Fat metabolism during high-intensity exercise in endurance-trained and untrained men

To determine whether trained individuals rely more on fat than untrained persons during high-intensity exercise, six endurance-trained men and six untrained men were studied during 30 minutes of exercise at 75% to 80% maximal oxygen consumption (VO2max). The rates of appearance (Ra) and disappearance (Rd) of glycerol and free fatty acids (FFAs) were determined using [1,1,2,3,3-2H]glycerol and [1-13C]palmitate, respectively, whereas the overall rate of fatty acid oxidation was determined using indirect calorimetry. During exercise, the whole-body rate of lipolysis (ie, glycerol Ra) was higher in the trained group (7.1 +/- 1.2 v 4.5 +/- 0.7 micromol x min(-1) x kg(-1), P < .05), as was the Ra (approximately Rd) of FFA (9.0 +/- 0.9 v 5.0 +/- 1.0 micromol x min(-1) x kg(-1), P < .001). FFA utilization was higher in trained subjects even when expressed as a percentage of total energy expenditure (10% +/- 1% v 7% +/- 1%, P < .05). However, this difference in plasma FFA flux could not account for all of the difference in fatty acid oxidation between trained and untrained subjects (20.8 +/- 3.3 v 7.9 +/- 1.6 micromol x min(-1) x kg(-1), or 23% +/- 3% v 13% +/- 2% of total energy expenditure, both P < .05). Thus, the oxidation of fatty acids derived from some other source also must have been greater in the trained men. We conclude that trained athletes use more fat than untrained individuals even during intense exercise performed at the same percentage of VO2max. The additional fatty acids appear to be derived from both adipose tissue and, presumably, intramuscular triglyceride stores.     

Growth hormone binding protein correlates strongly with leptin and percentage body fat in GH-deficient adults, is increased by GH replacement but does not predict IGF-I response.

GH-binding protein (GHBP) corresponds to the extracellular domain of the GH receptor (GHR) and has been shown to be closely related to body fat. This study aimed to examine the inter-relationship between GHBP, leptin and body fat, and to test the hypothesis that GHBP is modified by GH replacement in GH-deficient adults and predicts IGF-I response. Twenty adults, mean age 47 years (range 20-69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment. Plasma GHBP and leptin were measured at baseline and 2, 4, 8 and 12 weeks after each treatment. Whole body composition was measured at baseline by dual-energy X-ray absorptiometry (DEXA). There was a strong correlation between baseline leptin and GHBP (r = 0.88, P < 0.0001) and between baseline GHBP and percentage body fat, (r = 0.83, P < 0.0001). Mean GHBP levels were higher on GH compared with placebo, 1.53 +/- 0.28 vs 1.41 +/- 0.25nM, P = 0.049. There was no correlation between baseline IGF-I and GHBP (r = -0.049, P = 0.84), and GHBP did not predict IGF-I response to GH replacement. The close inter-relationship between GHBP, leptin and body fat suggests a possible role for GHBP in the regulation of body composition. GHBP is increased by GH replacement in GH-deficient adults, but does not predict biochemical response to GH replacement.     

Effects of high-dose growth hormone on glucose and glycerol metabolism at rest and during exercise in endurance-trained athletes

CONTEXT: Recombinant human-GH (r-hGH), in supraphysiological doses, is self-administered by athletes in the belief that it is performance enhancing. OBJECTIVE: The objective of this study was to determine whether r-hGH alters whole-body glucose and glycerol metabolism in endurance-trained athletes at rest and during and after exercise. DESIGN: This was a 4-wk double-blind placebo-controlled trial. SETTING: This study was conducted at St. Thomas Hospital (London, UK). PARTICIPANTS: Twelve endurance-trained male athletes were recruited and randomized to r-hGH (0.2 U/kg.d) (n = 6) or identical placebo (n = 6) for 4 wk. One (placebo group) withdrew after randomization. INTERVENTION: Intervention was conducted by randomization to r-hGH (0.2 U/kg x d) or identical placebo for 4 wk. MAIN OUTCOME MEASURES: Whole-body rates of appearance (Ra) of glucose and glycerol (an index of lipolysis) and rate of disappearance of glucose were measured using infusions of d-[6-6-2H2]glucose and 2H5-glycerol. RESULTS: Plasma levels of glycerol and free fatty acids and glycerol Ra at rest and during and after exercise increased during r-hGH treatment (P < 0.05 vs. placebo). Glucose Ra and glucose rate of disappearance were greater after exercise during r-hGH treatment (P < 0.05 vs. placebo). Resting energy expenditure and fat oxidation were greater under resting conditions during r-hGH treatment (P < 0.05 vs. placebo). CONCLUSIONS: r-hGH in endurance-trained athletes increased lipolysis and fatty acid availability at rest and during and after exercise. r-hGH increased glucose production and uptake rates after exercise. The relevance of these effects for athletic performance is not known.     

Continuation of growth hormone (GH) therapy in GH-deficient patients during transition from childhood to adulthood: impact on insulin sensitivity and substrate metabolism

The appropriate management of GH-deficient patients during transition from childhood to adulthood has not been reported in controlled trials, even though there is evidence to suggest that this phase is associated with specific problems in relation to GH sensitivity. An issue of particular interest is the impact of GH substitution on insulin sensitivity, which normally declines during puberty. We, therefore, evaluated insulin sensitivity (euglycemic glucose clamp) and substrate metabolism in 18 GH-deficient patients (6 females and 12 males; age, 20 +/- 1 yr; body mass index, 25 +/- 1 kg/m2) in a placebo-controlled, parallel study. Measurements were made at baseline, where all patients were on their regular GH replacement, after 12 months of either continued GH (0.018 +/- 0.001 mg/kg day) or placebo, and finally after 12 months of open phase GH therapy (0.016 mg/kg x day). Before study entry GH deficiency was reconfirmed by a stimulation test. During the double-blind phase, insulin sensitivity and fat mass tended to increase in the placebo group [deltaM-value (mg/kg x min), -0.7 +/- 1.1 (GH) vs. 1.3 +/- 0.8 (placebo), P = 0.18; deltaTBF (kg), 0.9 +/- 1.2 (GH) vs. 4.4 +/- 1.6 (placebo), P = 0.1]. Rates of lipid oxidation decreased [delta lipid oxidation (mg/kg x min), 0.02 +/- 0.14 (GH) vs. -0.32 +/- 0.13 (placebo), P < 0.05], whereas glucose oxidation increased in the placebo-treated group (P < 0.05). In the open phase, a decrease in insulin sensitivity was found in the former placebo group, although they lost body fat and increased fat-free mass [M-value (mg/kg x min), 5.1 +/- 0.7 (placebo) vs. 3.4 +/- 1.0 (open), P = 0.09]. In the group randomized to continued GH treatment almost all hormonal and metabolic parameters remained unchanged during the study. In conclusion, 1) discontinuation of GH therapy for 1 yr in adolescent patients induces fat accumulation without compromising insulin sensitivity; and 2) the beneficial effects of continued GH treatment on body composition in terms of decrease in fat mass and increase in fat-free mass does not fully balance the direct insulin antagonistic effects.     

GH-deficient survivors of childhood cancer: GH replacement during adult life.

Childhood survivors of cancer are prone to a number of adverse sequelae related to the therapeutic interventions undertaken to achieve remission. The endocrine system is frequently affected; hypothalamo-pituitary dysfunction, in particular GH deficiency, is common after cranial irradiation. It is unclear to what extent GH deficiency contributes to the abnormalities observed in adult survivors of childhood cancer, and whether GH replacement reverses these anomalies. We compared 27 GH-deficient survivors of childhood cancer with 27 adult age- and sex-matched controls and went on to replace GH in the patient group to determine whether GH resulted in improvements of the baseline abnormalities. The GH-deficient survivors of childhood cancer had an adverse lipid profile (total cholesterol, 5.4 vs. 4.6 mM, P = 0.004; high-density lipoprotein cholesterol, 1.05 vs. 1.6 mM, P < 0.001; and triglycerides, 1.3 vs. 1.0 mM, P < 0.001) and were osteopenic (lumbar spine z-score, -1.53 vs. -0.31 SD score, P < 0.001; femoral neck z-score, -1.23 vs. -0.27 SD score, P = 0.02); additionally, the female subgroup had an increased percentage body fat (43.6 vs. 32.8%, P = 0.016). In keeping with the selection criterion, quality of life in the patient cohort, relative to the healthy controls, was severely impaired [adult GH-deficiency assessment (AGHDA), 15.5 (range, 8-25) vs. 1 (range, 0-19), P < 0.0001; psychological general well-being schedule, 67.5 (range, 18-86) vs. 89.0 (range, 51-104), P < 0.0001]. After 12 months of GH replacement, small (but significant) improvements were observed in body composition in the male subgroup (waist-hip ratio, 0.871 vs. 0.863, P < 0.05); and in the female cohort, total cholesterol (6.0 vs. 5.2 mM, P = 0.01) and triglyceride (2.1 vs. 1.4 mM, P = 0.01) levels fell. Bone mineral density improved in only one of the four sites studied (ultradistal radius, -1.21 vs. -1.09, P = 0.048) after a median duration of GH therapy of 18 months. Quality of life improved dramatically by 3 months (AGHDA, 15.5 vs. 10.0, P < 0.001), and the improvement was maintained at 12 months (AGHDA, 15.5 vs. 9.0, P < 0.001). Importantly, there was no clinical suggestion of tumor recurrence during the 12 months of GH replacement. The minor improvements observed in body composition, the lipid profile, and bone mineral density in GH-deficient adult survivors of childhood cancer after 12-18 months of physiological GH replacement suggest that GH deficiency may not be the major etiological factor in their pathogenesis; the converse seems to be true for the quality of life status of these individuals. We propose that, as in patients with hypopituitarism caused by pituitary disease, the main indication for GH replacement in GH-deficient survivors of childhood cancer should be severe impairment of quality of life.     

High dose growth hormone exerts an anabolic effect at rest and during exercise in endurance-trained athletes

The anabolic actions of GH in GH-deficient adults and children are well documented. Replacement with GH in such individuals promotes protein synthesis and reduces irreversible loss of protein through oxidation. Although GH is known to be self-administered by athletes, its protein metabolic effects in this context are unknown. This study was designed to determine whether 4 wk of high dose recombinant human GH (r-hGH) administration altered whole body leucine kinetics in endurance-trained athletes at rest and during and after 30 min of exercise at 60% of maximal oxygen uptake. Eleven endurance-trained male athletes were studied, six randomized to receive r-hGH (0.067 mg/kg.d), and five to receive placebo. Whole body leucine turnover was measured at rest and during and after exercise, using a 5-h primed constant infusion of 1-[(13)C]leucine, from which rates of leucine appearance (an index of protein breakdown), leucine oxidation, and nonoxidative leucine disposal (an index of protein synthesis) were estimated. Under resting conditions, r-hGH administration increased rate of leucine appearance and nonoxidative leucine disposal, and reduced leucine oxidation (P < 0.01). This effect was apparent after 1 wk, and was accentuated after 4 wk, of r-hGH administration (P < 0.05). During and after exercise, GH attenuated the exercise-induced increase in leucine oxidation (P < 0.05). There were no changes observed in placebo-treated subjects compared with the baseline study. We conclude that GH administration to endurance-trained male athletes has a net anabolic effect on whole body protein metabolism at rest and during and after exercise.     

Norepinephrine infusion during moderate-intensity exercise increases glucose production and uptake

A role for the increase in circulating norepinephrine (NE) during intense exercise [IE; > or = 80% maximum O(2) uptake (VO(2max))] in the marked increment in glucose rate of production (Ra) during IE is hypothesized. Seven fit male subjects (27 +/- 2 yr old; body mass index, 23 +/- 1 kg/m(2); VO(2max), 63 +/- 5 mL/kg.min) underwent 40 min of postabsorptive moderate-intensity (53% VO(2max)) cycle ergometer exercise (126 +/- 14 W), once without [control (CON)] and once with NE infusion (0.1 microg/kg.min) from 30-40 min (NE). With infusion, plasma NE reached 15.9 +/- 1.0 nM (8-fold rest, 2-fold CON). Ra doubled to 4.40 +/- 0.44 in CON, but rose to 7.55 +/- 0.68 mg/kg.min with NE infusion (P = 0.003). Ra correlated strongly (r(2) = 0.92, P < 0.02) with plasma NE during and immediately after infusion. With NE infusion, peak glucose uptake [rate of disappearance (Rd), 6.57 +/- 0.59 vs. 4.53 +/- 0.55 mg/kg.min, P < 0.02] and glucose metabolic clearance rate (P < 0.05) were higher than in CON. Glycemia rose minimally during the NE infusion but did not differ between groups at any time during exercise. Glucagon-to-insulin ratio increased minimally, and epinephrine increased approximately 2.5- to 3-fold at peak but did not differ between groups. Thus, NE infusion during moderate exercise led to increments in Ra and Rd in fit individuals, supporting a possible contributory role for the increase of plasma NE in IE. NE effects on Rd and metabolic clearance rate during exercise may differ from its effects at rest.     

Effects of obesity phenotype on fat metabolism in obese men during endurance exercise

OBJECTIVE: The effects of obesity phenotype on fat metabolism during endurance exercise are unclear. This study aimed to investigate in obese men whether body fat distribution would influence plasma fat availability and oxidation during endurance exercise. DESIGN: Fourteen sedentary men (body mass index (BMI) > 25 kg/m2) were divided into two groups by visceral fat (VF) area: VF obese (VF-Ob) (n = 7, age; 52.0 +/- 2.5 (s.e.) years) and abdominal subcutaneous fat obese (SF-Ob) (n = 7, age; 57.3 +/- 2.8 (s.e.) years). All participants performed stationary cycling exercise for 60 min at 50% of peak oxygen uptake.Measurements:Blood and respiratory gas samples were taken for analysis of hormone, metabolite and substrate oxidation in each participant at rest and during exercise. RESULTS: There is a significant group x time interaction in the plasma concentration of free fatty acid (FFA) (P < 0.05) and glycerol (P < 0.05) during the exercise bout. In addition, total plasma concentration of FFA (area under the curve) was 59.2% higher in VF-Ob compared with SF-Ob men during endurance exercise (1.99 +/- 0.24 and 1.25 +/- 0.13 mEq/l/min, respectively; P < 0.05). Total plasma concentration of glycerol (area under the curve) was 102.3% higher in VF-Ob than SF-Ob men during the exercise (69.6 +/- 12.5 and 34.4 +/- 5.1 mg/dl/min, respectively; P < 0.05). However, fat oxidation was not different throughout the exercise between VF-Ob and SF-Ob men (176.5 +/- 25.7 and 183.0 +/- 12.8 kcal/60 min, respectively). CONCLUSION: During moderate endurance exercise, plasma fat availability may be higher in men with VF obesity compared to men with SF obesity. However, total fat oxidation is similar between obesity phenotype.     

Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24-64 yr) with pituitary disease and peak serum GH levels under 5 microg/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 microg/kg x day, final dose 4 microg/kg x day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean +/- SEM, 3.18 +/- 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 +/- 539 g; P = 0.0016), but remained slightly higher (1276 +/- 502 g above baseline; P = 0.0258) than at study initiation. In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 +/- 0.00042, g/cm2 x month; P = 0.005) between months 18-36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.     

Lower excess postexercise oxygen consumption and altered growth hormone and cortisol responses to exercise in obese men

CONTEXT: Obesity is associated with altered patterns of substrate utilization at rest and during exercise. OBJECTIVE: The relationship between obesity and fat oxidation during recovery from exercise was examined. HYPOTHESIS: The postexercise shift toward fat oxidation is blunted in the obese state, reflected by higher respiratory exchange ratio (RER), blunted GH, and increased cortisol values compared with lean controls. DESIGN: Each subject completed two 160-min protocols (baseline and exercise). During baseline, subjects rested for 160 min; during exercise, they completed 30 min of cycling at ventilatory threshold, followed by 130 min of rest. SETTING: This study was performed at the University of Alberta. SUBJECTS: Healthy untrained (maximal oxygen consumption, <45 ml/kg.min or <3.35 liter/min) lean (<16% body fat; n = 6) and obese (>25% body fat; n = 7) men, aged 30-39 yr, were studied. MAIN OUTCOME MEASURES: RER, GH, cortisol, oxygen consumption, heart rate, tympanic temperature, and lactate were obtained during both protocols at matched time intervals and analyzed by repeated measures ANOVA. RESULTS: During baseline, there were no differences detected between lean and obese groups for any of the measured variables. In contrast, during exercise, peak GH levels were blunted (P < 0.05) and cortisol levels were elevated (P < 0.05) in the obese compared with the lean subjects, but RER values were similar in the two groups. The differences in GH and cortisol persisted during the postexercise period accompanied by higher RER values (P < 0.05) and reduced total oxygen consumption (P < 0.05) in the obese group. CONCLUSION: These findings indicate that exercise-induced fat oxidation is diminished in obese men.     

Alterations in body composition and fat distribution in growth hormone-deficient prepubertal children during growth hormone therapy

Growth hormone (GH) deficiency in children results in increased body fat, reduced fat-free mass (FFM) including muscle (protein) and bone, and abdominal obesity. Thus, proper GH secretion likely has major developmental influences on later health risks including cardiovascular diseases and osteoporosis. However, the in vivo control of the development of the body composition and fat distribution by GH has not yet been accurately investigated using children with GH deficiency as a model. We determined the effect of GH therapy (GH replacement, n = 3; GH + physiologic cortisol and thyroxine replacement, n = 3) on body composition, the proportional composition of the FFM, and body fat distribution in GH-deficient prepubertal children compared with healthy control children (n = 6) not treated with GH. The GH-deficient and control children were initially matched for gender, bone age, and weight. As assessed by a 4-compartment model, GH therapy reduced percent body fat during the first 3 months of therapy but not thereafter. This change was primarily due to FFM, which increased 3-fold more in the GH-deficient group and accounted for 91.5% of the increase in body weight. Fat mass increased in the controls but was unchanged in the GH-deficient group. Therapy temporarily increased the proportional contribution of water to the FFM, decreased the proportion of mineral, and slightly increased the proportion of protein. Using magnetic resonance imaging (MRI), abdominal visceral fat was reduced in the GH-deficient group and unchanged in the controls. Abdominal subcutaneous fat measured in the same image was not changed. The abdominal and suprailiac skinfold thicknesses also were not decreased in the GH-deficient group. In conclusion, within 1 to 3 months, GH therapy accelerates lean tissue accrual, especially the water and protein components, but has a smaller effect on reducing fat mass. GH therapy has site-specific effects on reducing abdominal adiposity.     

Rapid leptin decrease in immediate post-exercise recovery

OBJECTIVE: Leptin concentrations in humans are known to decrease in response to fasting. The aim of this work was to investigate whether leptin levels might also be modified by exercise-induced negative energy balance. SUBJECTS: Eight male runners reported in the morning from 0800 to 1200 h for (i) one resting session (sitting) and (ii) one exercise-and-rest session (2 h run and 2 h rest). MEASUREMENTS: Plasma leptin, free fatty acids (FFA), glycerol, cortisol and salivary cortisol were assayed in both sessions at 1200 h. RESULTS: After exercise-and-rest the leptin concentrations were lower than after rest (1.7 +/- 0.1 vs 2.5 +/- 0.2 micrograms/l, P < 0.05), i.e. a mean decrease of 30.3 +/- 4.5% (range 9.5-45.8). Plasma FFA, glycerol and cortisol concentrations increased: FFA 0.78 +/- 0.08 vs 0.18 +/- 0.04 mmol/l, glycerol 0.13 +/- 0.01 vs 0.04 +/- 0.01 mmol/l, and cortisol 428 +/- 36 vs 279 +/- 27 nmol/l. A negative correlation was found between plasma FFA and leptin levels (r = -0.5, P < 0.05) and between plasma glycerol and leptin levels (r = -0.05, P < 0.05). No correlation was found between leptin and cortisol levels. CONCLUSIONS: In normal subjects with low body fat, a strenuous exercise-and-rest lowers leptin levels by a mean of 30%. A role of lipolysis possibly via increased plasma free fatty acids and glycerol levels is suggested. Cortisol does not seem to be involved.     

Impaired modulation of hepatic glucose output overnight after a 72-h fast in normal man

We have previously reported a 25% fall in glucose utilization (Rd) and glucose production (Ra) in normal volunteers during an overnight fast, when glycogenolysis accounts for approximately 70% of hepatic glucose output (HGO). This reduction in Ra and Rd was positively correlated with reductions in glycerol and FFA. To determine if a similar fall in HGO occurs after a prolonged fast when HGO depends solely upon gluconeogenesis, seven normal male volunteers were fasted for 72 h. Glucose kinetics were then assessed overnight using a [3-3H]glucose infusion from 2200-0800 h. Plasma glucose (3.6 +/- 0.1 mM), immunoreactive insulin (2.7 +/- 0.4 mU/L), C-peptide (0.22 +/- 0.03 nmol/l), Rd (1.30 +/- 0.03 mg/kg.min), and Ra (1.28 +/- 0.03 mg/kg.min) were suppressed, and plasma glucagon (98.8 +/- 13.2 pmol/L) was elevated compared to values obtained during the overnight fast, but none of these parameters changed overnight after the 3-day fast. Plasma lactate (0.98 +/- 0.09 mmol/L) and alanine (0.18 +/- 0.03 mmol/L) levels were also unchanged throughout the night. Plasma glycerol (0.14 +/- 0.03 mmol/L) and FFA (0.98 +/- 0.07 mmol/L) were significantly elevated compared to values during the overnight fast, but failed to fall during the study as had been observed during a 14-h fast. We conclude that the modulation of HGO observed during an overnight fast does not occur during prolonged fasting. The lack of nocturnal modulation of HGO when plasma FFA and glycerol levels are fixed at elevated concentrations supports a role of FFA and/or glycerol in the modulation of HGO during an overnight fast.     

Low-dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency

OBJECTIVE  The ob gene product, leptin, is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass. Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism.
SUBJECTS  Twenty adults, mean age 47 years (range 20–69) with proven GH deficiency were randomly allocated to either GH (up to 0.25 U/kg/week in daily doses) or placebo for 3 months before cross-over to the opposite treatment.
MEASUREMENTS  Body composition was measured by dual-energy X-ray absorptiometry (DEXA) in the whole body, trunk and limbs. Plasma leptin was measured by radioimmunoassay at baseline and +2, +4, +8 and +12 weeks in each treatment arm.
RESULTS  Total body tissue fat (mean±SE) was 30.1±2.2% after GH compared with 31.9±2.2% after placebo, P <0.001 (ANOVA). There were no significant changes in BMI (kg/m²), 29.1±1.3 after placebo vs 28.8±1.2 after GH; or waist to hip ratio (WHR), 0.91±0.01 after both placebo and GH. Baseline plasma leptin showed a significant correlation with baseline BMI, r =0.67, P <0.005 and baseline percentage total body fat, R =0.89, P <0.001. Plasma leptin (adjusted by using baseline percentage total body fat as a covariate) showed a significant linear decrease with time on GH compared with placebo ( P =0.03 ANOVA).
CONCLUSIONS  Plasma leptin and total body fat fall promptly in response to low-dose replacement of GH in GH-deficient subjects. Hormone-induced changes in leptin can occur in humans in the absence of change in body mass index.     

Effect of growth hormone on body composition and visceral adiposity in middle-aged men with visceral obesity

RATIONALE: GH replacement in GH-deficient adults results in an improvement in metabolic status. GH might also decrease visceral adiposity in obese adults that are not GH deficient. OBJECTIVE: Our objective was to determine the effects of supraphysiological GH therapy on the metabolic syndrome and visceral adiposity in men with low blood levels of IGF-I and the durability of these effects after stopping GH therapy. DESIGN: The study was a double-blind, placebo-controlled 6-month intervention trial followed by a blinded follow-up period of 6 months. SUBJECTS: Thirty nondiabetic middle-aged men with central adiposity (body mass index > 27 kg/m(2); waist circumference > 102 cm) participated. RESULTS: After 6 months of GH therapy, we observed an increase in weight and lean body mass (2.5 +/- 0.6 kg, P < 0.05 compared with baseline and placebo) and 8.8% reduction in visceral adiposity. GH increased resting energy expenditure by 172.5 +/- 41.6 kcal/24 h after 6 months of therapy. Fasting insulin, glucose, and the quantitative insulin sensitivity check index for insulin resistance increased during GH therapy. The effects of GH on fatness and visceral adiposity disappeared shortly after GH withdrawal, but weight remained increased over baseline and when compared with the placebo group (P < 0.05). CONCLUSION: These data suggest that GH therapy is associated with small but statistically significant decreases in visceral adiposity and an increase in lean mass and body weight. In viscerally obese subjects, supraphysiological GH administration is not an effective treatment; however, additional studies are needed to evaluate the effects of low-dose, physiological GH treatment.     

Improvement in insulin sensitivity without concomitant changes in body composition and cardiovascular risk markers following fixed administration of a very low growth hormone (GH) dose in adults with severe GH deficiency

OBJECTIVE: Untreated GH-deficient adults are predisposed to insulin resistance and excess cardiovascular mortality. We showed previously that short-term treatment with a very low GH dose (LGH) enhanced insulin sensitivity in young healthy adults. The present study was therefore designed to explore the hypothesis that LGH, in contrast to the standard GH dose titrated to normalize serum IGF-I levels (SGH), may have differing effects on insulin sensitivity, body composition, and cardiovascular risk markers [lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha) and adiponectin] in adults with severe GH deficiency. PATIENTS AND METHODS: In this 12-month open, prospective study, 25 GH-deficient adults were randomized to receive either a fixed LGH (0.10 mg/day, n = 13) or SGH (mean dose 0.48 mg/day, n = 12), and eight age- and body mass index (BMI)-matched GH-deficient adults acted as untreated controls. Fasting blood samples were collected at baseline and at months 1, 3, 6, 9 and 12. Assessments of insulin sensitivity, using the hyperinsulinaemic euglycaemic clamp technique, and body composition, using dual-energy X-ray absorptiometry, were performed at baseline and at month 12. RESULTS: The LGH decreased fasting glucose levels (P < 0.01) and enhanced insulin sensitivity (P < 0.02), but body composition, nonesterified fatty acid (NEFA) levels and cardiovascular risk markers were unchanged. The SGH did not modify insulin sensitivity, decreased truncal fat mass (P < 0.05), CRP (P < 0.05) and IL-6 (P < 0.05) levels, and increased NEFA levels (P < 0.05). No changes were observed with the untreated controls. CONCLUSION: Our data indicate that, in contrast to the SGH, fixed administration of the LGH enhances insulin sensitivity with no apparent effects on body composition, lipolysis and other surrogate cardiovascular risk markers in adults with severe GH deficiency. Thus, the LGH may potentially be a beneficial replacement dose in reducing type 2 diabetes risk in adults with severe GH deficiency.     

Free fatty acid kinetics in the late phase of postexercise recovery: importance of resting fatty acid metabolism and exercise-induced energy deficit

Free fatty acid (FFA) availability increases several-fold during exercise and remains significantly elevated for at least 3 to 6 hours after exercise cessation. Little, however, is known regarding the duration of the postexercise rise in FFA flux. In the present study, we used stable isotope–labeled palmitate infusion to examine fatty acid metabolism in 27 healthy untrained men and women (age, 29 ± 7 years; body mass index, 25 ± 4 kg/m²) between 13 to 16 hours and 21 to 24 hours after a single bout of moderate-intensity endurance exercise (1-2 hours at 60% of peak oxygen consumption), performed in the evening, and after a time-matched resting trial. Postabsorptive FFA rate of appearance (Ra) and FFA concentration in plasma were significantly greater after exercise than rest throughout the recovery period (P < .015), but the exercise-induced increases declined from approximately 40% at 13 to 16 hours to approximately 10% at 21 to 24 hours postexercise (P = .001). The magnitude of the exercise-induced increase in plasma FFA concentration was proportional to the increase in FFA Ra. Correlation analysis demonstrated that exercise-induced changes in plasma FFA Ra at 13 to 16 hours are (1) negatively associated with resting plasma FFA Ra and (2) positively associated with the net energy expenditure of exercise and the exercise-induced changes in whole-body fat oxidation rate (all P values < .05). In multivariate stepwise linear regression analysis, baseline plasma FFA Ra (P ≤ .008) and net energy expenditure of exercise (P ≤ .005) independently predicted the exercise-induced change in plasma FFA Ra at 13 to 16 hours. We conclude that the exercise-induced increase in FFA mobilization is (1) long-lived, persisting for 12 to 24 hours after exercise, with a progressive decline with time; (2) greater in subjects with low than high resting plasma FFA availability; and (3) greater after exercise with high than low energy demand.     

Gln27Glu polymorphism in the beta2 adrenergic receptor gene and lipid metabolism during exercise in obese women

BACKGROUND: The Glu27Glu genotype in the beta-2-adrenergic receptor (ADRB2) is associated with fat mass, body mass index and obesity in females. In our population, we previously found an association of higher body mass index (BMI) among women who reported more physical activity and carried the Glu27 allele as compared to non carriers with the same level of activity. OBJECTIVE: To examine the lipid metabolism differences, both at rest and during submaximal exercise in ADRB2 Glu27Glu vs Gln27Gln obese women. SUBJECTS: Eight obese women with the Glu27Glu genotype (age, 43+/-5 y; body mass index (BMI), 31.7+/-0.9 kg/m(2); percentage fat mass, 42.0+/-1.3; WHR, 0.83+/-0.02; and VO(2max), 21.6+/-0.9 ml/kg/min) were compared with seven obese women with the Gln27Gln genotype (age, 43+/-5 y; BMI, 33.9+/-1.3 kg/m(2); percentage fat mass, 41.6+/-1.2; WHR, 0.83+/-0.02; and VO(2max), 20.6+/-0.8 ml/kg/min). MEASUREMENTS: The ADRB2 polymorphism was identified by PCR-RFLP. Respiratory quotient was determined by indirect calorimetry at baseline, during 1 h of walking on a treadmill and 1 h after the exercise. Plasma triglycerides, glycerol, FFA, hydroxybutyrate, glucose and lactate were assayed by spectrophotometric methods. Insulin, leptin and progesterone were measured by radioimmunoassay. Adrenaline and noradrenaline were quantified by high performance liquid chromatography. RESULTS: The ADRB2 Glu27Glu subjects had lower plasma glycerol (P=0.047) and lower hydroxybutyrate (P=0.001) throughout the study than the Gln27Gln group. Plasma triglycerides (P=0.001), lactate (P<0.05) and serum insulin (P<0.05) remained higher in the Glu27Glu group vs the Gln27Gln group. The respiratory quotient (RQ) was higher in the Glu27Glu obese women along the study (P=0.046), and fat oxidation was significantly lower in this group during the recovery (P=0.048). The other variables did not differ statistically between groups. CONCLUSION: These data suggest that both lipolysis and fat oxidation promoted by an acute submaximal exercise intervention could be blunted in the polymorphic ADRB2 Glu27Glu group of our female obese population.     

Acute growth hormone administration causes exaggerated increases in plasma lactate and glycerol during moderate to high intensity bicycling in trained young men

We studied the acute effects of a single, sc GH dose on exercise performance and metabolism during bicycling. Seven highly trained men [age, 26 +/- 1 yr (mean +/- SEM); weight, 77 +/- 3 kg; maximal oxygen uptake, 65 +/- 1 ml O(2).min(-1).kg(-1)] performed 90 min of bicycling 4 h after receiving 7.5 IU (2.5 mg) GH or placebo in a randomized, double-blinded, cross-over design trial. A standardized pre-exercise meal was given 2 h before exercise. Blood was sampled at rest and during exercise and analyzed for GH, IGF-I, glucose, lactate, insulin, glycerol, and nonesterified fatty acids (NEFA). In the placebo trial, all subjects completed the exercise protocol without any difficulties. In contrast, two subjects were not able to complete the exercise protocol in the GH trial, and one subject barely managed to complete the protocol. In addition, GH administration resulted in exaggerated increases in plasma lactate concentrations during exercise (P < 0.0001). The combined lipolytic effect of GH and exercise, evidenced by increased plasma glycerol and serum NEFA concentrations, was 3-fold greater than the effect of exercise alone (P < 0.0001), but this increased substrate availability did not result in increased whole body fat oxidation (indirect calorimetry). Plasma glucose was, on average, 9% higher during exercise after GH administration compared with placebo (P < 0.0001). We conclude that a single, relevant GH dose causes exaggerated increases in plasma lactate and glycerol as well as serum NEFA during 90 min of subsequent bicycling at moderate to high intensity. The exaggerated increase in plasma lactate may be associated with substantially decreased exercise performance.     

Short- and long-term effects of growth hormone (GH) replacement on protein metabolism in GH-deficient adults

Reduced fat-free mass (FFM) in GH-deficient (GHD) adults is improved by GH replacement, but the protein metabolic changes are unclear. Using iv [(2)H(3)]leucine and oral l-[(13)C(1)]leucine infusions and dual emission x-ray absorptiometry, we compared leucine kinetics and body composition in eight GHD adults and eight healthy controls in the fasted and fed states, before and after 2 wk and 6 months of GH replacement. Leucine kinetics were not different between pretreatment GHD subjects and controls. After 2 wk of GH treatment, leucine oxidation decreased in the GHD subjects compared with baseline values [fasted, 41 +/- 6 vs. 30 +/- 5 micromol/kg FFM.h (P < 0.01); fed, 49 +/- 3 vs. 41 +/- 3.6 micromol/kg FFM.h (P < 0.05)], leucine balance improved [fasted, -14 +/- 4 vs. -3.5 +/- 3 micromol/kg FFM.h (P < 0.01); fed, 65 +/- 10 vs. 72 +/- 7 micromol/kg FFM.h (P = 0.07)], and protein synthesis increased [fasted, 116 +/- 5 vs. 131 +/- 6 micromol/kg FFM.h (P < 0.05); fed, 103 +/- 6 vs. 116 +/- 6 micromol/kg FFM.h (P < 0.05)]. After 6 months of GH treatment, these changes were not maintained in the fed state. The five GHD subjects with decreased FFM at baseline showed a significant increase after 6 months of GH treatment (P < 0.05). GH replacement in GHD acutely improves protein balance by stimulating synthesis and inhibiting catabolism. After 6 months, protein kinetics reached a new homeostasis to maintain the net gain in FFM.