David K. Snyder, MD, February 1995 The American Journal of Medicine@ Volume 98
PURPOSE: In previous studies in which obese volunteers were calorically restricted to 24, 18, or 12 kcal/kg of ideal body weight (lDW) per day, we observed that the growth-hormone-induced acceleration of body fat loss was variable and that the severity of caloric restriction modulated the magnitude of fat loss and the anabolic response to growth hormone. The present study was undertaken to characterize the effects of caloric restriction to 15 kcal/kg IDW per day on the metabolic responses to growth hormone and to determine whether acceleration of body fat loss by growth hormone could be reproduced under conditions predicted to be optimal.
PATENTS AND METHODS: Eleven obese subjects were studied during two 39-day periods of caloric restriction. During one of these periods they received injections of growth hormone, 0.05 mg/kg IDW, for 28 days. Measurements of nitrogen balance, body fat content, insulin like growth factor I (lGF-I), free fatty acids, and glycerol concentrations were performed.
RESULTS: Growth hormone injections caused an approximate 2.5 fold increase in lGF-I concentrations so that the mean IGF-1 concentration was significantly greater during the injections than during diet alone (growth hormone 69.3 +/- 29.3 nmol/L; diet alone 26.6 +/- 7,6 nmol/L; P <0.001). Growth hormone also caused nitrogen sparing, and the mean daily nitrogen balance was significantly greater during the injections (growth hormone 36.9 +/- 121.1 mmol/day; diet alone -122.3 +/- 125.9 mmol/day; P <0.001). This nitrogen-sparing response to growth hormone attenuated over the 4 weeks of the injections. Growth hormone had a persistent lipolytic effect manifested by increases in glycerol concentrations, and body fat loss was greater during injections than during diet alone (fraction of weight lost as fat during injections 0.77 +/- 0.07; diet alone 0.63 +/- 0.06; P <0.001).
CONCLUSION: conclude that growth hormone exerts anabolic effects that attenuate over time during caloric restriction but maintains its lipolytlc effect despite hyperinsulinism and results in accelerated fat loss.
Growth hormone administration to humans causes nitrogen retention, free fatty acid mobilization, and increases in insulin like growth factor I (IGF-I), a peptide that mediates the anabolic, nitrogen-sparing effect of growth hormone. In addition to growth hormone, IGF-I concentrations are modulated by nutritional status such that the IGF-I concentration is low in malnourished persons and declines during caloric restriction in normal-weight subjects.
Unlike lean individuals, basal IGF-I concentrations in obese subjects are less affected by caloric restriction, and obese subjects retain the ability to mount anabolic and IGF-I responses to exogenous growth hormone despite reductions in daily caloric intake to as little as 12 kcal/kg ideal body weight (lBW). In previous studies of calorically restricted obese adults given growth hormone injections, we have observed a variable effect of the hormone on acceleration of body fat loss. In one study 8 in which daily caloric intake was restricted to 18 kcal/kg lBW, growth hormone injections caused an increase in free fatty acid concentrations but no acceleration in the rate of fat loss compared with placebo. In a second study6 in which growth hormone injections were given to subjects restricted to 12 kcal/kg IBW, significantly greater body fat loss occurred during the injections than during
diet alone. In a subsequent study 9 of subjects receiving the same diet but twice as much growth hormone, fat loss varied widely and the hormone had no effect over diet alone. In the latter two studies, we found an inverse correlation between fat loss and insulin secretion, as determined by 24 hour urinary C-peptide excretion.
In the study using twice as much growth hormone, insulin secretion increased greatly, suggesting that growth-hormone- induced hyperinsulinism might oppose the ability of the hormone to accelerate fat loss. That is further supported by the observation that the free fatty acid response to growth hormone attenuated over time in all three studies.
The present study was undertaken to characterize the effects of caloric restriction to 15 kcal/kg IBW per day on the metabolic responses to growth hormone, to determine whether acceleration of body fat loss by growth hormone could be reproduced, and to determine if the attenuation of the free fatty acid response to growth hormone was associated with an attenuated increase in glycerol concentrations.
Materials & Methods
The two study periods were separated by an 18day interval during which the subjects ingested an ad libitum diet. During one study period, subjects were given daily subcutaneous injections of growth hormone, 0.05 mg/kg lBW, on study days 5 through 32 (a total of 28 injections). In the other period, they received only diet.
NOTE: There are 0.333 mg in a single IU of HGH. Thus an 80kg obese person would have been given a 12iu gose of growth hormone.
This study confirms that growth hormone accelerates body fat loss in calorically restricted obese subjects.
This acceleration was apparent in both of two independent measures of body composition, hydrostatic weighing and impedance analysis, and whether expressed as percentage body fat lost or the fraction of weight lost as fat. The degree of acceleration of fat loss was comparable to that observed when we administered growth hormone every other day to subjects receiving 12 kcal/kg IBW per day.6 This finding contrasts with the results obtained when we administered a larger dose of growth hormone (0.1 mg/kg
IBW per day) and noted no acceleration of body fat loss.9 The difference in these responses cannot be attributed to differences in body composition or age among subjects. The subjects who received 0.1 mg growth hormone/kg, IBW per day, however, had large increases in 24hour urinary C-peptide excretion in response to growth hormone that correlated inversely with fat loss, suggesting that failure of larger doses of growth hormone to accelerate fat loss might be due to insulin-mediated opposition of the lipolytic effect of growth hormone.
This conclusion is supported by the observed pattern of growth-hormone-induced increases in free fatty acid and glycerol concentrations. Initially, growth hormone injections caused acute increases in both serum glycerol and free fatty acid concentrations, but the free fatty acid response attenuated over the 4 weeks of the injections. However, the increment in glycerol concentrations caused by growth hormone was persistent, indicating a sustained lipolytic effect of growth hormone. A similar pattern of free fatty acid and glycerol responses has been reported in dogs given repeated growth hormone injections over 13 days.17 From measurements of glycerol turnover, growth hormone was shown not to influence glycerol uptake and disposal but to increase glycerol release from triglycerides. Because we measured free fatty acid and glycerol concentrations only at the 4 hour time point after growth hormone injection, we cannot distinguish between increased re esterification or oxidation of the liberated free fatty acid as the cause of the attenuated increase in concentrations. Growth hormone- induced hyperinsulinism, reflected by increases in C-peptide, would favor enhanced reesterification as the responsible mechanism.
There are several possible explanations for our failure to observe correlations between indices of basal or growth-hormone-stimulated insulin secretion and changes in body composition in the present study. First, the mean weight loss was only 7.3 +/- 1.4 kg in our growth-hormone-treated subjects and the hormone- induced acceleration of fat loss was small Although insulin secretion varied widely, fat loss did not, and our measurements of body composition may not be sufficiently precise to detect small differences over this narrow range. Alternatively, variables affecting our measurements of insulin secretion may have obscured any relationship of hyperinsulinism and fat loss. These might include variability in the fractional excretion of urinary C-peptide, growth- hormone- induced increases in glomerular filtration rate and renal plasma flow, or alterations in insulin metabolism, as suggested by the increased plasma insulin to C- peptide ratio previously observed during growth hormone treatment or IGF-I infusion.20
In keeping with our results, Salomon et al19 observed that growth hormone injections decreased body fat in growth-hormone-deficient adults despite increases in insulin concentrations, as did Rudman et al21 in a study of elderly men given growth hormone. Taken together with our data, these studies document dominance of the lipolytic effect of growth hormone despite the lipogenic effect of increased insulin concentrations. Unlike the studies of growth-hormone- deficient subjects and the study by Rudman et al, in which subjects were selected on the basis of having less than average IGF-I concentrations, our results show that growth hormone reduces body fat in subjects with intact pituitary function and normal IGF-I concentrations.
As in our previous studies 6-9 we observed that growth hormone injections promote nitrogen retention and increase IGF-I concentrations in obese subjects despite caloric restriction. In previous reports of obese subjects restricted to 24, 18, or 12 kcal/kg IBW per day, we found that the anabolic response to growth hormone diminished as caloric restriction was made more severe. In obese subjects ingesting 18 kca/kg IBW per day, growth hormone injections cause a 2.5-fold increase in IGF-I concentration, while at an intake of 12 kcal/kg IBW/day, this response falls to only a 54% increase. Feeding of a 15 kcal/kg IBW daily diet in the present study restored the ability to mount a 2.5 fold increase in IGF-I in response to growth hormone. Thus, 15 kcal/kg IBW is above the caloric threshold below which IGF-I responses of obese subjects attenuate significantly. Similarly, although the initial magnitude of the nitrogen-sparing response to growth hormone was similar to that seen in previous studies, the duration of this response was intermediate to that seen when 18 or 12 kcal/kg IBW is ingested. Although IGF-I is believed to mediate the nitrogen-sparing response to growth hormone, the loss or attenuation of this response has occurred repeatedly in the face of a sustained increase in IGF- I, suggesting the development of resistance to the anabolic actions of IGF-I.
A number of investigators have reported anabolic responses to exogenous growth hormone or IGF-I, but few have observed the loss of this effect over time consistently seen in our studies. Differences in subject population, nutritional status, duration of growth hormone treatment, or the dose of growth hormone employed might explain this discrepancy. The mechanism responsible for the loss of anabolic effect over time might be due to decreased tissue availability of IGF-I due to changes in IGF-binding proteins, downregulation of IGF receptors, or postreceptor defects in IGF action.
Conover and Powell 22 have reported down-regulation of fibroblast IGF-I receptors by IGF-I, but also observed that the reduction in receptor number was not sufficient to account entirely for the observed decrease in cellular response to IGF-I, suggesting an additional postreceptor defect may also be operative. Regardless of the mechanism involved, this loss of anabolic effect has important implications for regimens involving long-term growth hormone administration to nutritionally depleted patients.
This study provides further evidence of the importance of growth hormone in regulating body composition and confirms that dietary variables modulate the anabolic responses to growth hormone. Growth hormone holds promise as an anabolic agent in the treatment of patients who would benefit from increases in lean body mass, and nutritional deficits modulate but do not preclude anabolic responses to growth hormone. The nature of the interaction between growth hormone and nutrition deserves further study to allow the effective use of growth hormone as an anabolic agent.