted state. The marathon run withas a late 24–48 hours post-exercise,[31,32] thus thefeeding resulted in no change in plasma leptin con-time of blood sampling relative to the exercise boutcentration. Furthermore, the decreased leptin levelsmay have been a contributing factor to these dispa-following the 3 hours of cycling was independent ofrate results.[39,51]

fasting effects as fasted non-exercising controlStudies employing exercise bouts of considera-groups experienced only a 12% decrease in leptinbly high volume and substantial energy expenditureversus a mean decrease following cycling exercisehave resulted in decreases in circulating leptin. In 14of 32%.male runners, Landt et al.[31] demonstrated 32% and

The data from investigations examining single16% reductions in plasma leptin immediately andexercise bouts suggest that serum leptin concentra-18–24 hours following a 101-mile (162.5km) run,tions are unaltered by short duration (41 minutes orrespectively. Leal-Cerro et al.[25] reported a 10%less), non-exhaustive exercise, but may be affectedreduction in plasma leptin immediately following a

marathon run in 29 males compared with non-exer- by short duration, exhaustive exercise. More con-

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476 Hulver & Houmard

vincingly, studies investigating long duration exer- (glutamine : fructose-6-phosphate amidotransferasecise bouts indicate that serum leptin concentrations [GFAT]), observed increased levels of UDP-N-are reduced with exercise durations ranging from acetylglucosamine in adipose tissue of the transgen-one to multiple hours. These findings raise specula- ic mice, which coincided with 70% greater leptintion that exercise-associated reductions in leptin mRNA compared with control mice. Emilsson etmay be due to alterations in nutrient availability or al.[125] demonstrated hexosamine-induced leptin andnutrient flux at the level of the adipocytes, the OB-Rb production in clonal β cells. This hex-primary site of leptin production and secretion. osamine-induced production of leptin and OB-Rb

was corroborated in native islet cells treated withhigh glucose concentrations and excess free fatty3. Regulation of Leptin Via theacids. Moreover, the effect of high glucose concen-Hexosamine Biosynthetic Pathwaytrations was blocked by the inhibition of GFAT, the

The hexosamine biosynthetic pathway is thought rate-limiting step in the hexosamine biosyntheticto be a ‘nutrient-sensing pathway’ and is known to pathway. More recently, Zhang et al.[126] demonstra-regulate leptin gene expression. The hexosamine ted that glucose and hexosamines regulate leptinbiosynthetic pathway is a metabolic process that production through transcriptional mechanisms lo-uses a small percentage of the glucose that enters the calised to the proximal portion of the leptin genecell. In adipose and skeletal muscle cells, glucose is promoter in 3T3-L1 adipocytes. Taken together,transported into the cell and subsequently phospho- these findings[64,123,125,126] implicate the hexosaminerylated to become glucose-6-phosphate. biosynthetic pathway as a regulator of leptin geneGlucose-6-phosphate is then converted to fruc- expression at the whole body level.tose-6-phosphate. Glucose-6-phosphate is primarilyused in two major pathways: glycogen synthesis and

4. Plasma Leptin, Energy Balance,glycolysis.[109,110] However, 1–3% of the glucoseand Exercisethat is converted to fructose-6-phosphate enters the

hexosamine biosynthetic pathway.[111] The endHilton and Loucks[82] and van Aggel-Leijssen etproducts of the hexosamine pathway are uridine 5′-

al.[127] recently published data from investigations,diphosphate (UDP)-N-acetylglucosamine and UDP-which were discussed in detail in a recent reviewN-acetylgalactosamine, which are produced in afrom Hickey and Calsbeek.[55] These investigations3 : 1 ratio, respectively. The hexosamine pathwaywere carefully designed in an effort to tease out thehas been hypothesised to be a measure of nutrienteffects of exercise from those of energy balance onflux into the cell.[112]

circulating leptin levels. Hilton and Loucks[82] con-The hexosamine biosynthetic pathway has beencluded that the only influence of exercise on 24-hourimplicated in the development of insulin resistancemean and amplitude of leptin occurred via the im-in skeletal muscle and adipose tissue,[109,113-122] andpact of its energy cost on energy availability. vanmore recently in the regulation of leptin productionAggel-Leijssen et al.[127] observed a decrease inin rodent[64,123] and human[124] adipocytes as well as24-hour leptin levels in response to exercise-in-rodent skeletal muscle.[64] Wang et al.[64] originallyduced increases in 24-hour energy expenditure. Indemonstrated that increased tissue concentrations ofaddition, 24-hour leptin concentrations tended toUDP-N-acetylglucosamine resulted in rapid andincrease in response to overfeeding on a day ofmarked increases in leptin mRNA and protein levelsrelatively high physical activity. Thus, the findingsin skeletal muscle and adipose tissue. These findingsfrom these investigations[82,127] suggest that modula-provided an important link between nutrient availa-tions in circulating leptin concentrations are regulat-bility and leptin gene expression. McClain et al.,[123]

ed by changes in energy balance and not the stress ofusing a transgenic mouse over-expressing therate-limiting enzyme for hexosamine synthesis exercise.

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Leptin and Exercise 477

Reduced caloric intake has been shown to de- To our knowledge, Nelson et al.[130] is the onlystudy that has examined the effects of exercise oncrease glucose flux through the hexosamine biosyn-glucose flux through the hexosamine biosyntheticthetic pathway in rats.[128] Wetter et al.[129] observedpathway. This study[130] was conducted using rats,significantly lower glucose-6-phosphate and fruc-and the purpose was to assess whether or not de-tose-6-phosphate concentrations in muscle from cal-creased glucose flux through the hexosamine bio-orie-restricted rats compared with ad libitum fedsynthetic pathway contributed to the enhanced insu-controls. Fructose-6-phosphate is a substrate forlin response of muscles after an acute bout of exer-GFAT, the initial and rate-limiting step in the hex-cise. The authors stated that such an effect couldosamine biosynthetic pathway. These findings led tooccur if GFAT activity declined after vigorous exer-the presumption that a negative energy balance maycise or if the availability of the rate limiting sub-result in a reduced glucose flux through the hex-strate, fructose-6-phosphate, decreased due to in-osamine biosynthetic pathway.creased glucose flux via the major pathways, glycol-

In an effort to conclusively discern the effects of ysis and/or glycogen synthesis. The results did notcalorie restriction on glucose flux through this path- support their hypothesis as exercise had no effect onway, Gazdag et al.[128] measured skeletal muscle GFAT activity and the concentrations of UDP-N-concentrations of UDP-N-acteylhexosamine in calo- acteylhexosamine in skeletal muscle were un-rie restricted and ad libitum fed rats. UDP-N-ac- changed. Once again, no measures of either leptinteylhexosamine content was significantly lower in gene expression and/or secretion were obtained.calorie-restricted rats compared with ad libitum fed Furthermore, UDP-N-acetylhexosamine concentra-controls. The authors speculated that this reduction tions were not determined in adipose tissue, which isof UDP-N-acetylhexosamine was a result of reduced the predominant site for leptin production. Whetherglucose flux through the hexosamine biosynthetic or not glucose flux through the hexosamine biosyn-pathway. In addition, the authors also stated that a thetic pathway in adipocytes is altered during exer-decrease of glucose flux through this pathway does cise has yet to be discerned.not require extreme hypoglycaemia, as UDP-N- To date, there is no evidence directly linking theacetylhexosamine concentrations were significantly hexosamine biosynthetic pathway to long durationreduced with only an 8% decrease (not statistically exercise-induced decreases in plasma leptin levels.significant) in glucose concentrations in calorie re- Expression and secretion of leptin occurs primarilystricted compared with ad libitum fed rats. The in white adipose tissue[56-59] and, as stated previous-purpose of these investigations[128,129] was to exam- ly, the hexosamine biosynthetic pathway has beenine mechanisms by which energy restriction im- implicated in the regulation of leptin production inproves skeletal muscle insulin sensitivity; thus, no rodent[23,64] and human[124] adipocytes. The possibil-measures of leptin gene expression or secretion were ity exists that a slight decrease in plasma glucoseobtained. Nor were any measures of UDP-N- concentrations during the course of a long durationacetylhexosamine concentrations in adipocytes ob- exercise bout may result in reduced glucose uptaketained. Nonetheless, compelling evidence exists that at the level of the adipocyte, which would in turnimplicates the hexosamine biosynthetic pathway as decrease glucose flux through the hexosamine bio-a major regulator of leptin gene expression and synthetic pathway. Of the articles previously dis-secretion. This evidence combined with data sug- cussed in this review demonstrating reduced serumgesting that calorie restriction reduces glucose flux leptin concentrations with long duration exer-through this pathway, provides a basis for the hypo- cise,[25,29,31,32,36,37] three of them reported plasmathesis that exercise-induced energy deficit may glucose concentrations before and after exer-modulate leptin secretion through the hexosamine cise.[29,32,36] Koistinen et al.[29] observed 16% andbiosynthetic pathway. 33% reductions in circulating glucose concentra-

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478 Hulver & Houmard

tions in healthy and type I diabetic men, respective- These findings raise speculation that exercise-asso-ly, following 3 hours of cycle ergometry. These ciated reductions in leptin may be due to alterationsreductions in glucose concentrations occurred in in nutrient availability or nutrient flux at the level ofconcert with significant reductions in serum leptin. the adipocytes, the primary site of leptin productionOlive and Miller[32] reported significant reductions and secretion. The hexosamine biosynthetic path-in plasma leptin at 24 and 48 hours following a way is a cellular sensor of energy availability and60-minute treadmill run, which coincided with an mediates leptin expression. Future research is war-~8% decrease in plasma glucose concentrations ranted on the effects of long duration exercise boutscompared with pre-exercise values. Essig et al.[36] on glucose flux through the hexosamine biosynthet-observed significant reductions in serum leptin con- ic pathway and the concomitant effects, if any, oncentrations 48 hours following treadmill exercise leptin expression and secretion. The clinical rele-bouts that induced 800 and 1500 kcals of energy vance of the effects of exercise on circulating leptinexpenditure; however, no changes in plasma glucose concentrations has yet to be established. Although,concentrations were observed. It is important to based on the findings of this review, it appears thatnote, however, that 48 hours following exercise weight loss interventions may be a better treatmentplasma insulin concentrations were reduced by 11%. for hyperleptinaemia than exercise. Hyperlep-Thus, it is possible that glucose uptake at the level of tinaemia typically accompanies obesity and verythe adipocyte was reduced due to lower levels of long duration exercise bouts (i.e. 1–3 hours) are notcirculating insulin. practical for this population.

The hexosamine biosynthetic pathway is a cellu-Acknowledgementslar sensor of energy availability[109,118,119,131] and me-

diates the effects of glucose on the expression ofFunding support came from a National Research Serviceseveral gene products[132-135] including lep-

Award from the National Institutes of Health (grant #tin.[64,123-125] It is unclear at this time if this pathway F32DK6260501) awarded to Matthew W. Hulver.is the mechanism by which long duration exercisemediates circulating leptin concentrations. How- Referencesever, based on the findings that energy restriction 1. Zhang Y, Proenca R, Maffei M, et al. Positional cloning of the

mouse obese gene and its human homologue. Nature 1994;modulates glucose flux through the hexosamine bio-372 (6505): 425-32synthetic pathway, this metabolic pathway may be a

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4. Keim NL, Stern JS, Havel PJ. Relation between circulatingable insight to this mechanistic question. leptin concentrations and appetite during a prolonged, moder-

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8. Muoio DM, Dohm GL, Fiedorek Jr FT, et al. Leptin directlyserum leptin concentrations are reduced with exer- alters lipid partitioning in skeletal muscle. Diabetes 1997; 46cise durations ranging from one to multiple hours. (8): 1360-3

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Leptin and Exercise 479

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