Associations between melanocortin, dopamine and serotonin neurotransmission and physical activity.
Far into the 20th century, physical activity (PA) was indispensable for locomotor purposes and necessary for assuring everyday living in most populations. Nowadays, practically all needs can be provided without physical strain. For this reason, spontaneous PA has the greatest impact on the overall level of PA in humans. Unfortunately, the average amount of exercise undertaken by the majority of humans is not sufficient to ensure disease-free living.
In Europe, the sedentary lifestyle ranges between 43% (Sweden) and 88% (Portugal) . In a survey carried out in Poland, more than 50% of men did no leisure-time exercise . Direct costs of low physical activity (and obesity) may reach 9.4% of all health-care system expenses .
Health benefits of PA are unquestionable. It is worth underlining that reduced PA appeared to be a strong, independent predictor of all-cause mortality in the Nurses' Health Study (116 564 women followed since 1976) , the Cancer Prevention Study II, a prospective cohort of 230 298 women and 90 162 men who were enrolled in 1982  or Finnish cohorts (7925 men and 7977 women followed from 1975) [6,7]. What is especially important, moderate, regular exercise is a preventive measure against epidemics of our time: cardiovascular diseases , obesity  and diabetes .
It has been shown that a high level of PA in subjects aged 50 and more is associated with longer life expectancy and longer living without symptoms of cardiovascular diseases. In this model, moderately active (30-33 metabolic equivalents [METs]) and highly active (> 33 METs) men could expect to live longer by respectively 1.3 and 3.7 years when compared with men whose PA level was low (< 30 METs). Moderately and highly active subjects could also hope for by 1.1 and 3.2 years longer periods without symptoms of cardiovascular disease. The numbers for women were respectively 1.5 and 3.5 years for life expectancy and 1.3 and 3.3 years for living without symptoms of cardiovascular disease .
Physical activity together with basal metabolic rate (BMR) and thermic effect of food (TEF) are components of energy expenditure (EE). Physical activity is composed of spontaneous PA (SPA), non-volitional exercise or non-exercise activity thermogenesis (NEAT), obligatory PA, and volitional/voluntary PA (VPA). The first component (SPA or NEAT) comprises activities associated with daily living and the energy spent on activities such as fidgeting, muscle tone, and maintenance of posture. These seem to be particularly difficult to measure in humans. Obligatory PA means locomotor activity needed for survival (which is practically absent in modern populations). Volitional/ voluntary PA describes participation in exercise/ fitness programmes, individual training, conscious sport and active lifestyle. Among these, spontaneous PA seems to have the greatest impact on overall energy expenditure. In humans it may reach from 100 to 800 kcal/24 h [12,13].
It has been proven that energy expenditure (including PA) is dependent on stimulation of specific areas of the central nervous system. The hypothalamus plays the key role here as it collects sensory/metabolic stimuli and regulates energy balance. Energy balance is maintained through control of energy intake (food) and energy expenditure (PA, metabolism).
Lesions to specific brain areas have profound effects on PA and, to the contrary, strenuous exercise may influence functions of the central nervous system. For example, physical exercise is a stressor that can activate corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). Forced wheel running (FWR) in rats strongly activates CRH neurons in the PVN compared with spontaneous wheel running .
Damage made to certain nuclei modifies behaviour and may lead either to hypo-or to hyperactivity. Activity of neurotransmitters is thought to play the key role in these processes. PA of laboratory animals can be either enhanced (e.g. lesions to the cerebral frontal lobe or basal forebrain) or diminished (lesions to the ventromedial hypothalamus, anterior nucleus basalis magnocellularis) .
In the case of limited external stimulation for engaging in PA, genetic and metabolic factors that shape PA are a hypothetical target for intervention. But though associations between genes and physical fitness are evident [15,16], the actual role of genes for adherence to a physically active lifestyle has not been fully elucidated [17-19].
We concisely summarize information on inheritance of features associated with PA. Additionally, we discuss the importance of brain neuropeptides for human behaviour, as a range of observations suggest that physical activity is dependent on the intact brain dopamine, serotonin and melanocortin signalling.
Genetic mechanisms regulating PA
Data on molecular determinants of physically active lifestyle have been growing in recent years. Animal studies revealed loci for locomotor activity in insects and rodents [20-22]. In the fruit fly, genes encoding cGMP-dependent protein kinase decide on more or less active behaviour (in regard to food searching) . It has been shown that closely related mice strains have similar PA levels. Mice bred selectively for high wheel running, even after 35 generations, ran 170% more than controls . Autosomal recessive gene defects as in ob/ob mice (leptin is not produced in adipose tissue) result in decreased PA .
Genetic linkage studies investigate correlations between inheritance of a trait and genetic material within family units (siblings, multigeneration families). It is obvious that the importance of genes for a given feature should be confirmed by revealing resemblances of phenotypes in related persons. The best material for such studies are monozygotic twins that carry the same genotype. All the phenotypic variance in monozygotic twins is dependent on the environmental influences only. The genotype of dizygotic twins of the same gender is 50% identical. Resemblance of phenotypic features whose expression is highly dependent on genotype in dizygotic twins is significantly lower than in monozygotic twins.
It is common knowledge that some individuals are intrinsically keen on participating in exercise and others not. It may be observed in childhood, but becomes evident in older years. On the other hand, there is no doubt that the environment to which an individual is exposed may override genetic predispositions.
Most twin or family studies show a considerable influence of the genetic component on physically active phenotype/lifestyle [24,25]. In some estimates heritability coefficients for sport participation are between 0.35 and 0.83 and for daily PA between 0.29 and 0.62 .
Canadian authors aimed at distinguishing between genetic and cultural components influencing the level of habitual PA in the transmissible effect between generations. They questioned 1610 subjects from 375 families on the level of their habitual PA (3-day activity record 1978-1981). Familial correlations were computed after adjustments for the effects of age, sex, physical fitness, body mass index, and socioeconomic status, and analysed with a model of path analysis that allows the separation of the transmissible effect between generations into genetic and cultural components of inheritance. It was concluded that PA was determined mainly by non-transmissible, environmental factors, but genes affected the level of habitual PA in 29% .
An American study of 3344 male twins (aged 33-51) revealed a clear, familial aggregation in PA (with odds ratio from 2.9-4.6 and 1.4-1.9 for intense and moderate activities, P < 0.05) . In a study of 117 monozygotic twins aged 35-69, familial aggregation accounted for 43% of exercise variation in adulthood . In the Quebec Family Study, heritability estimates for the degree of inactivity, moderate to strenuous PA, total level of daily activity and time spent on PA in the past year were respectively 25%, 16%, 19% and 17% .
On the other hand, 24-hour energy expenditure measured in respiratory chambers of 71 siblings from 32 different families (Caucasian) showed that the variance among subjects was related mainly to fat-free mass (82%) and, to a lesser extent (10%), to spontaneous PA, fat mass, serum free triiodothyronine (FT3) and norepinephrine. Family aggregation of energy expenditure was suggested to be related to resemblance of body composition mainly (and not to spontaneous PA) .
An invaluable source of information on associations/linkage between genotype and PA in humans is the Human Gene Map for Performance and Health-Related Fitness Phenotypes (published annually, with updates from 2000) . In the 2005 update, the authors mentioned 165 autosomal loci/QTL and 5 on the X chromosome. Moreover, variants of 17 mitochondrial genes were found to be associated with fitness or performance phenotypes . The newest report was published in 2010 . Among other known causes, alterations of neurotransmitter systems have a high potency to influence locomotor activity .
The central dopaminergic system influences learning, motivation, reward, reinforcing mechanisms and addiction. The dopaminergic system regulates movement of both animals and humans. It is worth mentioning that interactions between PA and the dopaminergic system are reciprocal and exercise modifies production and actions of brain dopamine. On the other hand, dopamine signalling modulates effects of other neurotransmitters that are involved in the control of motor activity .
Dopamine exerts its actions through five receptors, D1-D5 (DRD1-DRD5), which are present in nearly all areas of the brain. DRD1 and DRD5 activate adenylyl cyclase and increase cAMP production. DRD2, DRD3 and DRD4 exert opposite effects and decrease cAMP production through inhibition of adenylyl cyclase activity. The above-mentioned effects are mediated by Gi-proteins .
The importance of dopamine in motor movement control is easiest to investigate in clinical conditions such as Parkinson's disease, ADHD (attention deficit hyperactivity disorder) or depression. Parkinson's disease comprises a range of problems such as muscular rigidity, resting tremor, difficulty with movement initiation (bradykinesia), slowness of voluntary movement, difficulty with balance and difficulty with walking. The underlying cause of the disease is loss of dopaminergic neurons in the substantia nigra of the basal ganglia. In patients with ADHD, hyperactivity derives from disturbances in dopamine signalling. Methylphenidate inhibits the reuptake of dopamine and is effective in controlling symptoms in 60-70% of ADHD patients. It has been found e.g. that specific genotypes of DRD4 and DRD5 are associated with increased risk of ADHD . It is also known that patients with depressive syndromes (low dopamine levels) benefit from regular exercise .
In experimental models, an increased level of dopamine within the midbrain stimulated locomotion , while a low level of dopamine resulted in hypoactivity .
In mice a positive relationship was observed between DRD2 deficiency and reduced locomotor activity . There are also convincing data indicating an association between DRD1 and PA . Expression of DRD1 was lower in high active as compared with low active mice . Application of an antagonist of D1 receptors decreased the level of voluntary PA in mice bred for high wheel running . Another study showed that selectively bred mice had higher expression of dopamine receptors DRD2 and DRD4 in the hippocampus than control lines .
Just recently there has been proposed a model of the central regulation of PA in which the dopamine system plays the key role . According to this model, low expression or impaired function of DRD1 and DRD5 increases the level of PA (through reduced inhibitory signalling), while high expression and intact function of DRD2, DRD3 and DRD4 have inhibitory effects on PA (through increased stimulatory transmission). At the same time, PA increases dopamine production and signalling.
Animal observations on the role of dopamine for locomotor activity were confirmed in human familial cohorts in the Quebec Family Study. There has been found an association between dopamine D2 receptor gene (DRD2) polymorphism and PA levels among white women. Heterozygotes or homozygotes C/C were more active than homozygotes T/T when evaluated by a questionnaire recalling PA in the previous year. However, no association was found in men or black women . Such findings are especially intriguing when one remembers that age-related deterioration in PA is - at least in part - dependent on the dopaminergic system . We could not prove the above-mentioned speculations in our own material (results in press).
The melanocortins (melanocyte-stimulating hormones, MSHs) are peptides that derive from proopiomelanocortin (POMC). POMC comprises three domains that contain forms of MSH: pro-[gamma]-MSH, ACTH and [beta]-lipotropin. MSHs exert their effects through five receptors (MC1-MC5). [alpha]-MSH and agouti-related protein (AgRP) are respectively an agonist and an antagonist of the brain melanocortin receptors [47,48]. MSHs influence a wide range of body functions: nervous, endocrine, immune and behavioural. MSHs stay in functional balance with opioids and are implicated as mediators of the central effects of leptin. MSHs have a prolonged, inhibitory effect on feeding in rodents and humans. Reduced activity of the CNS melanocortin system promotes reduced locomotor activity.
The status of CNS MC4R has been shown to influence the energy balance through direct effects on autonomic outflow and metabolism . Expression of MC4R is especially high in the hypothalamus and the spinal cord.
Interruption of the melanocortin signalling in the hypothalamus leads to reduced PA and obesity in mice. Male non-obese MC4R knockout mice are less physically active than wild-type controls . At the same time, administration of an antagonist of MC4R reduces spontaneous locomotor activity of rats .
Stimulation of MC4R increases PA/energy expenditure and leads to weight loss , while MC4R deficiency is the most common genetic cause of obesity .
Val103Ile is the most frequent polymorphism of MC4R that is linked with obesity [53,54]. In one study, subjects with the Val103Ile variant of the MC4R gene had higher energy expenditure than ones with the Val103Val variant. After a 3.5-year follow-up of a subgroup aged 70[+ or -]3 years (BMI 27.4[+ or -]4), subjects with 103Ile genotype gained weight whereas subjects with Val103Val genotype lost weight . The authors of another investigation found that a relatively infrequent G/A genotype of the Val103Ile MC4R polymorphism was negatively associated with average weight . It has been hypothesized that the Val103Ile polymorphism may be related to PA and parameters of the metabolic syndrome .
Lower levels of moderate/high PA and sedentary lifestyle were found in the T/T variant of the C-2745T polymorphism of MC4R gene. In a family study, T/T homozygous offspring (but not parents) had a lower level of PA and lower BMI than other variants. It was suggested that the T/T genotype could result in a weight gain in older years. The authors of the investigation pointed to the fact that T/T homozygotes were least physically active if they were concomitantly A/A homozygotes for the CART-A1475G variant. In turn they were most physically active if they carried the G allele of the CART-A1475G variant .
In our investigation performed in a sample of Polish men, there was no statistically significant association between the MC4R C-2745T polymorphism and the level of PA . T/T homozygotes led a more sedentary lifestyle and tended to be less physically active, but only in subgroups reporting a low or moderate amount of physical effort undertaken daily (these differences did not reach statistical significance).
The serotoninergic system plays an important role in human behaviour. Serotonin (5-HT) is a mediator in emotional disorders: depression, suicide, impulsive behaviour and aggression. It also affects temperature regulation, sensory perception and mood control. Many of these areas are controlled in concert with the central dopaminergic system. It is highly probable that effects of serotonin on locomotion are dependent on secondary effects on other neurotransmitter systems .
Acute exercise induces serotonin biosynthesis and release of brain serotonin . Animal studies suggest that interventions within the brain serotoninergic system affect motor control and locomotion. However, these relations are not elucidated yet. In an experimental model, dopamine transporter gene knockout mice displayed high levels of PA. Surprisingly, this feature could be attenuated by administration of selective 5-HT transporter inhibitor (fluoxetine) or 5-HT enhancers (5-hydroxytryptophan or L-tryptophan) .
The authors of another study showed that injecting an antagonist of the 5-[HT.sub.1B] receptor (RU 24969) into the substantia nigra of a rat causes rotary movements of the animal . It was also reported that stimulation of the 5-[HT.sub.1B] receptor with an active antagonist (CP 94253) may increase the locomotor activity of laboratory animals .
Our group has not observed relationships between the G861C polymorphism of the 5-[HT.sub.1B] serotonin receptor gene and the activity level in healthy men. However, in subjects presenting the lowest level of PA, the distribution of genotypes was different to that expected by the Hardy-Weinberg equilibrium .
It was hypothesized that deteriorating (after initial good effects) results of ADHD treatment with inhibitors of dopamine and noradrenaline reuptake indicate a role of 5-HT in these mechanisms . Serotonin, as well as dopamine, is supposed to increase PA in anorexia nervosa . On the other hand, exercise modulates serotonin signalling . However, to the best of our knowledge, there is no clear evidence that PA can modify serotonin or dopamine systems in such a way to prevent their age-related decline.
Increasing the level of PA remains the key target in the majority of health interventions. Unfortunately, effective tools to achieve this goal are still lacking.
Secretion and signalling within the central dopamine, serotonin and melanocortin systems reveal many interesting associations with locomotion and a propensity to be active. Animal observations offer promising areas for molecular investigation, though these models cannot be simply transferred to humans.
It is tempting to hypothesize that we could 'dose' and 'adjust' physical activity according to the genetic characteristics of a subject. Eg. carriers of BRCA1/ BRCA2 mutations are advised to undergo preventive mastectomy to avoid the development of breast cancer. Maybe efforts to maintain/increase the level of physical activity could be focused on subjects distinguished upon genetic examination? Newer methods allow scanning of the entire genome for associations with behavioural traits. Unfortunately, such an approach is not yet applicable to specific individuals in the foreseeable future.
Declaration of interest
The authors report no conflicts of interest.
(1.) Varo JJ, Martinez-Gonzalez MA, De Irala-Estevez J, et al. Distribution and determinants of sedentary lifestyles in the European Union. Int J Epidemiol 2003; 32(1): 138-46.
(2.) Kaleta D, Makowiec-Dabrowska T, Jegier A. Occupational and leisure-time energy expenditure and body mass index. Int J Occup Med Environ Health 2007; 20(1): 9-16.
(3.) Colditz GA. Economic costs of obesity and inactivity. Med Sci Sports Exerc 1999; 31(11): 663-7.
(4.) Hu FB, Willett WC, Li T, et al. Adiposity as compared with physical activity in predicting mortality among women. N Engl J Med 2004; 351(26): 2694-703.
(5.) Lauderdale DS. Adiposity and physical activity as predictors of mortality. N Engl J Med 2005; 352(13): 1381-4.
(6.) Kujala UM, Kaprio J, Koskenvuo M. Modifiable risk factors as predictors of all-cause mortality: the roles of genetics and childhood environment. Am J Epidemiol 2002; 156(11): 985-93.
(7.) Kujala UM, Kaprio J, Sarna S, et al. Relationship of leisure-time physical activity and mortality: the Finnish twin cohort. JAMA 1998; 279(6): 440-4.
(8.) Laufs U, Wassmann S, Czech T, et al. Physical inactivity increases oxidative stress, endothelial dysfunction, and atherosclerosis. Arterioscler Thromb Vasc Biol 2005; 25(4): 809-14.
(9.) Curioni CC, Lourenco PM. Long-term weight loss after diet and exercise: a systematic review. Int J Obes 2005; 29(10): 1168-74.
(10.) Laaksonen DE, Lindstrom J, Lakka TA, et al. Physical activity in the prevention of type 2 diabetes: the Finnish diabetes prevention study. Diabetes 2005; 54(1): 158-65.
(11.) Franco OH, de Laet C, Peeters A, et al. Effects of physical activity on life expectancy with cardiovascular disease. Arch Intern Med 2005; 165(20): 2355-60.
(12.) Tou JC, Wade CE. Determinants affecting physical activity levels in animal models. Exp Biol Med 2002; 227(8): 587-600.
(13.) Thorburn AW, Proietto J. Biological determinants of spontaneous physical activity. Obes Rev 2000; 1(2): 87-94.
(14.) Yanagita S, Amemiya S, Suzuki S, et al. Effects of spontaneous and forced running on activation of hypothalamic corticotropin-releasing hormone neurons in rats. Life Sci 2007; 80(4): 356-63.
(15.) Maes HH, Beunen GP, Vlietinck RF, et al. Inheritance of physical fitness in 10-yr-old twins and their parents. Med Sci Sports Exerc 1996; 28(12): 1479-91.
(16.) Rankinen T, Roth SM, Bray MS, et al. Advances in exercise, fitness, and performance genomics. Med Sci Sports Exerc 2010; 42(5): 835-46.
(17.) Kaprio J, Pulkkinen L, Rose RJ. Genetic and environmental factors in health-related behaviors: studies on Finnish twins and twin families. Twin Res 2002; 5(5): 366-71.
(18.) Simonen R, Levalahti E, Kaprio J, et al. Multivariate genetic analysis of lifetime exercise and environmental factors. Med Sci Sports Exerc 2004; 36(9): 1559-66.
(19.) Kalupahana NS, Moustaid-Moussa N, Kim JH, et al. The regulation of physical activity by genetic mechanisms: is there a drive to be active? In: Bouchard C, Hoffman EP, (ed.). Genetic and molecular aspects of sport performance. Chichester: Blackwell Publishing Ltd, 2011: 283-93.
(20.) Osborne KA, Robichon A, Burgess E, et al. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 1997; 277(5327): 834-6.
(21.) Koyner J, Demarest K, McCaughran J, et al. Identification and time dependence of quantitative trait loci for basal locomotor activity in the BXD recombinant inbred series and a B6D2 F2 intercross. Behav Genet 2000; 30(3): 159-70.
(22.) Radcliffe RA, Jones BC, Erwin VG. Mapping of provisional quantitative trait loci influencing temporal variation in locomotor activity in the LS x SS recombinant inbred strains. Behav Genet 1998; 28(1): 39-47.
(23.) Knab AM, Lightfoot JT. Does the difference between physically active and couch potato lie in the dopamine system? Int J Biol Sci 2010; 6(2): 133-50.
(24.) Maia JA, Thomis M, Beunen G. Genetic factors in physical activity levels: a twin study. Am J Prev Med 2002; 23(2): 87-91.
(25.) Frederiksen H, Christensen K. The influence of genetic factors on physical functioning and exercise in second half of life. Scand J Med Sci Sports 2003; 13(1): 9-18.
(26.) Beunen G, Thomis M. Genetic determinants of sports participation and daily physical activity. Int J Obes Relat Metab Disord 1999; 23(3): 55-63.
(27.) Perusse L, Tremblay A, Leblanc C, et al. Genetic and environmental influences on level of habitual physical activity and exercise participation. Am J Epidemiol 1989; 129(5): 1012-22.
(28.) Lauderdale DS, Fabsitz R, Meyer JM, et al. Familial determinants of moderate and intense physical activity: a twin study. Med Sci Sports Exerc 1997; 29(8): 1062-8.
(29.) Simonen RL, Videman T, Kaprio J, et al. Factors associated with exercise lifestyle--a study of monozygotic twins. Int J Sports Med 2003; 24(7): 499-505.
(30.) Simonen RL, Perusse L, Rankinen T, et al. Familial aggregation of physical activity levels in the Quebec Family Study. Med Sci Sports Exerc 2002; 34(7): 1137-42.
(31.) Toubro S, Sorensen TI, Ronn B, et al. Twenty-four-hour energy expenditure: the role of body composition, thyroid status, sympathetic activity, and family membership. J Clin Endocrinol Metab 1996; 81(7): 2670-4.
(32.) Rankinen T, Perusse L, Rauramaa R, et al. The human gene map for performance and health-related fitness phenotypes. Med Sci Sports Exerc 2001; 33(6): 855-67.
(33.) Rankinen T, Bray MS, Hagberg JM, et al. The human gene map for performance and health-related fitness phenotypes: the 2005 update. Med Sci Sports Exerc 2006; 38(11): 1863-88.
(34.) Viggiano D. The hyperactive syndrome: metanalysis of genetic alterations, pharmacological treatments and brain lesions which increase locomotor activity. Behav Brain Res 2008; 194(1): 1-14.
(35.) Meeusen R. Exercise and the brain: insight in new therapeutic modalities. Ann Transplant 2005; 10(4): 49-51.
(36.) Li D, Sham PC, Owen MJ, et al. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 2006; 15(14): 2276-84.
(37.) Ernst C, Olson AK, Pinel JP, et al. Antidepressant effects of exercise: evidence for an adult-neurogenesis hypothesis? J Psychiatry Neurosci 2006; 31(2): 84-92.
(38.) Tolliver BK, Carney JM. Comparison of cocaine and GBR 12935: effects on locomotor activity and stereotypy in two inbred mouse strains. Pharmacol Biochem Behav 1994; 48(3): 733-9.
(39.) Zhou QY, Palmiter RD. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 1995; 83(7): 1197-209.
(40.) Kelly MA, Rubinstein M, Phillips TJ, et al. Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 1998; 18(9): 3470-9.
(41.) Lightfoot JT, Turner MJ, Pomp D, et al. Quantitative trait loci for physical activity traits in mice. Physiol Genomics 2008; 32(3): 401-8.
(42.) Knab AM, Bowen RS, Hamilton AT, et al. Altered dopaminergic profiles: implications for the regulation of voluntary physical activity. Behav Brain Res 2009; 204(1): 147-52.
(43.) Rhodes JS, Garland T. Differential sensitivity to acute administration of Ritalin, apomorphine, SCH 23390, but not raclopride in mice selectively bred for hyperactive wheel-running behavior. Psychopharmacology (Berl) 2003; 167(3): 242-50.
(44.) Bronikowski AM, Rhodes JS, Garland T, et al. The evolution of gene expression in mouse hippocampus in response to selective breeding for increased locomotor activity. Evolution 2004; 58(9): 2079-86.
(45.) Simonen RL, Rankinen T, Perusse L, et al. A dopamine D2 receptor gene polymorphism and physical activity in two family studies. Physiol Behav 2003; 78(4-5): 751-7.
(46.) Roth GS, Joseph JA. Cellular and molecular mechanisms of impaired dopaminergic function during aging. Ann N Y Acad Sci 1994; 719: 129-35.
(47.) Adage T, Scheurink AJ, de Boer SF, et al. Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats. Neurosci 2001; 21(10): 3639-45.
(48.) Xiang Z, Litherland SA, Sorensen NB, et al. Pharmacological characterization of 40 human melanocortin-4 receptor polymorphisms with the endogenous proopiomelanocortin-derived agonists and the agouti-related protein (AGRP) antagonist. Biochemistry (Mosc) 2006; 45(23): 7277-88.
(49.) Bertolini A, Tacchi R, Vergoni AV. Brain effects of melanocortins. Pharmacol Res 2009; 59(1): 13-47.
(50.) Ste Marie L, Miura GI, Marsh DJ, et al. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci USA 2000; 97(22): 12339-44.
(51.) Marks DL, Ling N, Cone RD. Role of the central melanocortin system in cachexia. Cancer Res 2001; 61(4): 1432-8.
(52.) Stutzmann F, Tan K, Vatin V, et al. Prevalence of melanocortin-4 receptor deficiency in Europeans and their age-dependent penetrance in multigenerational pedigrees. Diabetes 2008; 57(9): 2511-8.
(53.) Geller F, Reichwald K, Dempfle A, et al. Melanocortin-4 receptor gene variant I103 is negatively associated with obesity. Am J Hum Genet 2004; 74(3): 572-81.
(54.) Young EH, Wareham NJ, Farooqi S, et al. The V103I polymorphism of the MC4R gene and obesity: population based studies and meta-analysis of 29 563 individuals. Int J Obes (Lond) 2007; 31(9): 1437-41.
(55.) Rutanen J, Pihlajamaki J, Karhapaa P, et al. The Val103Ile polymorphism of melanocortin-4 receptor regulates energy expenditure and weight gain. Obes Res 2004; 12(7): 1060-6.
(56.) Heid IM, Vollmert C, Hinney A, et al. Association of the 103I MC4R allele with decreased body mass in 7937 participants of two population based surveys. J Med Genet 2005; 42(4): 21.
(57.) Heid IM, Vollmert C, Kronenberg F, et al. Association of the MC4R V103I polymorphism with the metabolic syndrome: the KORA Study. Obesity (Silver Spring) 2008; 16(2): 369-76.
(58.) Loos RJ, Rankinen T, Tremblay A, et al. Melanocortin-4 receptor gene and physical activity in the Quebec Family Study. Int J Obes (Lond) 2005; 29(4): 420-8.
(59.) Jozkow P, Slowinska-Lisowska M, Laczmanski L, et al. Melanocortin-4 receptor gene polymorphism and the level of physical activity in men (HALS Study). Endocrine 2011; 39(1): 62-8.
(60.) Chaouloff F. Effects of acute physical exercise on central serotonergic systems. Med Sci Sports Exerc 1997; 29(1): 58-62.
(61.) Gainetdinov RR, Caron MG. Genetics of childhood disorders: XXIV. ADHD, part 8: hyperdopaminergic mice as an animal model of ADHD. J Am Acad Child Adolesc Psychiatry 2001; 40(3): 380-2.
(62.) Oberlander C, Hunt PF, Dumont C, et al. Dopamine independent rotational response to unilateral intranigral injection of serotonin. Life Sci 1981; 28(23): 2595-601.
(63.) Tatarczynska E, Antkiewicz-Michaluk L, Klodzinska A, et al. Antidepressant-like effect of the selective 5-HT1B receptor agonist CP 94253: a possible mechanism of action. Eur J Pharmacol 2005; 516(1): 46-50.
(64.) Haber E, Slowinska-Lisowska M, Jozkow P, et al. Relationships between the G861C polymorphism of the 5-HT1B serotonin receptor gene and the physical activity in men. Adv Clin Exp Med 2010; 19(4): 455-9.
(65.) Oades RD. Dopamine-serotonin interactions in attention--deficit hyperactivity disorder (ADHD). Prog Brain Res 2008; 172: 543-65.
Received: August 05, 2011
Accepted: March 15, 2012
Published: March 30, 2012
Address for correspondence:
Pawel Jozkow MD, PhD
Department of Sports Medicine and Nutrition
University School of Physical Education
ul. Paderewskiego 35,
51-612 Wroclaw, Poland
Tel.: +48 71 347 31 20
Fax: +48 71 347 30 53
Pawel Jozkow (1) (A,D,E,F,G), Malgorzata Slowinska-Lisowska (1) (D,E,G), Lukasz Laczmanski (2) (D,E), Marek Medras (1), (2) (D,E,G)
(1.) Department of Sports Medicine and Nutrition, University School of Physical Education, Wroclaw, Poland
(2.) Department of Endocrinology, Diabetology and Isotope Treatment, Wroclaw Medical University, Wroclaw, Poland
Malgorzata Slowinska-Lisowska: firstname.lastname@example.org
Lukasz Laczmanski: email@example.com
Marek Medras: firstname.lastname@example.org
A - Study Design
B - Data Collection
C - Statistical Analysis
D - Data Interpretation
E - Manuscript Preparation
F - Literature Search
G - Funds Collection
|Printer friendly Cite/link Email Feedback|
|Title Annotation:||REVIEW ARTICLE|
|Author:||Jozkow, Pawel; Slowinska-Lisowska, Malgorzata; Laczmanski, Lukasz; Medras, Marek|
|Date:||Mar 1, 2012|
|Previous Article:||Relationship between circulating osteocalcin and indices of lipid and carbohydrate metabolism in young women with ovulatory menstrual cycles.|
|Next Article:||Critical commentary: the nsca position statement on youth resistance training.|