REVIEW ARTICLE Sports Med 2012; 42 (5): 415-431 0112-1642/12/0005-0415/$49.95/0 Adis ª 2012 Springer International Publishing AG. All rights reserved. Effect of Acute Endurance and Resistance Exercise on Endocrine Hormones Directly Related to Lipolysis and Skeletal Muscle Protein Synthesis in Adult Individuals with Obesity Dominique Hansen,1,2,3 Romain Meeusen,4 Annelies Mullens5 and Paul Dendale1,2,3 1 2 3 4 5 Heart Centre Hasselt, Cardiovascular Medicine and Rehabilitation, Jessa Hospital, Hasselt, Belgium Rehabilitation Research Centre, PHL-University College, Hasselt, Belgium Faculty of Medicine, Hasselt University, Diepenbeek, Belgium Department of Human Physiology & Sportsmedicine, Vrije Universiteit Brussel, Brussels, Belgium Department of Endocrinology, Jessa Hospital, Hasselt, Belgium Contents Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Literature Search Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Impact of Acute Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1 Catecholamines: Epinephrine and Norepinephrine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Growth Hormone. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.3 Cortisol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.4 Insulin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.5 Atrial Natriuretic Peptide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.6 Endocrine Hormones which Remain to be Examined . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Can Disturbed Hormonal Responses to Acute Exercise be Reversed by Long-Term Exercise Intervention? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Need for Future Study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Abstract 415 416 417 417 417 423 424 425 427 427 429 429 429 In subjects with obesity, the implementation of long-term exercise intervention increases lean tissue mass and lowers adipose tissue mass. However, data indicate a blunted lipolytic response, and/or skeletal muscle protein synthesis, when subjects with obesity are exposed to acute endurance or resistance exercise, respectively. Therefore, subjects with obesity seem to display a suboptimal physiological response to acute exercise stimuli. It might be hypothesized that hormonal disturbances contribute, at least in part, to these abnormal physiological reactions in the obese. This review discusses the impact of acute endurance and resistance exercise on endocrine hormones directly related to Hansen et al. 416 lipolysis and/or skeletal muscle protein synthesis (insulin, [nor]epinephrine, cortisol, growth hormone, testosterone, triiodothyronine, atrial natriuretic peptide, insulin-like growth factor-1), as well as the impact of long-term endurance and resistance exercise intervention on these hormonal responses to acute endurance and resistance exercise. In the obese, some endocrinological disturbances during acute endurance and resistance exercise have been identified: a blunted blood growth hormone, atrial natriuretic peptide and epinephrine release, and greater cortisol and insulin release. These hormonal disturbances might contribute to a suppressed lipolytic response, and/or suppressed skeletal muscle protein synthesis, as a result of acute endurance or resistance exercise, respectively. In subjects with obesity, the impact of acute endurance and resistance exercise on other endocrine hormones (norepinephrine, testosterone, triiodothyronine, insulin-like growth factor-1) remains elusive. Furthermore, whether long-term endurance and resistance exercise intervention might reverse these hormonal disturbances during acute endurance and resistance exercise in these individuals remains unknown. 1. Introduction Besides caloric intake restriction and/or pharmacological support, the implementation of exercise intervention is a cornerstone in the care of patients with obesity. It has frequently been demonstrated that long-term exercise intervention effectively improves body composition (decrease in adipose tissue mass and/or increase in lean tissue mass) in the obese.[1] Moreover, exercise regimens additionally improve blood pressure and lipid profile, glycaemic control, and/or prevents the (further) development of obesity-related co-morbidities.[1] Even though acute endurance exercise stimulates lipolysis, and acute resistance exercise increases skeletal muscle protein synthesis, these responses seem blunted in the obese, as opposed to agematched lean controls.[2,3] Therefore, subjects who are obese display a suboptimal physiological response to acute exercise stimuli. Because a reduction in adipose tissue mass and an increase in lean tissue mass could be regarded as two important treatment goals during long-term exercise intervention in the obese, it is important to study the cause of these anomalies. The mobilization of fatty acids from adipocytes and increase in skeletal muscle protein synthesis due to acute exercise is, at least in part, governed by endocrine hormones. According to current literature, lipolysis is strongly related to endocrine Adis ª 2012 Springer International Publishing AG. All rights reserved. hormones such as insulin, growth hormone, triiodothyronine, atrial natriuretic peptide and/or catecholamine levels.[4,5] Skeletal muscle protein synthesis is strongly affected by anabolic and/or catabolic endocrine hormones such as insulin, testosterone, insulin-like growth factor-1 (IGF-1), growth hormone and cortisol.[6,7] It follows that the endocrinological response to acute exercise warrants examination to further understand the blunted lipolysis and/or skeletal muscle protein synthesis, as a result of acute exercise in the obese. It has to be mentioned that lipolysis during acute endurance exercise is, besides endocrine hormones, further governed by many other local, paracrine and/or autocrine factors. For example, it has been shown that lipolysis is also affected by genetic polymorphisms, amount and type of membrane receptors, intracellular adenosine monophosphate-activated protein kinase (AMPK) activation, intracellular lipolytic enzyme levels, cytokines, adipokines, adenosine, prostaglandin and lactate levels, to mention a few examples.[4,5] Consequently, the rate of lipolysis during acute exercise in the obese is related to many more determinants than endocrine hormones only. In analogy to lipolysis, skeletal muscle protein synthesis is, beside endocrine hormones, further governed by many other factors.[6] For example, it has been demonstrated that by manipulating blood testosterone and growth hormone concentrations in Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity humans, muscle mass gain, as a result of long-term resistance training, is not always affected as expected by these manipulations.[8] Data indicate that intrinsic and paracrine/autocrine factors and mechanotransduction processes are also of critical importance in the stimulation of skeletal muscle protein synthesis, due to acute resistance exercise.[6] Additionally, many hormonal interactions occur during acute exercise. A recent review highlights these complex inter-relationships.[9] In conclusion, when examining the impact of acute exercise on blood hormone levels, one has to take many other factors into account, such as macronutrient and total caloric intake, environmental factors (temperature, humidity, etc.), subjects’ factors (age, gender, ethnicity, body mass index [BMI], years of being obese, etc.). Evidently, it becomes clear that a review with full and complete examination of the hormonal response to acute exercise, with integration of all affecting local, paracrine/autocrine, environmental and subject-related factors in this hormonal response is unattainable. In order to prevent excessive complexity in this review, we will restrict our literature overview to the impact of acute endurance and resistance exercise on endocrine hormones in adult individuals with obesity, without a further in-depth exploration of hormonal inter-relationships, local factors, paracrine/autocrine factors, personal and environmental factors. Therefore, in this article, the endocrinological response to acute endurance or resistance exercise in adult subjects who are obese, but without diabetes mellitus, will be reviewed. This review is restricted to endocrine hormones that are known to significantly and directly affect lipolysis and/or skeletal muscle protein synthesis. Moreover, the authors examined whether blunted hormonal responses to acute exercise might be reversed by long-term exercise intervention in individuals with obesity. Such a review might contribute to a significantly greater understanding of exercise physiology and intervention in obesity. 2. Literature Search Methodology PubMed and the Cochrane Library was consulted up to March 2012, with a combination of the Adis ª 2012 Springer International Publishing AG. All rights reserved. 417 following keywords: ‘exercise’, ‘obesity’, ‘epinephrine’, ‘adrenaline’, ‘norepinephrine’, ‘noradrenaline’, ‘cortisol’, ‘growth hormone’, ‘testosterone’, ‘IGF-1’, ‘insulin’, ‘glucocorticoid’, ‘natriuretic peptide’ and ‘triiodothyronine’ (see figure 1). In addition, Google Scholar was consulted. Animal studies were a priori excluded. Seventy-four abstracts were carefully evaluated. The following inclusion criteria were used to select proper studies: human subjects who are obese (BMI >30 kg/m2) and adults (aged >18 years) had to be examined, subjects were not under a dietary regimen at the time of experiment, subjects were not diagnosed with diabetes and blood hormones had to be evaluated before, during and immediately after acute endurance or resistance exercise. Studies had to evaluate the changes in one or more of the following endocrine hormones: epinephrine, norepinephrine, cortisol, growth hormone, testosterone, IGF-1, insulin, atrial natriuretic peptide and triiodothyronine. These hormones were selected for this literature search because they are known to have a direct impact on lipolysis and/or skeletal muscle protein synthesis. Subsequently, hormones that do not directly affect lipolysis/skeletal muscle protein synthesis (such as satiety hormones) were not evaluated in this review. Moreover, the impact of acute endurance and resistance exercise on local and autocrine/paracrine factors (cytokines, adipokines) will not be examined in this manuscript. Exclusion of manuscripts from this review occurred when nonobese (BMI <30 kg/m2), non-adult (aged <18 years), and/or type 2 diabetes subjects were examined; when subjects followed a dietary intervention at the time of examination; and/or when no data on changes in endocrine hormones as a result of acute resistance or endurance exercise are presented. Eventually, 34 relevant full-text manuscripts were selected for further review, from which 24 were included in this review. Ten papers were excluded because they did not meet the inclusion criteria. 3. Impact of Acute Exercise 3.1 Catecholamines: Epinephrine and Norepinephrine Norepinephrine is synthesized at the sympathetic nervous fibre extremities, while both Sports Med 2012; 42 (5) Hansen et al. 418 Literature search with keywords up to March 2012 Exercise obesity glucocorticoid, n = 29 hits Exercise obesity adrenaline, n = 90 hits Exercise obesity noradrenaline, n = 93 hits Exercise obesity epinephrine, n = 86 hits Exercise obesity norepinephrine, n = 82 hits Exercise obesity insulin, n = 2226 hits Exercise obesity glucagon, n = 65 hits Exercise obesity testosterone, n = 78 hits Exercise obesity IGF-1, n = 67 hits Exercise obesity cortisol, n = 74 hits Exercise obesity growth hormone, n = 152 hits Exercise obesity triiodothyronine, n = 23 hits Exercise obesity thyroid hormone, n = 58 hits Exercise obesity natriuretic peptide, n = 20 hits References from papers checked Abstracts excluded when: - not evaluating adult subjects with obesity - non-English studies - data on hormones are lacking - impact of acute exercise not evaluated Full manuscript analysis, n = 34 Manuscripts further excluded because: - not comparing with healthy controls (n = 1) - hormonal changes during exercise not evaluated (n = 1) - patients with type 2 diabetes mellitus included (n = 1) - subjects not obese [BMI <30 kg/m2] (n = 4) - subjects who are obese under caloric intake restriction (n = 2) - subjects too young [<18 years] (n = 1) Manuscript inclusion, n = 24 Fig. 1. Literature study flowchart. BMI = body mass index; IGF-1 = insulin-like growth factor-1. norepinephrine and epinephrine are synthesized in the chromaffin cells of the adrenal gland medulla, as a response to direct stimulation from the sympathetic nervous system, adrenocorticotropic hormone and/or cortisol, in an enzymatic pathway that converts tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), which is subsequently Adis ª 2012 Springer International Publishing AG. All rights reserved. decarboxylated to dopamine.[10] Oxidation of dopamine initiates further conversion to norepinephrine, which is further methylated to epinephrine.[10] Norepinephrine is both a neurotransmitter as well as a hormone, while epinephrine is only a hormone. Norepinephrine and epinephrine are nonselective agonists of all Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity adrenergic receptors, including a1, a2, b1, b2 and b3 receptors.[10] Norepinephrine primarily activates a-receptors, while epinephrine primarily activates b-receptors, even though it also activates a-receptors at higher concentrations.[10] Binding to a-adrenergic receptors stimulates hepatic and skeletal muscle glycogenolysis and skeletal muscle glycolysis, and inhibits pancreatic insulin secretion, lipolysis and gastrointestinal arterial vasodilatation. Binding to the b-adrenergic receptor stimulates pancreatic insulin and pituitary gland adrenocorticotropic hormone secretion, increases cardiomyocyte contractility and skeletal muscle arterial vasodilatation, causes bronchial smooth muscle relaxation and stimulates lipolysis.[10] Catecholamines stimulate lipolysis by the selective binding to b1, b2 and b3 receptors. These receptors are coupled to stimulatory G-proteins that activate adenylate cyclase, contributing to an augmentation in cyclic AMP (cAMP) production.[4] Intracellular cAMP subsequently activates protein kinase A (PKA), leading to the activation of lipolysis stimulating enzymes (such as hormone-sensitive lipase, adipose triglyceride lipase and monoglyceride lipase).[4] On the other hand, lipolysis is inhibited by the selective binding of catecholamines to a2 receptors.[4] Therefore, the rate of lipolysis is significantly affected by the selective binding of catecholamines to b- or a2-receptors.[4] It is important to notice that b-receptors are predominantly present in visceral adipocytes, while a2-receptors are predominantly present in subcutaneous adipocytes.[4] In healthy subjects, acute exercise significantly increases blood catecholamine concentrations.[10] The increase in blood catecholamine concentrations seems mainly related to increased secretion, rather than lowered clearance or elimination.[10] Parallel to the activation of skeletal muscle, it seems that the increased secretion of catecholamines during acute exercise results from direct stimulation of driving centres of the brain (central order) to the adrenal glands.[10] This might explain the rapid change in blood catecholamine levels at the initiation of exercise, or even before initiating exercise (the mental preparation of the subject). Moreover, certain factors seem to affect Adis ª 2012 Springer International Publishing AG. All rights reserved. 419 the magnitude of this hormonal response to acute exercise: caffeine intake (generates greater blood catecholamine levels during exercise), familiarization to training or test mode (lowers blood catecholamine levels when subjects are accustomed to training/test mode), posture (greater increase in blood catecholamine content when exercising upright vs lying down), upper or lower extremity exercise (greater increase in blood catecholamine content when exercising with the arms vs legs), exercise duration (greater increase in blood catecholamine content when exercising for a prolonged period) and intensity (greater increase in blood catecholamine content when exercising at higher intensity).[10] Based on table I (12 studies, n = 103 subjects with obesity), it seems that acute endurance exercise results into lower,[11,14-18,20-22] equal[12,19] or higher[13] blood epinephrine concentrations in the obese, as opposed to their lean counterparts. Thus, most data seem to indicate a blunted increase in blood epinephrine concentration, as a result of acute endurance exercise in the obese, as opposed to healthy subjects. It is hypothesised that a blunted epinephrine release during an acute exercise bout in the obese is due to blunted sympathetic nervous activity.[12] The few reports that failed to find a significant difference in change in blood epinephrine content between individuals who are either obese and lean during acute endurance exercise did not deviate from other studies when considering gender, age, exercise modalities and BMI. Therefore, no apparent reason for the contradiction in results between studies could be found. Besides a blunted epinephrine release during acute endurance exercise in subjects with obesity, it has also been shown that lipolysis, especially from the visceral depot after adrenergic stimulation, is lowered in these subjects.[31] The latter might be a consequence of a decreased number and/or function of b2-adrenoreceptors, greater binding of catecholamines to a2-adrenoreceptors, reduced hormone-sensitive lipase, activity/expression, reduced aquaporin-7 expression and/or lower adipose tissue blood flow.[31] Blood norepinephrine concentrations seem elevated,[13,23] normal[12,16-19,22] or lower[11,14,15,20] during acute endurance exercise in the obese, as Sports Med 2012; 42 (5) Hansen et al. 420 Table I. Impact of acute endurance exercise on endocrine hormones in the obese vs normal-weight controls Study No. of subjects and sex (normal-weight controls) No. of subjects and sex (obese subjects) Exercise bout characteristics Found effect Berlin et al.[11] 8 F (BMI 21.1 kg/m2) 8 F (BMI 32.5 kg/m2) Suppressed increase in the obese, when compared with controls Ezell et al.[12] 5 obese F (BMI 20.6 kg/m2) 5 obese F (BMI 30.0 kg/m2) Giacca et al.[13] 7 M/F (BMI 23.2 kg/m2) 7 M/F (BMI 32.8 kg/m2) Gustafson et al.[14] 7 F (BMI 22.9 kg/m2) 7 F (BMI 48 kg/m2) Koppo et al.[15] 8 M (BMI 23.3 kg/m2) 8 M (BMI 33.5 kg/m2) Mittendorfer et al.[16] 5 M (BMI 21 kg/m2) 5 M (BMI 34 kg/m2) Incremental cycling test until exhaustion . Cycling at 60-65% VO2max for 60 min . Cycling at 50% VO2max for 45 min . Walking at 70% VO2max for 10 min . Cycling at 50% VO2max for 60 min . Cycling at 50% VO2max for 90 min Salvadori et al.[17] 12 M/F (22 kg/m2) 12 M/F (BMI 40 kg/m2) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Salvadori et al.[18] 12 M/F (BMI 22.2 kg/m2) 12 M/F (BMI 39.9 kg/m2) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Stich et al.[19] 7 M (BMI 23.2 kg/m2) 7 M (BMI 31.4 kg/m2) Cycling at 50% HRR for 60 min Equal increase in the obese vs controls Vettor et al.[20] 10 M/F (BMI 20 kg/m2) 9 M/F (BMI 32 kg/m2) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Weber et al.[21] 55 M/F (BMI 23.9 kg/m2) 21 M/F (BMI 31.8 kg/m2) Incremental treadmill walking test until exhaustion Suppressed increase in the obese, when compared with controls Yale et al.[22] 8 M/F (106% of ideal body weight) 12 M/F (193% of ideal body weight) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Berlin et al.[11] 8 F (BMI 21.1 kg/m2) 8 F (BMI 32.5 kg/m2) Suppressed increase in the obese, when compared with controls Ezell et al.[12] 5 obese F (BMI 20.6 kg/m2) 5 obese F (BMI 30.0 kg/m2) Giacca et al.[13] 7 M/F (BMI 23.2 kg/m2) 7 M/F (BMI 32.8 kg/m2) Goodpaster et al.[23] 7 M (BMI 23.7 kg/m2) 7 M (BMI 33.0 kg/m2) Gustafson et al.[14] 7 F (BMI 22.9 kg/m2) 7 F (BMI 48 kg/m2) Koppo et al.[15] 8 M (BMI 23.3 kg/m2) 8 M (BMI 33.5 kg/m2) Mittendorfer et al.[16] 5 M (BMI 21 kg/m2) 5 M (BMI 34 kg/m2) Incremental cycling test until exhaustion . Cycling at 60–65% VO2max for 60 min . Cycling at 50% VO2max for 45 min . Cycling at 50% VO2max for 60 min . Walking at 70% VO2max for 10 min . Cycling at 50% VO2max for 60 min . Cycling at 50% VO2max for 90 min Salvadori et al.[17] 12 M/F (BMI 22 kg/m2) 12 M/F (BMI 40 kg/m2) Incremental cycling test until exhaustion Equal increase in the obese vs controls Salvadori et al.[18] 12 M/F (BMI 22.2 kg/m2) 12 M/F (BMI 39.9 kg/m2) Incremental cycling test until exhaustion Equal increase in the obese vs controls Stich et al.[19] 7 M (BMI 23.2 kg/m2) 7 M (BMI 31.4 kg/m2) Cycling at 50% HRR for 60 min Equal increase in the obese vs controls Epinephrine Equal increase in the obese vs controls Elevated levels in the obese vs controls Suppressed increase in the obese, when compared with controls Suppressed increase in the obese, when compared with controls Suppressed increase in the obese, when compared with controls Norepinephrine Equal increase in the obese vs controls Elevated levels in the obese vs controls Elevated increase in the obese vs controls Suppressed increase in the obese, when compared with controls Suppressed increase in the obese, when compared with controls Equal increase in the obese vs controls Continued next page Adis ª 2012 Springer International Publishing AG. All rights reserved. Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity 421 Table I. Contd Study No. of subjects and sex (normal-weight controls) No. of subjects and sex (obese subjects) Exercise bout characteristics Found effect Vettor et al.[20] 10 M/F (BMI 20 kg/m2) 9 M/F (BMI 32 kg/m2) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Yale et al.[22] 8 M/F (106% of ideal body weight) 12 M/F (193% of ideal body weight) Incremental cycling test until exhaustion Equal increase in the obese vs controls Gossain et al.[24] 7 F (91% of ideal body weight) 6 F (168% of ideal body weight) Incremental cycling test until exhaustion Suppressed increase in the obese vs controls Bray et al.[25] 10 M (BMI 22.2 kg/m2) 10 M (BMI 33.7 kg/m2) No significant difference between the obese and controls Ezell et al.[12] 5 obese F (BMI 20.6 kg/m2) 5 obese F (BMI 30.0 kg/m2) Gustafson et al.[14] 7 F (BMI 22.9 kg/m2) 7 F (BMI 48 kg/m2) Kanaley et al.[26] 8 F (BMI 21.6 kg/m2) 23 F (BMI 32.2 and 33.3 kg/m2) Koppo et al.[15] 8 M (BMI 23.3 kg/m2) 8 M (BMI 33.5 kg/m2) Incremental cycling test/ treadmill walking test until exhaustion . Cycling at 60–65% VO2max for 60 min . Walking at 70% VO2max for 10 min . Walking at 70% VO2max for 30 min . Cycling at 50% VO2max for 60 min Hansen[27] 6 M (99% of normal body weight) 6 M (169% of normal body weight) 225 kgm/min for 60 min on bike No increase in the obese, while increase in controls Salvadori et al.[28] 8 M/F (BMI 22.1 kg/m2) 16 M/F (BMI 35.8 kg/m2) Incremental cycling test until exhaustion Suppressed increase in the obese, when compared with controls Vettor et al.[20] 10 M/F (BMI 20 kg/m2) 9 M/F (BMI 32 kg/m2) No increase in the obese, while increase in controls Weltman et al.[29] 8 M (BMI 23.3 kg/m2) 8 M (BMI 30.6 kg/m2) Incremental cycling test until exhaustion . Cycling at midway VT-VO2max for 30 min Wong and Harber[30] 6 M (BMI 21.7 kg/m2) 7 M (BMI 31.9 kg/m2) Giacca et al.[13] 7 M/F (BMI 23.2 kg/m2) 7 M/F (BMI 32.8 kg/m2) Gustafson et al.[14] 7 F (BMI 22.9 kg/m2) 7 F (BMI 48 kg/m2) Wong and Harber[30] 6 M (BMI 21.7 kg/m2) 7 M (BMI 31.9 kg/m2) Cycling at VT for 30 min Greater increase in the obese vs controls Bray et al.[25] 10 M (BMI 22.2 kg/m2) 10 M (BMI 33.7 kg/m2) Incremental cycling and walking test until exhaustion Decreases in the obese, but remains elevated as opposed to controls Ezell et al.[12] 5 obese F (BMI 20.6 kg/m2) 5 obese F (BMI 30.0 kg/m2) . Cycling at 60–65% VO2max for 60 min Giacca et al.[13] 7 M/F (BMI 23.2 kg/m2) 7 M/F (BMI 32.8 kg/m2) . Cycling at 50% VO2max for 45 min Goodpaster et al.[23] 7 M (BMI 23.7 kg/m2) 7 M (BMI 33.0 kg/m2) . Cycling at 50% VO2max for 60 min Growth hormone Cycling at VT for 30 min Equal increase in the obese vs controls No increase in the obese, while increase in controls Suppressed increase in the obese vs controls Suppressed increase in the obese, when compared with controls Suppressed increase in the obese vs controls Suppressed increase in the obese vs controls Cortisol . Cycling at 50% VO2max for 45 min . Walking at 70% VO2max for 10 min Greater increase in the obese vs controls Equal change in the obese, when compared with controls Insulin Decreases in the obese, but remains elevated as opposed to controls Decreases in the obese, but remains elevated as opposed to controls Decreases in the obese, but remains elevated as opposed to controls Continued next page Adis ª 2012 Springer International Publishing AG. All rights reserved. Sports Med 2012; 42 (5) Hansen et al. 422 Table I. Contd Study No. of subjects and sex (normal-weight controls) No. of subjects and sex (obese subjects) Exercise bout characteristics Found effect Gossain et al.[24] 7 F (91% of ideal body weight) 6 F (168% of ideal body weight) Incremental cycling test until exhaustion Decreases in the obese, but remains elevated as opposed to controls Gustafson et al.[14] 7 F (BMI 22.9 kg/m2) 7 F (BMI 48 kg/m2) . Walking at 70% VO2max for 10 min Koppo et al.[15] 8 M (BMI 23.3 kg/m2) 8 M (BMI 33.5 kg/m2) . Cycling at 50% VO2max for 60 min Mittendorfer et al.[16] 5 M (BMI 21 kg/m2) 5 M (BMI 34 kg/m2) . Cycling at 50% VO2max for 90 min Hansen[27] 6 M (99% of normal body weight) 6 M (169% of normal body weight) 225 kgm/min for 60 min on bike Remains elevated in the obese during exercise vs controls Salvadori et al.[17] 12 M/F (BMI 22 kg/m2) 12 M/F (BMI 40 kg/m2) Incremental cycling test until exhaustion Decreases in the obese and lean subjects Stich et al.[19] 7 M (BMI 23.2 kg/m2) 7 M (BMI 31.4 kg/m2) Cycling at 50% HRR for 60 min Decreases in the obese, but remains elevated as opposed to controls Vettor et al.[20] 10 M/F (BMI 20 kg/m2) 9 M/F (BMI 32 kg/m2) Incremental cycling test until exhaustion Decreases in the obese, but remains elevated as opposed to controls Yale et al.[22] 8 M/F (106% of ideal body weight) 12 M/F (193% of ideal body weight) Incremental cycling test until exhaustion No change in the obese and lean controls Decreases in the obese, but remains elevated as opposed to controls Decreases in the obese, but remains elevated as opposed to controls Decreases in the obese, but remains elevated as opposed to controls Atrial natriuretic peptide . No increase in the obese, while Cycling at 50% VO2max for increase in controls 60 min . BMI = body mass index; F = female; HRR = heart rate reserve; M = male; VO2max = maximal oxygen uptake; VT = ventilatory threshold. Koppo et al.[15] 8 M (BMI 23.3 kg/m2) 8 M (BMI 33.5 kg/m2) opposed to age-matched lean individuals (see table I, 12 studies, n = 99 subjects with obesity). It remains uncertain as to whether blood norepinephrine concentrations increase normally in the obese, due to acute endurance exercise. Explaining the contradiction in the literature is difficult: different gender, exercise type (walking or cycling), exercise intensity, nutrition, being in a fed or fasting condition, age, exercise capacity, essay used, etc., might all affect the impact of acute endurance exercise on blood norepinephrine content. As a result of 30 or 40 minutes of acute resistance exercise (six exercises, two sets of 10 repetitions at 85% of 1-repetition maximum [1-RM], and a third set with repetitions until exhaustion, or ten exercises, three sets of 10–12 repetitions at 70–75% of 1-RM), the increase in blood Adis ª 2012 Springer International Publishing AG. All rights reserved. epinephrine content seems reduced in the obese versus lean controls.[32,33] In studies that reported a reduced increase in blood epinephrine concentration during acute endurance and acute resistance exercise, we are in agreement that such an endocrinological anomaly is present in subjects with obesity. The impact of acute resistance exercise on blood norepinephrine content in the obese seems more difficult to interpret. In one study, the increase of this hormone in the circulation is equal between subjects who are lean or obese (ten exercises, three sets of 10–12 repetitions at 70–75% of 1-RM),[33] while another study (six exercises, two sets of 10 repetitions at 85% of 1-RM, and a third set with repetitions until exhaustion) found a greater increase in subjects with obesity versus lean subjects.[32] Further Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity study seems warranted to elucidate the contradiction in results between studies. Because a reduced epinephrine secretion is present in the obese during acute endurance and resistance exercise, this may contribute to a lowered lipolytic response. Such an anomaly might lower the loss of adipose tissue mass during longterm exercise intervention. In conclusion, during acute endurance and resistance exercise, blood epinephrine release in the obese is smaller, when compared with healthy subjects. The impact of acute endurance and resistance exercise on blood norepinephrine content in the obese subjects remains uncertain. 3.2 Growth Hormone Growth hormone is synthesized, stored and secreted by the somatotrophic cells within the anterior pituitary gland, after stimulation from the growth-hormone releasing hormone and/or suppression of somatostatin, growth hormone itself or IGF-1 release.[34] Moreover, studies suggest that ghrelin might be able to increase growth hormone release from the adenohypophysis in basal conditions, even though the contribution of ghrelin to growth hormone release during exercise seems less consequential.[35] It is important to regard growth hormone as a family of hormones because growth hormone is released from different types of somatotrophs that will give rise to different types (>100 forms) of secretory products.[34] Growth hormone is secreted in a pulsatile manner throughout the day, but the majority of this hormone is released at night.[34] Such pulsatile release seems, at least in part, to determine the magnitude of metabolic and growth-promoting effects.[36] Growth hormone exerts many effects on human physiology, such as the regulation of reproductive and neural function, increase in IGF-1 release, stimulation of calcium retention, longitudinal bone growth and organogenesis, inhibition of skeletal muscle and adipocyte glucose uptake and stimulation of hepatic gluconeogenesis (which will result in an elevation of blood glucose content). Moreover, growth hormone is believed to stimulate skeletal muscle protein synthesis indirectly, by facilitatAdis ª 2012 Springer International Publishing AG. All rights reserved. 423 ing amino acid transport and availability via the release of IGF-1 and/or local hormonal factors.[34] In conclusion, lipolysis, mainly of visceral adipocytes, is stimulated by growth hormone by various mechanisms: increasing the sensitivity of adipocyte b-receptors (for catecholamines), stimulating lipolytic enzymes (such as hormone-sensitive lipase) and/or inhibiting triglyceride storing enzymes (such as fatty acid synthase, lipoprotein lipase, or acetylCoA carboxylase).[34,37] During acute exercise, growth hormone is an important mediator of physiological adaptations. Growth hormone levels start to increase immediately after the onset of endurance or resistance exercise, and decreases again immediately after exercise cessation.[34] Greater growth hormone release during acute exercise is anticipated in younger subjects with greater physical fitness, in different environmental conditions and during exercise at greater intensity, longer duration and/or with greater repetition.[38] Moreover, the magnitude of growth hormone release during acute endurance or resistance exercise is confounded by nutrition, amount of sleep, gender and prior exercise.[34] In females, different changes in blood growth hormone content have been observed when executing resistance exercises during a different period in the menstrual cycle.[34] Therefore, even within the same individual, different growth hormone levels can be detected when executing endurance or resistance exercises with different modalities, and/or when executing such exercises under various conditions. After reviewing the literature, it seems that blood growth hormone secretion during acute endurance exercise is severely reduced in subjects with obesity,[14,15,24,26-30] when compared with their lean counterparts (table I, nine studies, n = 90 subjects with obesity). This finding has been noted during cycling and walking exercise, in males and females, at various continuous exercise intensities (from . 50% up to 70% of maximal oxygen uptake [VO2max]), as well as during incremental exercise testing until exhaustion. Only a few studies failed to reproduce these findings[12,25] (two studies, n = 15 subjects with obesity). It remains speculative as to why the latter studies failed to find a significantly different growth Sports Med 2012; 42 (5) Hansen et al. 424 hormone response during acute endurance exercise between subjects who are lean versus obese. In addition, as a result of a 40-minute bout of resistance exercise (six exercises, two sets of 10 repetitions at 85% of 1-RM, and a third set with repetitions until exhaustion), growth hormone secretion is significantly reduced in obese subjects, as opposed to their lean counterparts.[32] A recent study also found a significant reduction in the release of bioactive growth hormone in obese subjects after a bout of acute resistance exercise (six exercises, three sets of 10 repetitions at 85–95% of 1-RM), but not of immunoreactive growth hormone.[39] This study thus indicated that a distinction between bioactive and immunoreactive growth hormone should be made when evaluating the impact of acute exercise. Moreover, recent reviews also point out that the detection of growth hormone changes during acute exercise seems significantly different when using divergent detection techniques.[34] Therefore, laboratories examining growth hormone responses during various forms of acute exercise in different populations should carefully decide what detection method to use. Data indicate that this blunted response is related to a reduced hormone release per pulse, and/or lowered halflife of the hormone, but with a normal number of hormone pulses.[26,36] A lowered growth hormone release in subjects with obesity during acute exercise might result from an elevated blood free-fatty acid level (which inhibits growth hormone release), and/or normal plasma IGF-1 levels (despite lower growth hormone release, individuals with obesity seem to produce adequate amounts of IGF-1 by enlarged adipocytes, which will inhibit growth hormone release).[37] Moreover, it is speculated that the amount of growth hormone released during acute exercise is strongly related to the visceral fat mass, regardless of gender and age.[29] A reduced blood growth hormone release in obesity as a response to acute endurance or resistance exercise may have important clinical consequences, as growth hormone stimulates lipolysis and skeletal muscle protein synthesis. It follows that a deficient growth hormone secretion during acute exercise in the obese might lower the loss in Adis ª 2012 Springer International Publishing AG. All rights reserved. adipose tissue mass and/or increase in lean tissue mass during long-term exercise intervention. In conclusion, blood growth hormone secretion is significantly reduced in the obese during acute endurance and/or resistance exercise, as opposed to healthy subjects. 3.3 Cortisol Cortisol is synthesized from cholesterol by the adrenal gland in the adrenal cortex zona fasciculata.[40] The secretion of corticotropin-releasing hormone by the hypothalamus triggers pituitary secretion of the adrenocorticotropic hormone.[40] The adrenocorticotropic hormone triggers glucocorticoid secretion at the adrenal cortex.[40] The amount of cortisol present in the blood undergoes diurnal variation; the cortisol level peaks in the early morning and reaches its lowest level at about midnight, or 3–5 hours after the onset of sleep.[40] Cortisol has a profound acute impact on glucose metabolism; it increases blood glucose levels by mobilizing amino acids and subsequent conversion to glucose and glycogen by gluconeogenesis.[40] Moreover, cortisol acutely stimulates lipolysis in the periphery.[40] Such stimulation results from an elevation of intracellular cAMP production, and consequently activates protein kinase A, which finally activates hormone-sensitive lipase and adipose triglyceride lipase.[41] Furthermore, cortisol seems to stimulate the phosphorylation of perilipin, a lipid-droplet-associating protein that modulates lipolysis.[41] In addition, many other organs are targets to the action of cortisol (skeletal muscle, bone, skin, viscera, haematopoeitic and lymphoid tissue, central nervous system) on which this hormone has multiple actions: reduced immune and inflammatory reaction, suppression of bone formation, impairment of gastrointestinal calcium uptake and/or alteration of mood and cognition.[40] In skeletal muscle, cortisol causes muscle mass loss by a combination of a suppression of protein synthesis and augmentation of protein breakdown. The inhibition of skeletal muscle protein synthesis from cortisol action seems to result from a lowered transport of amino acids into the muscle, inhibition of insulin and IGF-1 action, and/or inhibition of phosphorylation Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity of eIF4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1).[42] The stimulatory effect of cortisol on muscle protein breakdown results from the activation of cellular proteolytic systems: ubiquitin-proteasome system (UPS), lysosomal system (cathepsins) and calcium-dependent system (calpains).[42] In healthy subjects, physical exercise is considered as a physiologically stressful situation to the body, which activates the hypothalamicpituitary-adrenal axis; elevated secretion rates of corticotropin-releasing hormone lead to hypersecretion of adrenocorticotropic hormone and cortisol.[40] Therefore, hypercortisolaemia can occur during acute endurance and resistance exercise,[40,43] especially during vigorous-intensity exercise, even though highly-trained individuals display a lower blood cortisol release during acute endurance exercise, as opposed to sedentary subjects.[40] A greater release during acute endurance exercise can be expected in case of higher exercise intensities, prolonged exercise and/or anxiety/psychological stress, while a lower cortisol release is seen in subjects with clinical depression and/or anorexia nervosa.[40,44] During acute resistance exercise, cortisol release seems to be affected by the type of resistance training (hypertrophic vs maximal strength), previous longterm sports participation and neuromuscular performance.[44] The acute impact of endurance exercise on blood cortisol levels in subjects who are obese has been examined in a few studies (see table I, three studies, n = 21 subjects with obesity). A significantly greater blood cortisol release is found in the obese when cycling at the ventilatory thres. hold for 30 minutes, or at 50% of VO2max for 45 minutes, as opposed to healthy subjects.[13,30] On the other hand, one study finds similar changes in blood cortisol levels in subjects. who are obese or lean when walking at 70% of VO2max for 10 minutes.[14] It is speculated that prolonged exercise is necessary to effectively increase blood cortisol levels.[40] It follows that the Gustafson et al.[14] study might have applied an acute exercise bout with insufficient duration to detect a significantly different endocrinological response between subjects who are obese or lean. Adis ª 2012 Springer International Publishing AG. All rights reserved. 425 To our knowledge, the acute impact of resistance exercise on blood cortisol levels in the obese has been studied in two studies (ten exercises, three sets of 10–12 repetitions at 70–75% of 1-RM, or six exercises, three sets of ten repetitions at 85-95% of 10RM).[33,45] In one study, blood cortisol levels increase significantly in the obese after 30 minutes of resistance exercise, while no significant change was observed in lean subjects.[33] Another study failed to find a significantly different blood cortisol content between lean and obese males immediately after an acute resistance exercise bout.[45] More studies are warranted to examine the impact of acute resistance on blood cortisol level in subjects with obesity. A greater blood cortisol level during acute endurance exercise in subjects with obesity, as opposed to healthy controls, might be clinically relevant. This finding suggests a greater physiological stress reaction during acute exercise in individuals who are obese, leading to a greater stimulation of skeletal muscle protein catabolism but, also, to a greater lipolytic response. However, more studies should to be initiated to examine the impact of acute exercise on blood cortisol content in subjects with obesity. In conclusion, during acute endurance exercise, a greater blood cortisol level seems present in the obese, as opposed to healthy controls. 3.4 Insulin Insulin is a central glucose and fatty acid regulating hormone, and is secreted by pancreatic b-cells of the islets of Langerhans. Insulin exerts many actions, such as an increase in skeletal muscle and hepatic glycogen synthesis and lower glycogenolysis, an increase in adipocyte fatty acid storage and fatty acid esterification, a decrease in hepatic protein degradation, and an increase in amino acid uptake. The synthesis and secretion of insulin is complex and controlled by humoral communication (such as blood glucose, amino acids), hormones (such as glucagon-like peptide-1 and gastric inhibitory polypeptide), pancreatic cell-to-cell communication and neural communication (cholinergic stimulation augments insulin release, while adrenergic stimulation can both have an inhibitory and stimulatory effect).[46] Sports Med 2012; 42 (5) 426 Insulin inhibits lipolysis by the stimulation of the activity of phosphodiesterase-3B, which subsequently degrades cAMP.[4] Such degrading will lead to a lower activation of lipolytic enzymes due to protein kinase A activation being lowered. Moreover, insulin suppresses the expression of adipose triglyceride lipase, probably via the transcription factor FoxO1.[4] In analogy to catecholamines, the effect of insulin on lipolysis is different according to various adipose tissue depots: the antilipolytic effect of insulin is blunted in visceral compared with subcutaneous adipocytes.[31] In addition, insulin stimulates skeletal muscle protein synthesis. Insulin binds to its receptor on the skeletal muscle cell, hereby phosphorylating the insulin receptor substrates 1 and 2. The phosphorylated insulin receptor substrates bind to the 85 kDa subunit of PI3K, which results in the activation of the kinase and PI3K-mTOR signalling pathway.[47] During exercise, glucoregulation is tightly controlled by changes in blood insulin levels. Because of a greater glucose uptake through an enhanced insulin sensitivity, and greater glucose uptake by non-insulin dependent pathways (other mechanisms increasing GLUT-4 translocation activity),[48] pancreatic insulin release has to lower, especially during prolonged exercise, to allow greater hepatic glucose synthesis and release, and prevent hypoglycaemia.[49] Consequently, in healthy subjects, blood insulin levels lower slowly during acute endurance exercise, especially during prolonged exercise. In subjects with obesity, exercise is often prescribed to lower the insulin resistant and/or hyperinsulinaemic state. In accordance, in table I (13 studies, n = 101 subjects with obesity), it can be observed that acute endurance exercise significantly lowers blood insulin levels, especially during prolonged exercise.[12-17,19,20,23-25,27] However, despite a significant decrease in blood insulin levels during acute endurance exercise, a state of hyperinsulinaemia remains present in the obese, even after prolonged exercise (90 min).[16] The hyperinsulinaemic state during exercise in subjects with obesity could be related to persistent skeletal muscle insulin resistance. A number of contributing factors to skeletal muscle insulin Adis ª 2012 Springer International Publishing AG. All rights reserved. Hansen et al. resistance in individuals with obesity have been proposed as follows: increased fatty acid uptake (by a higher concentration of cell membrane fatty acid transport proteins) and therefore accumulation of fatty acids and metabolites, lowered lipid oxidation capacity (by lowered activity of enzymes involved in lipid oxidation), defects in insulinsignalling pathways (such as GLUT-4 translocation) and/or defects in mitochondria (lowered density and/or morphological defects).[50] Consequently, in the obese, greater insulin levels seem necessary to overcome skeletal muscle insulin resistance, even during exercise. Because of the antilipolytic capabilities of insulin, the reduced release of free-fatty acids from the adipocytes is, at least in part, related to this hyperinsulinaemic state. As a result of acute resistance exercise, the development of acute hyperinsulinaemia has been discovered in the obese. When executing 30 minutes (ten exercises, three sets of 10–12 repetitions at 70–75% of 1-RM) or 40 minutes (six exercises, two sets of 10 repetitions at 85% of 1-RM, and a third set with repetitions until exhaustion) of resistance exercise, or executing six resistance exercises, three sets of ten repetitions at 85–95% of 10-RM, blood insulin content increases significantly in subjects with obesity, while no change, or a much smaller increase, occurred in their lean counterparts.[32,33,45] The authors speculated that a reduced skeletal muscle insulin sensitivity in the obese contributed to this effect.[32] The first data therefore indicate that the hyperinsulinaemic state that is present before exercise in the obese, is worsened during acute resistance exercise in the obese. The latter might contribute to a suppressed lipolysis during acute resistance exercise, but also to an enhanced skeletal muscle protein synthesis. The hyperinsulinaemic state that is often prevalent during acute endurance and resistance exercise in individuals with obesity might blunt lipolysis, and therefore lower the impact of exercise intervention on adipose tissue mass. On the other hand, a state of hyperinsulinaemia might promote skeletal muscle protein synthesis when executing resistance exercises. In conclusion, as a result of acute endurance exercise, blood insulin levels decrease significantly Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity in the obese, even though a hyperinsulinaemic state remains present and in acute resistance exercise, the state of hyperinsulinaemia might be worsened. 3.5 Atrial Natriuretic Peptide Until recently, it was assumed that lipolysis was exclusively mediated by the cAMP-dependent protein kinase-regulated pathway. However, during the last decade, an endocrine messenger in the control of lipolysis has been discovered that exerts its effect through another mechanism: atrial natriuretic peptide. Atrial natriuretic peptide is a peptide hormone, structurally similar to B-type natriuretic peptide and C-type natriuretic peptide, but genetically distinct.[51] Atrial natriuretic peptide is secreted by atrial cardiomyocytes after distension of these cells, with a relatively short half-life (2–5 minutes). However, the magnitude of the release of atrial natriuretic peptide from the atrial cardiomyocytes is further mediated by endothelin-1, a-adrenergic agonists, and/or angiotensin II.[51] Currently, more of these mediating molecules remain to be discovered.[51] Atrial natriuretic peptide regulates a variety of physiological events: it affects diuresis and natriuresis, vasodilation, myocardial relaxation, and exerts cytoprotective, antihypertrophic and antifibrotic actions on cardiomyocytes and cardiac fibroblasts.[52] Moreover, atrial natriuretic peptide facilitates lipolysis, but not through the ‘traditional’ activation of the cAMP-dependent protein kinase pathway. On the contrary, atrial natriuretic peptide binds to the type A-NP receptor (NPR-A), located on the adipocyte membrane.[52] Next, atrial natriuretic peptide stimulates NPR-Adependent guanylyl cyclase activity and cGMP production. Subsequently, cGMP contributes to the protein kinase-dependent phosphorylation of hormone-sensitive lipase and perilipin.[52] As a result of acute endurance or resistance exercise the heart rate increases, as well as the stretch on atrial cardiomyocytes; therefore, atrial natriuretic peptide blood levels rise rapidly after initiation of exercise, and decrease rapidly after cessation of exercise because of the short halfAdis ª 2012 Springer International Publishing AG. All rights reserved. 427 life.[52,53] In accordance, lipolysis is initiated when adipocytes are being exposed to greater atrial natriuretic peptide levels.[52,53] Because of its recent discovery, more studies are warranted to examine the impact of various conditions, training modalities, and local factors on the change in atrial natriuretic peptide levels during acute exercise in healthy subjects. The impact of acute exercise on blood atrial natriuretic peptide levels has only been studied recently in subjects with obesity (see table I, one study, n = 8 obese men). By executing 60 minutes . of cycling at 50% of the VO2max, it has been observed that the atrial natriuretic peptide level did not increase as a result of this acute exercise bout in male obese individuals, while a significant increase in blood atrial natriuretic peptide level was found in male lean controls.[15] It was hypothesized that the lack of an increase in blood atrial natriuretic peptide levels, due to acute endurance exercise in the obese, resulted from a reduced atrial natriuretic peptide secretion and/ or increased atrial natriuretic peptide clearance because of more natriuretic peptide-clearance receptors, which are located on adipocytes. Further studies are warranted to examine the impact of acute endurance and resistance exercise on blood atrial natriuretic peptide levels in the obese. In conclusion, the first data that are available indicate that blood atrial natriuretic peptide levels do not increase with sufficient magnitude in subjects with obesity as a result of acute endurance exercise, which might contribute to a suppression of lipolysis during exercise. 3.6 Endocrine Hormones which Remain to be Examined In the obese, the impact of acute endurance and resistance exercise on blood IGF-1, triiodothyronine and testosterone have not yet been examined. IGF-1, also referred to as somatomedin-c, is synthesized and released from the liver after stimulation from the growth hormone.[54] Recent evidence indicates that IGF-1 might also be produced by skeletal muscle (also known as mechano growth factor) and/or bone cells.[54,55] It Sports Med 2012; 42 (5) 428 is believed that IGF-1 regulates somatic growth and development (such as skeletal muscle protein synthesis), cell replication and/or differentiation.[55] IGF-1 stimulates skeletal muscle protein synthesis in part by stimulating the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, resulting in a downstream activation of targets that induce protein synthesis (such as TORC1/p70S6K proteins).[56] Moreover, IGF-1 contributes to the maintenance of skeletal muscle mass by inhibiting skeletal muscle atrophy pathways.[56] As a result of acute endurance exercise, blood IGF-1 content increases significantly in healthy subjects, even though the impact of different training modalities and other factors remains to be examined in greater detail.[55] The impact of acute resistance exercise on blood IGF-1 content in healthy subjects is unclear. Many studies report a significant increase in the circulatory IGF-1 content, while others fail to reproduce these findings.[54] In addition, it is uncertain whether acute exerciseinduced changes in blood IGF-1 concentrations are dependent on gender, training modalities or other factors.[54] Triiodothyronine and its prohormone thyroxine are released from the thyroid gland after stimulation from thyroid-stimulating hormone[57] and is the metabolically active hormone that is produced from thyroxine, which is deiodinated by two deiodinase enzymes to triiodothyronine.[57] Triiodothyronine is bound to plasma proteins in the circulation and has a half-life of about 2.5 days. Triiodothyronine is a hormone with many actions: increase in basal metabolic rate, protein synthesis and degradation, gluconeogenesis, cardiomyocyte contractility and neurogenesis.[57] Lipolysis is stimulated by triiodothyronine through the activation of lipolytic enzymes (such as hormonesensitive lipase) and/or by an increase of the lipolytic action of other hormones (such as growth hormone and catecholamines).[57] Presently, impact of acute endurance exercise on blood triiodothyronine content remains uncertain; some authors found acute increase in blood triiodothyronine content as a result of acute endurance exercise,[58] while others did not.[59] Because of the few data that are available, further study needs to be performed in order to understand the impact of Adis ª 2012 Springer International Publishing AG. All rights reserved. Hansen et al. acute endurance and resistance exercise on blood triiodothyronine content. Testosterone is a steroid hormone, produced after multiple conversions of cholesterol, catalyzed by specific enzymes.[60,61] Several hormones, such as dihydroepiandrosterone and androstenedione, are intermediate products of this process. Testosterone production is governed by hypothalamic release of gonadotrophin releasing hormone, followed by the subsequent release of follicle-stimulating and luteinizing hormone by the anterior pituitary gland into the circulation.[60,61] The Leydig cells in the testes are the primary production sites of testosterone, even though testosterone is also produced in the zona reticularis of the adrenal cortex and/or ovaries.[60,61] Eventually, testosterone is secreted in the circulation, from which most molecules are bound to albumin or sex-hormone binding globuline, with only a small fraction as free testosterone.[60,61] Testosterone has many biological effects, such as the development of secondary male sexual characteristics, support of spermatogenesis, increase in insulin sensitivity and/or promotion of ossification.[60,61] The stimulation of skeletal muscle protein synthesis and inhibition of protein degradation by testosterone, seems to be the result of an increased amino-acid uptake into the cell, binding of this hormone to intracellular androgen receptors (causing transcription of specific genes), increase in IGF-1 production and/or inhibition of cortisol signalling;[61] therefore, in acute endurance exercise, testosterone release is significantly enhanced in healthy subjects, especially in males.[60] However, in acute resistance exercise, a significant increase in blood testosterone content has been observed in healthy men, while the impact of this training mode in healthy women is unclear.[61] Moreover, certain training modalities/subject characteristics may affect the magnitude of the change in blood testosterone content due to acute resistance exercise: intensity and volume, choice and/or order of exercise, rest period duration, training status, nutrition and/or age.[60,61] In conclusion, in healthy individuals, acute endurance exercise significantly increases blood IGF-1 and testosterone content, while its impact on blood triiodothyronine content is unclear. Sports Med 2012; 42 (5) Exercise Endocrinology in Obesity During acute resistance exercise, the impact on blood IGF-1 and triiodothyronine levels are uncertain, while a significant increase in blood testosterone level has been shown in males. The effects of acute endurance and resistance exercise on these endocrine hormones need further examination in the obese. 4. Can Disturbed Hormonal Responses to Acute Exercise be Reversed by Long-Term Exercise Intervention? From the findings in section 3, we can conclude that acute endurance and resistance exercise in subjects who are obese is characterized by the following endocrinological anomalies: elevated blood insulin and cortisol levels, and blunted blood growth hormone, atrial natriuretic peptide and epinephrine release. It is relevant to examine whether long-term exercise intervention reverses these endocrinological abnormalities during an acute bout of endurance or resistance exercise in the obese. Unfortunately, to our knowledge, only two studies have examined the impact of longterm exercise intervention on the endocrine hormonal response to acute exercise in individuals who are obese.[26,28] In these studies, individuals with obesity were included into a 4-week (12 · 30 minute exercise session at 70% of maximal heart rate, or 12 · 30 minute exercise session from 70% to 85% of maximal heart rate) and a 16-week endurance exercise intervention (48 · 20-40 minute exercise bouts at 65–80% of maximal heart rate) without caloric intake restriction.[26,28] In both studies, blood growth hormone levels were evaluated. As a result of the long-term exercise intervention, the blunted growth hormone release during acute endurance exercise at entry of intervention, as opposed to healthy controls, could not be entirely reversed,[28] or could not be reversed at all.[26] It follows that the first data that are available on the impact of long-term exercise intervention on hormonal response to acute endurance exercise in the obese, indicate that these hormonal abnormalities might not be reversed that easily. On the other hand, it has been shown that a significant weight loss might contribute to the normalization Adis ª 2012 Springer International Publishing AG. All rights reserved. 429 of basal blood growth hormone content in the obese.[62,63] So it seems that obese subjects probably need to lose a significant amount of body weight before a restoration of endocrine function can be detected, which can be achieved through long-term exercise intervention. The impact of a long-term exercise intervention on the change in blood insulin, cortisol, atrial natriuretic peptide and epinephrine concentrations during acute endurance exercise for the obese need to be examined. Moreover, data on the impact of long-term resistance exercise intervention on the hormonal response to acute resistance exercise in individuals with obesity are, to our knowledge, not available. 5. Need for Future Study From this review, it is apparent that there is a need for further study, particularly for the changes in blood testosterone, IGF-1 and triiodothyronine that result from acute endurance and resistance exercise in obese individuals. With this in mind, mechanistic studies should be initiated to explain the aetiology of hormonal anomalies during acute endurance and resistance exercise in these individuals. Further, it remains to be addressed whether hormonal anomalies during acute endurance and resistance exercise can be normalized by means of long-term exercise endurance and resistance exercise interventions. Finally, factors that affect the hormonal response (local, paracrine, autocrine, environmental, subject related, exercise modalities, etc.) during an acute exercise bout in subjects with obesity should be further examined. 6. Conclusion In the obese, some endocrinological disturbances during acute endurance and resistance exercise have been identified: a blunted blood growth hormone, atrial natriuretic peptide and epinephrine release, greater cortisol release, and hyperinsulinaemia. The impact of acute endurance and resistance exercise on many other hormones in obese subjects remains elusive. Furthermore, whether long-term exercise endurance and resistance exercise Sports Med 2012; 42 (5) Hansen et al. 430 intervention might reverse these hormonal disturbances during acute endurance and resistance exercise remains unknown. Acknowledgements This study was funded by a research grant from Hartcentrum Hasselt, Belgium. The authors declare that they have no conflicts of interest. References 1. Hansen D, Dendale P, van Loon LJC, et al. The effects of training modalities on clinical benefits of exercise intervention in cardiovascular disease risk patients or type 2 diabetes mellitus. Sports Med 2010 Nov; 40 (11): 921-40 2. Horowitz JF. Regulation of lipid mobilization and oxidation during exercise in obesity. Exerc Sports Sci Rev 2001; 29 (1): 42-6 3. Augert G, Monier S, Le Marchand-Brustel Y. Effect of exercise on protein turnover in muscles of lean and obese mice. Diabetologia 1986 Apr; 29 (4): 248-53 4. Kolditz CI, Langin D. Adopise tissue lipolysis. 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