Only a few days of overeating in humans reduces plasma GH concentration by about 80% prior to any gain in body weight.
Abstract
Context:
The very low GH concentration in obesity is commonly attributed to high body fat mass; however, the influence of overeating on GH secretion is not clear.
Objective:
The aim of the study was to examine the effects of 2 wk of overeating on changes in GH secretion.
Setting:
Subjects were admitted to the hospital and stayed within the Michigan Clinical Research Unit throughout the entire 2-wk overeating period.
Participants:
We studied seven healthy, nonobese men (body mass index, 24 ± 1 kg/m2; age, 25 ± 1 yr).
Intervention:
Subjects ate standardized meals containing 70 kcal/kg fat free mass/d (∼4000 kcal/d) for 2 wk.
Main Outcome Measures:
Twenty-four-hour plasma concentrations of GH (every 20 min) and insulin (every 2 h) were measured before overeating (baseline), on d 3, and after 2 wk of overeating.
Results:
Compared with baseline, average 24-h plasma GH concentration declined nearly 80% by d 3 of overeating (1.30 ± 0.18 vs. 0.36 ± 0.09 ng/ml; P = 0.01). This marked suppression of GH secretion occurred in the absence of an increase in body weight (77.0 ± 2.2 vs. 76.4 ± 2.4 kg). At the same time, average 24-h insulin concentration doubled (16.6 ± 2.1 vs. 31.7 ± 5.8 μU/ml; P = 0.009). After 2 wk, body weight significantly increased (79.0 ± 2.1 kg; P < 0.001), and body fat increased by more than 10% (P = 0.002). However, this did not induce a further suppression in plasma GH concentration (0.33 ± 0.08 ng/ml).
Conclusion:
Only a few days of overeating markedly suppressed GH secretion before any measurable weight gain and was accompanied by chronic hyperinsulinemia. Increased body weight and body fat by 2 wk of overeating did not further suppress GH secretion.
Obesity is characterized by abnormal metabolic and hormonal responses, including impaired glucose metabolism (1), high lipolytic rates with a resultant overabundance of circulating fatty acids (2), hyperinsulinemia, and low GH secretion (3–5). The consequences of this reduced plasma concentration of GH in obesity has been the source of much speculation, with several studies suggesting that low GH contributes to the abnormal metabolic function in obesity (3, 5). The reduction in GH secretion in obesity has been attributed to total adiposity (4), abdominal adiposity (6), and intramyocellular and intrahepatic lipid content (7).
The underlying mechanisms responsible for this obesity-related suppression in GH secretion in obesity are not completely understood. Additionally, whether GH deficiency can precede (rather than follow) obesity, possibly facilitating its future progression, has not been investigated. Clearly, weight gain can only occur under conditions when energy intake exceeds energy expenditure (i.e.“overeating”). Therefore, the purpose of this study was to determine the effects of a short-term period of 2 wk of overeating on the regulation of GH secretion.
Subjects and Methods
Subjects
Seven men participated in a 2-wk overeating protocol. All subjects were nonobese (body mass index, 24.0 ± 0.3 kg/m2; age, 24 ± 2 yr), weight stable, in good health, relatively sedentary (physical activity, ≤2 h/wk), and were not taking any medications. All procedures of this study were approved by the Institutional Review Board at the University of Michigan. Written, informed consent was obtained from all subjects before their participation in the study.
Experimental design
Subjects were admitted to the Michigan Clinical Research Unit (MCRU) at the University of Michigan Hospital on two separate occasions. The first hospital visit, referred to as the “baseline” visit, lasted 2 d (one overnight), during which we performed a battery of baseline metabolic tests while the subjects consumed a weight maintaining diet (39 ± 1 kcal/kg fat-free mass/d; 50% carbohydrate, 35% fat, and 15% protein). During the second hospital visit, subjects adhered to a supervised overeating intervention, and they remained in the hospital without leaving throughout this entire 2-wk period. During this 2-wk overeating period, subjects consumed standardized meals containing 70 kcal/kg fat-free mass/d (∼4000 kcal/d; 50% carbohydrate, 35% fat, and 15% protein), which represents about 75% more calories than a weight-maintaining diet. The daily diet was provided as three meals (at 0800, 1200, and 1900 h) and four snacks (at 1000, 1400, 1600, and 2200 h). During both the baseline and overeating hospital visits, subjects were restricted to the MCRU ward, and their physical activity was limited to 1500 steps per day, as measured by a pedometer (Digi-walker SW200; Yamax, San Antonio, TX). Daily energy intake and physical activity were strictly monitored by the research staff. Body weight was measured at 0730 h each morning, and body composition was assessed using dual-energy x-ray absorptiometry (Lunar Prodigy Advance; GE Healthcare, Buckinghamshire, UK) before and after the 2-wk overeating period.
Blood samples were obtained every 20 min for 24 h during the baseline visit, as well as on d 3 and d 13 of the overeating period. These samples were collected in tubes containing sodium heparin and then centrifuged at 1600 × g for 20 min. Plasma was removed and stored at −80 C for later analysis. Plasma GH concentration was measured every 20 min during the 24-h periods at baseline, d 3, and 2 wk. Plasma insulin and cortisol concentrations were assessed every 2 h at baseline, d 3, and 2 wk. In addition, every morning of the 2-wk overeating period (after an overnight fast), one blood sample was drawn and collected into tubes containing EDTA for assessment of fasting plasma concentrations of insulin, fatty acids, IGF-I, and IGF-I binding proteins (IGFBP).
Analytical procedures
Plasma hormone concentrations
Plasma GH, free IGF-I, IGFBP3, and cortisol concentrations were determined using chemiluminometric assays from Siemens with an Immulite System (Diagnostic Products, Los Angeles, CA). Total IGF-I and IGFBP1 were determined by ELISA kits (Diagnostic Systems Laboratories, Brea, CA). Insulin concentration was determined by RIA (Millipore, Billerica, MA).
Plasma substrate concentrations
Plasma concentrations of fatty acid (HR Series NEFA; Wako Chemicals USA, Richmond, VA), glucose (glucose oxidase; Thermo Fisher Scientific Inc., Waltham, MA), and triacylglycerol (triglyceride reagent; Sigma Aldrich Inc., St. Louis, MO) were measured by commercially available colorimetric assay kits.
Calculations
Analyses of GH pulse amplitude, pulse frequency, and interpulse level were conducted using the Pulse_XP hormone cluster analysis software through the generosity of Dr. Michael Johnson at the University of Virginia. Plasma GH concentrations used in this cluster analysis were measured every 20 min over a 24-h period on three separate occasions (baseline, d 3, and 2 wk). Measurement error, for the basis of pulse detection, was found through repeated sampling of a single specimen. Missing values were not included in the analysis, and values below the point of detection were set at the lowest level of detection (0.01 ng/ml).
Statistical analysis
Repeated measures one-way ANOVA in conjunction with a Tukey post hoc test was used to test for significant differences at baseline, d 3, and 2 wk. Analysis was conducted using Sigma Stat version 3.0.1a for Windows (Systat Software Inc., Chicago, IL). Statistical significance was defined by a P value less than 0.05. All data are presented as mean ± se.
Results
Changes in body composition
By d 3 of the overeating period, subjects did not exhibit measurable changes in body mass (Table 1). However, after 2 wk of overeating, subjects gained 3.0 ± 0.5 kg body mass and 1.7 ± 0.3 kg of fat mass (both P < 0.01 vs. baseline). There was a tendency for fat-free mass to increase after 2 wk of overeating; however, this did not reach statistical significance (P = 0.068) (Table 1).
Table 1.
Subject characteristics
| Baseline | Day 3 | 2 wk | |
|---|---|---|---|
| Body mass (kg) | 77.9 ± 2.3 | 77.3 ± 2.6 | 80.1 ± 2.1a |
| Body mass index (kg/m2) | 24.0 ± 0.3 | 24.0 ± 0.4 | 25.4 ± 0.2a |
| Body fat (%) | 23.7 ± 2.9 | 25.2 ± 2.6a | |
| Fat mass (kg) | 18.7 ± 2.7 | 20.4 ± 2.5a | |
| Fat free mass (kg) | 58.8 ± 1.6 | 59.7 ± 1.5 |
Values are expressed as mean ± se.
Significantly different from baseline, P < 0.05.
Changes in fasting plasma substrates
Overnight fasted plasma glucose concentration remained stable throughout the 2-wk overeating period (Table 2). In contrast, fasting plasma fatty acid concentration was reduced by more than half in the first few days of the overeating period (P < 0.001) and remained low at 2 wk (P < 0.001 vs. baseline) (Table 2). Fasting plasma triglyceride concentration tended to increase by d 3 (P = 0.07) and was significantly increased compared with baseline at 2 wk of overeating (P = 0.05) (Table 2).
Table 2.
Plasma substrate concentrations
| Baseline | Day 3 | 2 wk | |
|---|---|---|---|
| Plasma glucose (mm) | 5.4 ± 0.2 | 5.5 ± 0.4 | 4.9 ± 0.1 |
| Plasma fatty acid (mm) | 0.35 ± 0.05 | 0.14 ± 0.02a | 0.14 ± 0.01a |
| Plasma triglyceride (mm) | 0.70 ± 0.13 | 1.23 ± 0.23 | 1.28 ± 0.29a |
Values are expressed as mean ± se.
Significantly different from baseline, P < 0.05.
Plasma GH concentration
The 24-h average plasma GH concentration was 1.26 ± 0.2 ng/ml at baseline (Fig. 1). Only a few days of overeating suppressed 24-h GH concentration by approximately 80% (0.28 ± 0.1 ng/ml by d 3 of overeating; P < 0.05 vs. baseline; Fig. 1). There was no further reduction in 24-h average plasma GH concentration after 2 wk of overeating (0.32 ± 0.1 ng/ml; P < 0.05 vs. baseline). The reduction in the GH profile was due exclusively to a reduction in GH pulse amplitude (Table 3). There was no significant change in GH pulse frequency (Table 3) or the average GH concentration between pulses (i.e.“interpulse level”; Table 3).
Fig. 1.
Mean plasma GH concentration every 20 min for 24 h before overeating (baseline), on d 3 of overeating, and at the end of the 2-wk overeating period. Inset, The average plasma GH concentration at baseline, d 3, and 2 wk of overeating. *, P < 0.05 vs. baseline.
Table 3.
Average 24-h plasma GH concentration and plasma GH profile
| Baseline | Day 3 | 2 wk | |
|---|---|---|---|
| 24-h mean GH (ng/ml) | 1.26 ± 0.2 | 0.28 ± 0.1a | 0.32 ± 0.1a |
| Pulse frequency (per day) | 3.6 ± 0.4 | 2.7 ± 0.8 | 3.1 ± 0.5 |
| Mean pulse amplitude (ng/ml) | 6.38 ± 1.11 | 2.46 ± 1.03a | 1.48 ± 0.53a |
| Mean interpulse level (ng/ml) | 0.32 ± 0.07 | 0.20 ± 0.11 | 0.24 ± 0.11 |
Values are expressed as mean ± se.
Significantly different from baseline, P < 0.05.
Plasma insulin and cortisol concentration
Not surprisingly, mean 24-h plasma insulin concentration was increased by about 2-fold, while overeating compared with baseline (Fig. 2A). In contrast, the increase in fasting plasma insulin concentration (8.1 ± 1.6, 11.7 ± 2.9, and 11.8 ± 4.5 μU/ml the morning after an overnight fast at baseline, d 3, and 2 wk, respectively) did not quite reach statistical significance (P = 0.12). Overeating also did not affect 24-h plasma cortisol concentrations (Fig. 2B; all P = 0.56).
Fig. 2.
Mean 24-h plasma concentrations of insulin (A) and cortisol (B) before overeating (baseline), on d 3 of overeating, and at the end of the 2-wk overeating period. *, P < 0.05 vs. baseline.
Plasma IGF-I concentration
Although GH is known to augment hepatic IGF-I production, we found that the marked suppression in plasma GH concentration during overeating period did not translate into a change in total plasma IGF-I (Fig. 3A). However, plasma concentrations of IGF-I binding proteins (IGFBP3 and IGFBP1), which can impact the bioavailability of IGF-I, were affected by overeating (Fig. 3, B and C). Plasma IGFBP3 concentrations underwent a small but significant increase (3.5 ± 0.2, 4.1 ± 0.1, and 4.2 ± 0.2 ng/liter at baseline, d 3, and 2 wk, respectively; P = 0.004). In contrast, there was a significant main effect (P = 0.044) for a reduction in IGFBP1 (36.2 ± 11.2, 17.4 ± 4.7, and 14.7 ± 3.1 ng/ml at baseline, d 3, and 2 wk). Furthermore, we also found a significant main effect (P < 0.05) of overeating on plasma free IGF-I concentration (1.3 ± 0.4, 1.1 ± 0.2, and 2.3 ± 0.4 ng/ml at baseline, d 3, and 2 wk, respectively; Fig. 3D) with a significant increase in free IGF-I concentration at 2 wk (P < 0.05 vs. d 3).
Fig. 3.
Mean plasma concentrations of total IGF-I (A), IGFBP-3 (B), IGFBP-1 (C), and free IGF-I (D) in the morning after an overnight fast before overeating (baseline), on d 3 of overeating, and at the end of the 2-wk overeating period. *, P < 0.05 vs. baseline; #, P = 0.057 vs. baseline; and +, P < 0.05 vs. d 3.
Discussion
Overeating induces complex endocrine responses that can alter metabolism. The major finding of this study demonstrated a marked reduction in daily GH secretion after only a few days of overeating. Although low GH concentration is a common feature associated with obesity, the reduction in GH concentration we observed in this study occurred before any change in body mass. Additionally, the reduction in GH did not coincide with changes in many factors known to regulate GH secretion (i.e. plasma concentrations of IGF-I, cortisol, fatty acids, or glucose during fasting). However, GH suppression was accompanied by an increase in the average 24-h insulin concentration, which has been demonstrated to reduce GH secretion in vitro (8, 9), and may play a key role in the suppression in the GH secretion that we observed with overeating.
Excessive body fat has long been associated with suppressed GH concentration (4, 6, 7). Our findings suggest that overeating can markedly suppress GH secretion in advance of an increase in body fat. Although we did not assess body fat content after 3 d of the overeating period, body weight did not change, and previous studies have reported no measurable increase in fat mass or body weight after 5 d of overeating (10). Therefore, the suppression in GH after 3 d of overeating in our study was due to the more immediate metabolic or endocrine responses to overeating per se, rather than increase in fat mass. Indeed, GH secretion is known to be regulated by several factors, including IGF-I (11), cortisol (12), fatty acids (13), and insulin (8).
The stimulatory effect of GH on IGF-I production is well described (14–16), and we recently reported that plasma IGF-I production was determined by basal GH concentration rather than GH pulses (14). Therefore, given that the suppression in GH concentration we observed with overfeeding was a consequence of a reduction in GH pulse amplitude, with no change in basal GH concentration (i.e. plasma interpulse GH concentration), it was not surprising that total IGF-I concentration was not affected by overeating in our study. Converse to the stimulatory effects of GH on IGF-I production, IGF-I provides a well-described negative feedback on GH secretion (11, 17–19). IGF-I is known to inhibit GH secretion by decreasing GH mRNA and GH production in cultured primate pituitary cells (9). Although we found total plasma IGF-I concentration to remain unchanged throughout the 2-wk overeating period, total IGF-I may not adequately reflect IGF-I bioactivity (20). It has been reported that plasma free IGF-I, rather than total IGF-I, plays a key role in the inhibition of GH release (20). Only approximately 1% of all plasma IGF-I is found in the free/unbound form (21). At least seven IGFBPs can bind IGF-I (20, 22), and in doing so, can modify or interfere with interactions between IGF-I and its receptor (23). We measured the concentration of two key IGFBPs (IGFBP3 and IGFBP1) because approximately 90% of IGF-I is typically bound to IGFBP3 (24), and IGFBP1 has been suggested to be pivotal in the acute regulation of IGF-I activity (25). Although most of IGF-I is bound to IGFBP3 (24), the increase in plasma free IGF-I concentration by the end of our overfeeding period corresponded with a slight, yet significant increase in IGFBP3. In contrast, the abundance of plasma IGFBP1 declined during overeating, which is consistent with the known effect of chronic hyperinsulinemia on IGFBP1 (26, 27). Although we did find plasma free IGF-I concentration to be elevated by the end of the 2-wk overeating period, the large suppression in plasma GH concentration that we observed occurred before any increase in free IGF-I. Therefore, free IGF-I was unlikely to be contributing to the reduction in GH secretion after a few days of overeating, which agrees with work from previous studies in obesity (28, 29).
Glucocorticoids, such as cortisol, are known to augment pituitary GH secretion by increasing the pituitary expression of GHRH receptor (30) and the GH-secretagogue receptor (12), as well as reducing the IGF-I-mediated feedback inhibition of GH release (31). However, because we found no change in the average plasma cortisol concentration over 24 h during the overeating period, it is unlikely that plasma cortisol contributed to the suppression in GH secretion in our study. Additionally, fatty acids are known to impair GH secretion by reducing the mRNA of GH, GHRH receptor, and GH secretagogue receptor in cultured pituitary cells (9), and this may be due to a fatty acid-induced reduction in protein kinase A activity in the pituitary (32). Reducing plasma fatty acid concentration in obese adults using the antilipolytic agent, acipimox, was found to augment the GH response to GHRH (33). Therefore, the elevated fatty acid availability present in obesity (2) may be a major contributor to the obesity-related reduction in GH secretion. However, changes in plasma fatty acid concentration could not explain the suppression in GH concentration we found in our study because plasma fatty acid concentration remained very low during the 2-wk overeating period, likely due in large part to the chronically elevated plasma insulin concentrations. Importantly, by itself the low fatty acid concentration in our study would be expected to enhance GH secretion. However, the potent suppressive effect of hyperinsulinemia has been found to override the sensitizing effects of low fatty acid concentration of GH secretion (34).
Previous studies demonstrated that insulin inhibits pituitary GH secretion by reducing the mRNA of GH, GHRH receptor, and GH secretagogue receptor, as well as GH production in cultured pituitary cells (8, 9, 35). In humans, increasing plasma insulin concentration, via low-level insulin infusions, has been found to reduce the GH response to GHRH in a dose-dependent manner (34). Although the GHRH-induced GH response was not significantly reduced when plasma insulin concentration was increased to only approximately 13 mU/ml, increasing plasma insulin concentration to approximately 35 mU/ml significantly reduced GH secretion (34). Because postprandial plasma insulin concentrations often increase to levels well above 35 mU/ml, the findings from Lanzi et al. (34) indicate that even relatively small meals can suppress GH. This suppression in GH secretion after meals appears to be independent of the postprandial rise in plasma glucose concentration because hyperglycemia was found to not alter GH secretion when plasma insulin was kept constant (36). Therefore, the GH suppression induced by overeating in our study was likely due to the rapid and sustained elevation in plasma insulin concentration resulting from the frequent ingestion of high-calorie meals and snacks during the overeating period.
The suppression in GH secretion with overeating may have important metabolic impact. Several studies have observed low plasma GH concentration in obese patients (37–39), leading some to suggest that reduced GH secretion may underlie some obesity-related metabolic abnormalities (5, 40). However, our data illustrate that overeating, per se, can suppress GH secretion before the actual weight gain. Importantly, overeating rapidly and consistently suppressed the GH pulse amplitude, which is known to selectively regulate several metabolic processes, including lipolytic rate (38, 41). As a result, GH suppression can influence metabolic substrate selection through its effect on lipolysis (42). Additionally, GH is also known to impair insulin sensitivity (42). The insulin-desensitizing effects of GH have been attributed in part to fatty acid-induced insulin resistance that occurs in consequence to the GH-mediated increase in lipolysis (43). In addition, GH has been reported to induce insulin resistance through a down-regulation in the insulin-signaling pathway via the p85α subunit of phosphatidylinositol-3-kinase (44, 45). Therefore, the impairment in insulin sensitivity commonly found with overeating (10, 46) would likely be even more severe without this suppression in GH secretion. Additional experiments are needed to better understand the physiological impact of the rapid suppression of GH pulsatility with overeating.
It is important to note that during the 2-wk protocol, our participants were not only overeating, but they were also restricted in physical activity level (1500 steps per day). Therefore, we cannot directly distinguish the effects of the overeating from the potential impact of very low physical activity levels. It is clear that exercise augments plasma GH concentration (47), and there appears to be a dose response because heavy resistance exercise (48) and sprinting (49, 50) can induce relatively high transient elevations in plasma GH concentration. However, plasma GH concentration returns to basal levels within a few to several hours after the exercise session. Moreover, available evidence suggests that plasma GH concentration is not associated with habitual physical activity or inactivity (51). Therefore, we do not believe that the reduction in physical activity in our sedentary subjects contributed much, if anything to the marked suppression in plasma GH concentration, but we cannot rule out this possibility.
In summary, overeating induced rapid and sustained suppression of GH pulse amplitude even before an increase in body weight. The accompanying hyperinsulinemia was a likely mediator of this rapid reduction in GH secretion.
Acknowledgments
We thank Kathleen Symons for the analysis of GH, IGF-I, and IGFBPs, as well as Lisa Michael, R.D., for her tireless efforts as research dietitian and study coordinator. We also thank our participants and the staff of the University of Michigan Clinical Research Unit.
www.ClinicalTrials.gov Identifier: NCT00355784.
This work was supported by National Institutes of Health (NIH) Grant R01DK71955, with additional support from the Michigan Clinical Research Unit (NIH-UL1RR024986), the Michigan Nutritional Obesity Research Center (P30-DK-089503), and the Michigan Metabolomic Obesity Center.
Disclosure Summary: The authors have nothing to disclose.
Footnotes
- IGFBP
- IGF-I binding protein.
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