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ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
* Animal Physiology Research Unit, ARS-USDA, Columbia, MO 65211 and
and
University of Missouri, Columbia 65211
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionImplicationsLiterature Cited |
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0.05). In both treatment groups, peripheral concentrations of leptin increased from d 7 to 8, and cortisol decreased from d 1 to 5 of the experiment. These observations provide evidence that ghrelin may positively influence weight gain and concomitantly increase GH, insulin, and cortisol secretion in weaned pigs.
Key Words: Appetite • Feed Intake • Ghrelin • Pigs • Weaning
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionImplicationsLiterature Cited |
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; Forbes, 1995). There would be benefits to pork producers if this period of low feed consumption could be shortened or eliminated.
Ghrelin, an appetite-stimulating hormone produced and secreted primarily from the stomach, is an important variable in the initiation of feeding behavior in rats (Nakazato et al., 2001; Shintani et al., 2001; Wren et al., 2001a), mice (Asakawa et al., 2001a), and humans (Cummings et al., 2001; Wren et al., 2001b). In previous work, we presented the pattern of ghrelin secretion in weaned pigs during a 72-h feed deprivation and refeeding period (Salfen et al., 2003); however, the pattern of ghrelin secreted during weaning in pigs has not been investigated, nor have the effects of ghrelin treatment of pigs during this period been examined.
Although the orexigenic action of ghrelin is a powerful stimulus to motivate renourishment of the animal, ghrelin is also a potent GH secretagogue, which may be as important for metabolic partitioning of feedstuffs. It is currently believed that ghrelin’s orexigenic functions and GH secretagogue effects are independent of each other (Tschop et al., 2000; Nakazato et al., 2001).
The objectives of this experiment were to determine ADFI, ADG, and feeding behavior in weanling pigs that received exogenous ghrelin. The endocrine responses elicited by ghrelin were also characterized, as were the patterns of hormones that influence feed intake and somatotropic response during an 8-d period following weaning. Effects on the stress response, as measured by serum cortisol, were also measured during this period.
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Materials and Methods |
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) on the day of weaning, allowed free access to water and a commercial starter feed (25% CP, as-fed basis; MFA Muscle Pig 1 C; MFA Inc., Columbia, MO) and allowed to recover overnight. Pigs were assigned to one of two treatment groups as follows. Ghrelin-treated pigs (n = 12) were infused, via jugular catheter, thrice daily with human ghrelin (2 µg/kg BW; No. 031-30; Phoenix Pharmaceuticals Inc., Belmont, CA) at 0800, 1600, and 2400 for 5 d. Ghrelin was diluted to 20 µg/mL in physiological saline every 2 d during the infusion period and kept in light-shielded glass bottles at 4°C. Control pigs (n = 12) were infused similarly with 0.9% saline. Blood samples (4 mL) were collected at –15, 0, 15, 30, 60, 90, 120, 240, and 480 min relative to the first infusion and at 0800, 1600, and 2400 every day for 8 d. Blood was collected before the treatment infusions via the jugular catheter. Catheters were flushed with 4 mL of saline and 1.5 mL of heparinized saline after each blood sample was collected or treatment delivered through the catheter. Blood samples were allowed to clot at 4°C for 8 h and were centrifuged at 1,600 x g for 20 min; aliquots of serum were collected into three microcentrifuge tubes per sample and stored at –60°C until hormone analysis.
ADFI and ADG
Pig BW and feeder weights were collected to determine ADG and ADFI (as-fed basis) at d 0 (weaning), 2, 3, 4, 5, 6, 7, and 8 of the experiment. Pig BW measurements were collected after the collection of the 0800 blood samples to avoid influencing stress hormones.
Behavioral Observations
Immediately before each blood sample collection during the intensive sampling period, a single observer at a single time point noted the activity of the pigs over time. Activities recorded were lying, standing, sitting, and eating. For subsequent observations, activity was noted 20 to 30 min after each blood sample was taken throughout the duration of the experiment.
Hormone and Glucose Assays
Serum concentrations of ghrelin, GH, IGF-I, leptin, insulin, glucose, and cortisol were quantified during the intensive sampling period and concentrations of ghrelin, IGF-I, leptin, glucose, and cortisol were determined from d 1 to 8 of the experiment using the 0800 serum sample. Additionally, samples collected at 2400 on d 5 and at 0800, 1600, and 2400 on d 6 were analyzed for serum ghrelin, GH, IGF-I, leptin, insulin, glucose, and cortisol to determine the hormonal response following the last infusion at 2400 on d 5.
Total serum ghrelin was quantified using a commercially available radioimmunoassay kit (Phoenix Pharmaceuticals Inc.) that has previously been validated in our laboratory (Salfen et al., 2003). The kit protocol was followed per manufacturer’s instructions with the exception that 25 µL of serum was diluted with 75 µL of assay buffer for use in the assay. Mean inter- and intraassay CV were 13%.
Serum GH was quantified using a specific porcine GH (Linco Research, St. Charles, MO) that has been previously validated in our laboratory (Salfen et al., 2003). Mean inter- and intraassay CV were less than 6% and assay sensitivity was 0.25 ng/mL.
Serum IGF-I was quantified without extraction using an immunoradiometric assay kit (Diagnostic Systems Laboratories, Webster, TX) that has been validated for use in our laboratory (Salfen et al., 2003). Inter- and intraassay CV were 11% and 3%, respectively.
Serum concentrations of leptin were determined as previously described and validated (Berg et al., 2003). Dilutions of a pool of porcine serum were parallel to the standard curve. The interassay CV was 15% and the intraassay CV was 10%.
Serum cortisol was determined using a Coat-A-Count solid-phase RIA kit (Diagnostic Products Corp., Los Angeles, CA) that has been validated in our laboratory (Daniel et al., 1999). Sera were analyzed in one assay and the intraassay CV was 5%.
Serum insulin was measured using a commercially available RIA kit specific for porcine insulin (Linco Research, St. Charles, MO). Mean inter- and intraassay CV were 12% and 6%, respectively.
Serum glucose was determined via the glucose oxidase method (Trinder, 1969) using commercially available components (Thermo DMA, Louisville, CO). Mean inter and intraassay CV were less than 4%.
Statistical Analysis
Serum concentrations of ghrelin, GH, IGF-I, insulin, leptin, cortisol, and glucose were determined following the initial ghrelin infusion. Additionally, four sampling periods surrounding the last infusion of ghrelin (d 5 at 2400 [last infusion] and d 6 at 0800, 1600, and 2400) were also analyzed for ghrelin, GH, IGF-I, insulin, leptin, and glucose to determine the hormonal return to baseline concentrations after the ghrelin infusion period was terminated. The 0800 samples from d 1 to 8 of the experiment were used to determine the serum concentrations of ghrelin, IGF-I, insulin, leptin, cortisol, and glucose during the weaning transition.
Feed intake, weight gain, and hormonal data were analyzed by ANOVA for repeated measures and mean comparisons were made using Fisher’s protected LSD with the StatView statistical analysis program (SAS Inst. Inc., Cary, NC; Littell et al., 1998). Main effects were treatment, time (minute, sample, or day), and the treatment x time interaction. Behavioral data were analyzed using the polytomous logistical regression analysis of StatView.
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Results |
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). During the infusion period (d 1 to 5) and during the postinfusion period (d 6 to 8), there was an effect of time on pig BW (both P < 0.001). There tended to be a treatment x time interaction (P = 0.08), with the ghrelin pigs being heavier than control pigs during the infusion period. This interaction was not present during the postinfusion period (P = 0.99) as the weight gains of both treatment groups were parallel during d 7 and d 8 of the experiment (Figure 1a). The ghrelin pigs gained over 2.5 times more weight (0.57 ± 0.1 kg) than control pigs (0.21 ± 0.13; P = 0.04) during the infusion period, largely because the control pigs took longer to regain weight lost following weaning than did the ghrelin pigs (Figure 1b). By d 3 after weaning, ghrelin pigs had gained weight, whereas it took the control pigs until d 5 to regain weight lost following weaning. During the postinfusion period, BW gain did not differ between treatment groups (P = 0.68).
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). Feed intake was not affected by treatment (P = 0.29) or treatment x time interactions (P = 0.84) during the infusion period (0.47 ± 0.07 kg and 0.58 ± 0.08 kg for control and ghrelin treatments, respectively; Figure 1d). Likewise, there was no effect of treatment (P = 0.26) or treatment x time interaction (P = 0.13) on feed intake during the postinfusion period (0.52 ± 0.05 kg and 0.60 ± 0.04 kg for control and ghrelin treatments, respectively). Behavioral responses to the infusions were not remarkable. However, on d 2 at 2400 and on d 3 at 1600, more ghrelin pigs were observed eating following treatment than control pigs (P < 0.04).
Serum concentrations of ghrelin, as determined during the intensive blood sampling following the first infusion, followed a predictable pattern consistent with the effects of treatment, time, and treatment x time interaction (P < 0.001; Figure 2a). Specifically, there was no difference in serum concentrations of ghrelin at the –15- and 0-min time points (P = 0.17 and 0.35, respectively), but serum ghrelin in the ghrelin group peaked at 809 pg/mL within 15 min of the i.v. infusion and then decreased to nearly half-maximal values (387 pg/mL) by 30 min after infusion. Serum concentrations of ghrelin remained greater in the ghrelin than in the control pigs until 240 min after infusion when peripheral concentrations of ghrelin did not differ with respect to treatment (P = 0.16; Figure 2a).
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There was an effect of treatment (P < 0.001), day (P < 0. 001), and a treatment x day interaction (P < 0.001) on daily ghrelin concentrations throughout the experiment. Serum ghrelin was similar between treatment groups by d 7 of the experiment (P = 0.85) but were elevated on d 2, 3, 4, 5, and 6 in the ghrelin pigs. Even though blood samples during this part of the experiment were all collected 8 h after the previous infusion was administered, serum ghrelin was greater on d 1 than on d 2 (P < 0.001), was greater on d 2 than on d 3 (P = 0.004), and tended to be greater on d 3 than on d 4 (P = 0.07; Figure 3a) in the ghrelin pigs. Thereafter, serum ghrelin remained relatively constant and was not different. In contrast, serum ghrelin in control pigs gradually increased throughout the postweaning period (P < 0.001). By d 4 following weaning, ghrelin was greater than on d 1, 2, or 3 and continued to increase until the end of the experiment (d 8) when it was at its greatest concentration (Figure 3a) in the control pigs.
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). Before the initial infusion of ghrelin, serum GH did not differ between treatment groups at –15 min but was greater in control pigs at 0 h (P = 0.03). Serum GH increased dramatically within 15 min following ghrelin infusion (130 ± 18.9 ng/mL) compared with control pigs (10.7 ± 3.7 ng/mL; P < 0.001). Serum GH was increased in the ghrelin pigs throughout the 60-min time interval. Interestingly, serum GH was lower in the ghrelin pigs at 120 min after infusion compared with control pigs (3.7 ± 0.5 and 11.9 ± 3.3, respectively; P < 0.02). In contrast to serum ghrelin, there were no differences in GH at the end of the 5-d infusion period (P = 0.93). The samples collected at these time points were at least 8 h following the previous ghrelin or saline infusion. The general pattern of secretion was similar between the ghrelin and control pigs, and there was no effect of time (P = 0.90) or treatment x time interaction (P = 0.30).
Serum IGF-I did not change owing to the initial infusion of ghrelin; therefore, there was no effect of treatment (P = 0.71). There was an effect of time with a continual decrease in serum IGF-I throughout the intensive sampling period in both treatment groups (Figure 2c). Serum IGF-I was at its lowest point 480 min following the initial infusion in both treatments (P < 0.001). There was no effect of treatment on daily IGF-I concentrations, and, in both treatment groups, the decrease in serum IGF-I on d 1 of the experiment was dramatic and continued until d 2, at which point it remained relatively stable (Figure 3b). By d 4, IGF-I reached its lowest concentration and increased from d 5 to 6, d 6 to 7, and again from d 7 to 8. By d 8 of the experiment, serum IGF-I had risen to concentrations comparable to those of d 1. This gradual increase in IGF-I was also evidenced in samples taken on d 5 and 6. There was no effect of treatment during this sampling period, but IGF-I increased from the 2400 sample on d 5 throughout the 2400 sample on d 6 (P < 0.001).
Serum concentrations of leptin were not affected by treatment (P = 0.45), and leptin did not change throughout the intensive sampling time period following the initial infusion (P = 0.92), nor was there a treatment x time interaction (P = 0.31; Figure 2d). Serum leptin also did not differ between treatments at the end of the infusion period (P = 0.39); however, when both treatments were combined and daily leptin values throughout the experiment were analyzed, there was an effect of days after weaning (P = 0.003). Leptin remained relatively constant from d 1 to 6 but increased at d 7 after weaning compared with d 1 (P = 0.04). Concentrations of leptin continued to increase, with concentrations being greater on d 8 than 7 (P = 0.05; Figure 3c).
There was an effect of time and a treatment x time interaction on serum insulin concentrations during the intensive sampling period (Figure 2e). Insulin was elevated in the ghrelin treatment group at the 15-min time point compared with the control pigs (4.41 ± 0.43 and 2.55 ± 0.30 µU/mL, respectively; P = 0.002). There were no differences at any other time point before or after infusion of ghrelin or saline during the intensive sampling period. Serum insulin did not differ between treatment groups at the end of the infusion period (P = 0.24), nor was there a time (P = 0.29) or a treatment x time interaction (P = 0.42).
There tended to be an effect of time relative to the first infusion on serum glucose (P = 0.06); however, there was no effect of treatment (P = 0.46) or a treatment x time interaction (P = 0.49). When both treatment groups were combined, there was an increase in serum glucose at 15 min and 480 min compared with the –15-min time point (Figure 2f). Glucose was lower in both treatment groups at 2400 on the fifth day of infusion compared with the 0800 and 2400 samples collected on the sixth day (P < 0.02). Daily glucose concentrations throughout the experiment were influenced by day after weaning (P = 0.01) and tended to be affected by a treatment x day interaction (P = 0.09; Figure 3d). Glucose increased on d 2 in the ghrelin pigs compared with d 1 (P = 0.002) and decreased until d 4 of the experiment. It increased again from d 6 until the experiment ended on d 8 (P = 0.006). In contrast, glucose concentrations remained relatively constant throughout the postweaning experimental period in the control pigs (P = 0.60).
Serum concentrations of cortisol increased following the initial ghrelin infusion and were increased at the 15-min (P = 0.01) and 30-min (P < 0.001) time points (Figure 2g). Additionally, there was an effect of time following the last ghrelin infusion with the 2400 sample on d 6 having greater cortisol concentrations than the 2400 sample from d 5 or the 0800 and 1600 samples collected on d 6 (P < 0.03). Serum cortisol decreased from d 1 through d 5 of the experiment (Figure 3e). Cortisol concentrations were greatest on d 1 (65.2 ± 5.5 ng/mL) and continued to decrease until d 5 (14.2 ± 1.6 ng/mL), at which point it remained unchanged throughout d 8.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionImplicationsLiterature Cited |
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), which also differs from porcine ghrelin by three amino acids (Kojima et al., 1999). Cross-species comparisons of biological activity must be viewed with caution because ghrelin effects on appetite and effects on GH secretion may occur via two separate receptors. This is evidenced by the fact that administration of a neuropeptide Y1 antagonist reversed a ghrelin-induced increase in food intake (Shintani et al., 2001), but treatment with a ghrelin agonist (GHRP-2) increased weight gain in neuropeptide Y-null mice (Tschop et al., 2002).
Weaning resulted in a temporary decrease in BW in both the control and ghrelin pigs; however, pigs in the ghrelin treatment regained the lost weight more rapidly than control pigs. Although an effect of ghrelin on feed intake was not detected throughout the infusion or post-infusion period, a positive effect on appetite may be present but at a level that was unable to be resolved given the number of pigs utilized in this experiment. Ghrelin acutely stimulates feeding in rats (Nakazato et al., 2001; Wren et al., 2001a) and mice (Asakawa et al., 2001a) when administered via intracerebroventricular injection. Cumulative feed consumption is also increased during chronic systemic or intracerebroventricular infusion in rats (Wren et al., 2001a).
The intravenous dose of ghrelin in the present experiment was within the range of 0.2 to 5.0 µg/kg body weight doses used by Takaya et al. (2000) in human studies. Doses of 1 µg/kg BW have also been used to determine the effects of ghrelin in humans (Broglio et al., 2001) with significant findings; however, we chose to increase the dose to 2 µg/kg BW because the activity of human ghrelin in this age of pig was unknown and we wanted to ensure an elevated serum ghrelin concentration throughout the infusion phase of the experiment. Ghrelin has a relatively short half-life; therefore, the route of administration and dose might also influence the effect it has on feed intake. This concept is supported by a 28% increase in voluntary energy intake in humans continuously infused with ghrelin as opposed to intake in saline-infused individuals (Wren et al., 2001b). The apparent half-life of ghrelin following the initial i.v. infusion is approximately 15 min in pigs of this age as evidenced by the disappearance rate. This is a shorter duration than the 30-min half-life of exogenous ghrelin reported in rats (Tolle et al., 2002) but close to the 10-min half-life in reported in humans (Nagaya et al., 2001). Even with this relatively short half-life, serum ghrelin remained above control concentrations throughout 120 min after infusion. It is also interesting to note that concentrations of ghrelin 8 h after the previous ghrelin infusion were less on d 3, 4, 5, and 6 than concentrations determined on d 2. An up-regulation of specific metabolic clearance mechanisms for ghrelin may be responsible for this difference. Increased clearance of a hormone has been demonstrated previously, as insulin-stimulated phosphorylation of carcinoembryonic antigen–related cell adhesion molecule-1 leads to up-regulation of receptor-mediated insulin endocytosis and degradation (Poy et al., 2002). Ghrelin was sufficiently cleared from one infusion to the next so that there was no accumulation of ghrelin in the serum throughout the experimental time period, as evidenced by the serum ghrelin concentrations measured on d 5 and 6. By 16 h following the last ghrelin infusion, there was no difference in ghrelin between the pigs administered ghrelin and control.
Another objective of the present experiment was to characterize concentrations of ghrelin in pigs following weaning. We determined that ghrelin concentrations in pigs that had been weaned increased by d 4 and continued to gradually increase through at least d 8 after weaning. Ghrelin concentrations have been shown to increase throughout the postnatal life of rats (Lee et al., 2002), and ghrelin concentrations at d 8 were similar to what we observed in a previous experiment using pigs 10 d after weaning (Salfen et al., 2003). The increase in serum ghrelin on d 4 occurs at approximately the same time as cortisol also reaches a nadir following the acute rise at weaning. There are physiological changes in the pig’s gastrointestinal tract during this period, and weaning anorexia during the first 4 d following weaning involves local inflammation of the intestinal tract (McCracken et al., 1999). This may also be a factor in lowering serum concentrations of ghrelin because interleukin-6, a key player in the systemic inflammatory response, also negatively influences body weight and fat pad weight in rats (Wallenius et al., 2002).
The lack of difference in feed intake between treatment groups agrees with the lack of a difference in activity scores of pigs during the intensive sampling/observation periods throughout the experiment. Observation periods conducted following ghrelin and saline infusions were arranged at a point where any increased feeding activity should have been detectable.
Ghrelin elicits an increase in cortisol as well as an increase in corticotropin-releasing hormone mRNA expression in the hypothalamus (Asakawa et al., 2001b) and a chronic nonspecific stress imposed on rats is capable of inducing hyperphagia and weight gain in rats (Rowland et al., 1976) as well as increased ghrelin mRNA abundance (Asakawa et al., 2001b). Weaning encompasses a myriad of social, nutritional, and environmental challenges, and the activity of animals in the ghrelin group may have been masked by behaviors due to weaning alone. When individually penned, weaned pigs that were deprived of feed after the transition to solid feed and maternal/offspring separation anxiety had been completed, cortisol increased within 12 h, whereas serum ghrelin concentrations were not elevated until 36 to 48 h into the feed-deprivation period (Salfen et al., 2003). The potential of ghrelin to increase feed intake in pigs that are not undergoing concurrent stressors has not yet been investigated, but concurrent stressors are typically additive in their negative effects on general productivity indices (Hyun et al., 1998).
In the present experiment, cortisol decreased from d 1 to 5 in both treatment groups. This is similar to what was reported previously from our laboratory for newly weaned pigs (Carroll et al., 1998). Infusion of ghrelin induced a transient increase in serum cortisol in the ghrelin treatment group; however, cortisol was still elevated from weaning at this time point and any increased cortisol may not have been reflected in an increase in feeding behavior or activity. The fact that cortisol is increased in pigs following an infusion with human ghrelin is evidence that human ghrelin does act on the porcine ghrelin receptor that may be involved with anxiogenesis and possibly feed intake. It is interesting to note that ghrelin generally promotes anxiogenic activities, rather than the anxiolytic action that is associated with neuropeptide Y (Heilig et al., 1988).
The identification of ghrelin as the endogenous ligand for the G-protein coupled orphan growth hormone secretagogue receptor was reported by Kojima et al. (1999). The stimulatory effect of ghrelin is synergistic with GHRH (Hataya et al., 2001), and evidence exists that it acts at the level of the hypothalamus to modulate GHRH secretion (Kamegai et al., 2001) as well as at the level of the somatotrope (Glavaski-Joksimovic et al., 2003) to induce GH secretion. Our results support the hypothesis that ghrelin may act as a GH secretagogue in pigs owing to the fact that there was a significant increase in GH following the initial ghrelin infusion. This release was followed by a period of lower serum GH at 120 min in the ghrelin group, presumably resulting from depletion of intracellular calcium stores (Petit et al., 1999) or secretagogue-sensitive pools of intracellular GH (Richardson and Twente, 1988). The magnitude of GH release in response to the subsequent infusions of ghrelin is unknown in pigs; however, repeated injection of L-692,585, a GH secretagogue that binds to the growth hormone secretagogue receptor, did not cause desensitization when repeatedly administered to dogs (Jacks et al., 1994). Exogenous administration of porcine GH has been shown to increase growth rate and muscle mass and decrease carcass lipid content in swine (Etherton et al., 1986); therefore, the potential for ghrelin to affect these same variables also exists.
Serum IGF-I was not affected by treatments of ghrelin in the present experiment. During the intensive sampling period on d 1, IGF-I decreased through 1600. The explanation for this gradual decrease was elucidated when daily IGF-I concentrations were analyzed throughout the experiment. A dramatic decrease in serum IGF-I occurred from d 1 to 2 after weaning and remained low until d 6, at which point it began to increase. This agrees with past work from our laboratory (Carroll et al., 1998) and elsewhere (White et al., 1991) in which a rapid decrease in IGF-I occurred following weaning. Although fasting increases both IGF-I and GH in newborn pigs (Farmer et al., 1992), an apparent uncoupling of the GH/IGF axis develops by 2 wk of age in pigs (Carroll et al., 1998). Thus, repeated elevations in GH via ghrelin infusions may not result in an increase in serum IGF-I, at least in pigs during a period of nutritional restriction. If there is little or no increase in IGF-I in response to elevations in GH, then it is unknown how the weight gain observed in the present experiment could have been achieved, if not by way of increased muscle accretion. This may be explained by paradoxical effects of ghrelin in inducing adiposity by decreasing fat utilization (Tschop et al., 2000) while independently increasing GH secretion, which is generally associated with a loss of adipose tissue and an increase in muscle accretion. An increased efficiency of nutrient utilization via an alteration in the metabolic state is therefore a distinct possibility.
Leptin concentrations were seemingly unaffected by ghrelin infusions. This was not unexpected because ghrelin is thought to be part of the orexigenic pathway downstream from leptin. Ghrelin antagonizes leptin’s actions via an activation of the neuropeptide Y/Y1 receptor pathway in the hypothalamus and is negatively regulated by leptin (Asakawa et al., 2001a; Shintani et al., 2002). Weaned pigs have very little fat stores and therefore secrete very little leptin. Furthermore, leptin has been previously reported to fall to low concentrations within 12 h following the initiation of feed deprivation in young weaned pigs (Salfen et al., 2003); thus, a further decrease in leptin would be difficult to achieve or detect. As the pigs started to consume more feed and gain more weight by d 7 and 8 of the experiment, leptin concentrations started to increase, concomitant with the time when ghrelin infusions were no longer being administered.
Ghrelin infusions caused an immediate increase in serum insulin within 15 min of the initial infusion in the present experiment, which is in agreement with what other investigators have observed in rats (Lee et al., 2002). Ghrelin and ghrelin receptor transcripts are present in the pancreas and isolated rat islets, and ghrelin binding to the receptor potentiates in vitro insulin secretion in response to glucose via a Ca2+-mediated second messenger mechanism (Date et al., 2002). The relative roles and quantities of stomach (endocrine)- vs. pancreatic (paracrine)-derived ghrelin in stimulating insulin secretion have not yet been determined; however, the stomach is thought to be the primary source for most of ghrelin’s effects. It is also interesting to note that at least some of ghrelin’s effects take place through vagal mediation (Masuda et al., 2000), which plays a role in the control of the endocrine pancreas (Cryer and Polonsky, 1998).
Serum glucose was not acutely affected by the first infusion of ghrelin, and both treatment groups exhibited numerical increases in serum glucose at the 15-min time point. This may have been due to increased activity during the intensive sampling period and concomitant increase in appetite in the daytime after a low level of feed intake during the night. Blood glucose concentrations are thought to be a regulator of ghrelin secretion because serum ghrelin decreased after an oral or i.v. administration of glucose in humans (Shiiya et al., 2002); however, a ghrelin injection in fasted humans has been shown to increase glucose, which was followed by a decrease in insulin. This response occurred when ghrelin was administered, but it did not occur when a synthetic GH secretagogue was administered (Broglio et al., 2001). Insulin or insulin effectiveness may also be a regulator of ghrelin secretion, as an increase in insulin via infusion was sufficient to elicit a fall in serum concentrations of ghrelin in rats (McCowen et al., 2002). The fact that serum glucose was elevated in the ghrelin-treated pigs at d 2 compared with d 1 may have been due to either an increase in feed intake or glycogenolytic activity within the ghrelin pigs at d 2 that was not present following the initial ghrelin infusion. Serum glucose in both treatments was low from d 4 to 6 of the experiment but glucose started to increase at d 7 and 8 in the ghrelin pigs whereas it lagged in the control pigs and remained low throughout d 7 and 8.
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2 Correspondence: 114 Animal Sciences Research Center (phone: 573-882-6261; fax: 573-884-4798; e-mail: carrollja{at}missouri.edu).
Received for publication December 1, 2003. Accepted for publication March 12, 2004.
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