J. Anim Sci. 2006. 84:1682-1690. doi:10.2527/jas.2005-484
© 2006 American Society of Animal Science
ANIMAL GROWTH, PHYSIOLOGY, AND REPRODUCTION |
Oral and intravenous carbohydrate challenges decrease active ghrelin concentrations and alter hormones related to control of energy metabolism in horses1
M. E. Gordon and
K. H. McKeever2
Equine Science Center, Department of Animal Sciences, Rutgers, the State University of New Jersey, 84 Lipman Drive, New Brunswick 08901
 |
Abstract
|
|---|
This study tested the hypothesis that grain and intravenous dextrose challenges would alter plasma concentrations of active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol in Standardbred mares. To deliver 0.5 g of glucose (dextrose solution for the intravenous test)/kg of BW, mares received intravenous dextrose (50% solution) or oral grain administration in 2 trials. In response to the oral grain challenge, plasma glucose and insulin concentrations increased (P < 0.001) by 56 and 802%, respectively. Plasma ghrelin concentration initially decreased (P < 0.001) by 40%, then subsequently increased (P < 0.05) from its nadir by 259%. Plasma leptin concentration decreased (P = 0.002) 17% compared with baseline. There was no change (P = 0.34) in plasma adiponectin concentration in response to oral grain challenge; however, plasma cortisol concentrations decreased (P < 0.001) by 24%. In response to the intravenous dextrose challenge, plasma glucose and insulin concentrations increased (P < 0.001) by 432 and 395%, respectively. Plasma active ghrelin concentration initially decreased (P < 0.001) by 56%, then subsequently increased (P < 0.001) from its nadir by 314%. Plasma leptin concentration also increased (P < 0.001) by 33% compared with baseline. There was no change (P = 0.18) in plasma adiponectin concentration throughout the dextrose challenge. Plasma cortisol concentration increased (P = 0.027) by 20%. Hence, oral grain and intravenous nutrient challenges have the ability to alter variables potentially related to energy metabolism in mares, with acute changes in glucose and insulin possibly modulating changes in ghrelin and leptin.
Key Words: adiponectin • ghrelin • horse • leptin
|
INTRODUCTION
|
|---|
Understanding the control of hormones such as active ghrelin, leptin, and adiponectin is important to understand the complex regulation of energy homeostasis. Peripheral concentrations of the orexigenic hormone ghrelin are negatively correlated with body composition in humans (Tschop et al., 2001
) and horses (Gordon et al., 2005). However, whereas ghrelin concentrations are altered in response to feeding and glucose infusion in humans (Caixas et al., 2002; Shiiya et al., 2002), debate remains as to the mechanism for those alterations. Leptin, an adipocyte hormone, decreases feed intake and increases energy expenditure in rodents (Caro et al., 1996). In horses, plasma leptin concentration is proportional to fat mass (Kearns et al., 2005) with a link to meal feeding (McManus and Fitzgerald, 2000) that may be regulated by insulin (Cartmill et al., 2005). Adiponectin is another adipocyte hormone (Scherer et al., 1995) correlated with fat mass in horses (Kearns et al., 2005). Adiponectin has insulin sensitizing properties (Berg et al., 2001) and a role in metabolic substrate use (Berg et al., 2002). Studies of adiponectin have been contradictory, with an increase in plasma concentration after a mixed meal in obese individuals and no change in lean humans (English et al., 2003; Imbeault et al., 2004). On the other hand, hyperinsulinemic/euglycemic clamps decrease plasma adiponectin in rats and humans (Yu et al., 2002), leaving open the question as to the effect of changes in glucose concentration.
The secretion of the aforementioned hormones is affected by changes in glucose and insulin in humans and rodents (Meier and Gressner, 2004); however, we are unaware of similar studies in horses. With intravenous administration of glucose, one can study the acute effects of a rapid change in glucose concentration. On the other hand, the oral administration of grain allows for the examination of the effects of a slower rate of glucose appearance in the bloodstream. Therefore, this study tested the hypothesis that grain and intravenous dextrose administration would alter plasma concentrations of active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol and that there would be differences in the pattern of the responses to the 2 manipulations.
|
MATERIALS AND METHODS
|
|---|
The Rutgers University Institutional Animal Care Review Board approved all methods and procedures used in this experiment.
Animals
Twelve healthy, normally cycling, unfit, Standardbred mares (age 11 ± 2 yr, 521 ± 77 kg of BW; mean ± SD) were used for oral testing, and 11 of the same horses were used for intravenous testing. Horses were housed indoors in 3 x 3 m stalls at the Rutgers University Equine Research Facility (New Brunswick, NJ) during the experimental period. They had gradually become acclimated to being housed in stalls over a 6-wk period before the experiment. Mares were accustomed to a diet consisting of grass hay (~10 to 12 kg/horse) and a commercially pelleted grain mix (~3 kg/horse), split into 2 feedings at 0730 and 1530, for at least 6-wk before the experiments.
The diet was balanced to meet or exceed the 1989 NRC requirements for horses at maintenance. The concentrate contained 3.09 Mcal/kg of DE, 18.4% CP, 18.0% ADF, 34.5% NDF, 5.4% lignin, 38.2% nonfibrous carbohydrate (NFC), 14.3% sugar, and 4.6% crude fat (DM basis, Dairy One Forage Lab, Ithaca, NY). The hay contained 1.84 Mcal/kg of DE, 7.1% CP, 42.8% ADF, 64.7% NDF, 8.9% lignin, 21.2% NFC, 12.2% sugar, and 2.2% crude fat (DM basis). All mares maintained their BW within 2 to 3% for 2 wk before and through the completion of the study and had BCS of 5 to 7 (Henneke et al., 1983). A plain salt block and fresh water were available ad libitum.
Testing Procedures
The study was conducted in 2 independent phases with mares receiving intravenous dextrose (50% solution) or oral grain on separate occasions, separated by at least 1 wk. To minimize any cues related to feeding, there were strict controls over the timing of the feeding and blood sampling. Therefore, there was no mixing of treatments; in other words, all intravenous trials were performed in 1 wk and all grain trials in the next week. Doses were formulated to deliver 0.5 g of glucose (dextrose solution for intravenous test)/kg of BW, resulting in intravenous infusions of 454 to 593 mL per horse and oral grain challenges of 674 to 887 g/horse. The dextrose solution was gradually infused manually over 5 min. The NFC content in the grain (38.2%) was used to calculate the grain doses. The pellet was a commercially produced equine pellet (Brown and Sons, Pennington, NJ; Table 1). Glucose and NFC are not equivalent; therefore, we chose to base the grain dose on NFC because we wanted to be sure not to miss any NFC that had the potential to be digested in the foregut.
After an overnight period of feed deprivation, mares undergoing dextrose infusion were catheterized percutaneously into the left and right jugular veins, using sterile technique and lidocaine anesthesia. The left catheter served for blood sampling, and the right catheter served for dextrose infusion. Mares undergoing oral grain administration also had feed withheld the night before the test, yet received only one catheter in the left jugular vein for blood collection. Catheters were inserted at 0600, and feeding/infusion took place at 0715.
For the grain trials, steps were taken to avoid cues that could stimulate behavioral and physiological effects that could cause an anticipatory endocrine response. After catheterization and collection of the initial blood samples, only one investigator remained in the lab to quietly monitor the facility. No one else was allowed in the barn until feeding time, and noise cues in and around the barn were eliminated until after entry of the team to feed the mares. At that time, a team of 6 people was used to quietly deliver the aliquoted ration to all 6 horses at the same time. All mares finished ingestion of the grain bolus within 10 min.
Blood samples for the measurement of active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol were taken at time 0 (immediately before administration) and 30, 60, 90, 120, 150, 180, 210, and 240 min postadministration (between 0715 and 1200). Samples were also taken at 5 and 10 min postadministration during the dextrose challenge. Approximately 30 mL of blood was collected into a syringe and then transferred into 3 prechilled 10-mL Vacutainer tubes (Becton Dickinson Inc., Franklin Lakes, NJ). Tubes with heparin anticoagulant were used for glucose and insulin samples, whereas tubes with EDTA anticoagulant were used for ghrelin, leptin, and adiponectin samples. All blood tubes were immediately centrifuged at 1,500 x g for 15 min then aliquoted and frozen at –80°C until analyses. Plasma samples for active ghrelin were treated with 50 uL of 1 N HCl and 10 uL of phenylmethylsulfonyl fluoride per 1 mL of plasma to retard the breakdown of active ghrelin before freezing (Gordon and McKeever, 2005).
Plasma Biochemical and Hormone Analyses
Plasma active ghrelin and adiponectin concentrations were measured using RIA kits (Linco Research, St. Louis, MO) previously validated for use in horses (Gordon and McKeever, 2005; Kearns et al., 2005). In the absence of purified equine active ghrelin and adiponectin, results are expressed as human equivalents of immunoreactive ghrelin and adiponectin. Sensitivities of the assays were 7.8 pg/mL for ghrelin and 1.0 ng/mL for adiponectin. The intraassay CV for active ghrelin and adiponectin kits were <10%. Plasma leptin concentrations were determined using a multispecies leptin RIA kit (Linco Research), as previously validated for use in horses, (McManus and Fitzgerald, 2000; Cartmill et al., 2003; Kearns et al., 2005), with a sensitivity of 1.0 ng/mL and an intraassay CV of 8.5%. Plasma insulin and cortisol concentrations were measured utilizing a commercial solid-phase RIA kit (Coat-a-Count, Diagnostic Products Corp., Los Angeles, CA) previously validated for use in horses (Freestone et al., 1991); and plasma glucose concentrations were measured via colorimetric kits (kit number 635, Sigma-Aldrich, St. Louis, MO). Sensitivity of the insulin assay was 1.2 µIU/mL, and the cortisol assay was 0.2 µg/mL. The intraassay CV for the insulin, cortisol, and glucose assays were <3%. All samples were run in duplicate and within a single assay for all assays.
Statistics
A 1-way ANOVA for repeated measures and Dunnett’s test were used to determine changes in active ghrelin, adiponectin, leptin, glucose, insulin, and cortisol (Sigma Stat, version 3.1, SPSS Inc., Chicago, IL). Separate ANOVA were performed for each trial (e.g., one for the intravenous and one for the oral grain trial). Where appropriate, t-tests were used to compare responses between methods. Finally, where appropriate, relationships between glucose, insulin, and the other measured variables within a trial were analyzed using the Pearson product moment correlation analysis. An a priori level of statistical significance was set at P < 0.05 for all tests.
|
RESULTS
|
|---|
Data are presented as means ± SE, both in the text and in the figures. Analysis was performed on empirical data, and calculated percent changes are presented below only for illustrative purposes to allow the reader to see the proportionality of the responses.
Oral Grain Test
All mares finished consuming the grain within 10 min of placement in their feeders. Plasma glucose and insulin concentrations subsequently increased (P < 0.001) by 56 and 802%, respectively, during the test. Plasma glucose concentration peaked between 90 and 120 min (Figure 1A), whereas plasma insulin concentration peaked between 60 and 90 min (Figure 2A). Plasma active ghrelin concentration initially decreased (P < 0.001) by 40% at 120 min postinfusion, then subsequently increased (P < 0.05) by 259% at 240 min postinfusion from its nadir (Figure 3A). Plasma leptin concentration decreased (P = 0.002) to a nadir at 150 min; there was a 17% decrease compared with baseline (Figure 4A). There was no change (P = 0.34) in plasma adiponectin concentration throughout the oral testing period (Figure 5A). Plasma cortisol concentration decreased (P < 0.001) 24%; the lowest observed mean occurred at 150 min (Figure 6A). Finally, regression analysis of data from the grain trial revealed that there was a positive correlation between glucose and insulin (r = 0.80, P < 0.001) and negative correlations between glucose and ghrelin (r = –0.50, P < 0.001), glucose and cortisol (r = –0.21, P = 0.03), insulin and ghrelin (r = –0.44, P < 0.001), insulin and cortisol (r = –0.24; P = 0.013), and insulin and adiponectin (r = –0.22, P = 0.024).
View larger version (9K):
[in this window]
[in a new window]
|
Figure 1. Mean ± SE plasma glucose in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 2. Mean ± SE plasma insulin in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 3. Mean ± SE plasma ghrelin in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 4. Mean ± SE plasma leptin in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
View larger version (10K):
[in this window]
[in a new window]
|
Figure 5. Mean ± SE plasma adiponectin in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
View larger version (11K):
[in this window]
[in a new window]
|
Figure 6. Mean ± SE plasma cortisol in response to (A) an oral grain challenge and (B) an intravenous dextrose challenge. Arrows at time zero denote the feeding time or the beginning of the infusion time. An asterisk (*) denotes that the time point is different (P < 0.05) from time 0.
|
|
Intravenous Dextrose Test
Plasma glucose and insulin concentrations increased (P < 0.001) by 432 and 395%, respectively, during the intravenous test. Plasma glucose concentration peaked at 5 min (Figure 1B
), corresponding with the end of the dextrose infusion, whereas plasma insulin concentration peaked at 90 min postinfusion (Figure 2B). Plasma active ghrelin concentration initially decreased (P < 0.05) by 56% at 60 min postinfusion, then subsequently increased (P < 0.05) by 314% from its nadir at 240 min postinfusion (Figure 3B). Plasma leptin concentration also increased (P < 0.05) to a peak at 240 min postinfusion, with a 33% increase compared with baseline (Figure 4B). Plasma adiponectin concentration did not change (P > 0.18) throughout the intravenous testing period (Figure 5B). Plasma cortisol concentration increased (P < 0.05) 19.5 ± 10.6%, peaking at 210 min postinfusion (Figure 6B). Analysis of data from the intravenous trial revealed that there was a positive correlation between glucose and insulin (r = 0.35, P < 0.001) and negative correlations between glucose and ghrelin (r = –0.21, P = 0.02), glucose and leptin (r = –0.28, P = 0.002), insulin and ghrelin (r = –0.52, P < 0.001), insulin and cortisol (r = –0.22; P = 0.02), and insulin and adiponectin (r = –0.24, P = 0.009).
|
DISCUSSION
|
|---|
There were 2 major new findings of the current study. First, active ghrelin was suppressed during both the intravenous and the oral carbohydrate challenges. Second, plasma leptin concentrations were decreased when the challenge was orally administered but not when the challenge was by dextrose infusion. Insight into the reason for these responses may lie in the examination of changes in glucose and insulin that may be partly responsible for the alterations seen in the secretion of ghrelin and leptin. Furthermore, it is of interest to mention how the different routes of administration of each challenge, and rates at which glucose entered the bloodstream, may have uniquely affected the hormones and blood constituents. These data add to a growing body of papers (Cartmill et al., 2005; Gordon and McKeever, 2005; Pratt et al., 2005) on the glucose insulin response and interactions with other hormones. Obviously, the glucose responses to the oral and intravenous challenges were very different, whereas the insulin responses were strikingly similar. This suggests that despite the great variance in glucose concentrations, the horses’ homeostatic mechanisms were able to keep insulin concentrations within a normal physiological range. The fact that we observed a similar decrease in ghrelin concentration after both treatments suggests that the mode of glucose administration per se may not be the primary factor affecting ghrelin secretion. However, the rate and magnitude of the increase in glucose concentration appears to have had a pronounced effect on the rate of ghrelin suppression. We have no explanation for the apparent increase in ghrelin at the end of the grain trial. On the other hand, leptin and cortisol responses to the treatments were variable, suggesting that nutrient content, mode of administration, and rates at which nutrients enter the bloodstream may affect these hormones more easily.
Ghrelin concentration increases with meal anticipation or initiation in humans (Cummings et al., 2001; 2004) and other mammals (Sugino et al., 2002), and exogenous ghrelin infusion increases feed intake in rats and humans (Wren et al., 2000; 2001a,b). Interestingly, we did not see an increase in ghrelin concentration with the initiation of feeding in the current study; however, we did observe a slow decrease in plasma ghrelin concentration after the oral grain challenge, which may have been be related to increases in plasma glucose, insulin, or both. Furthermore, the qualitative apparent difference in the rate of the responses to the 2 routes of glucose administration suggests a role for glucose and insulin rather than gastrointestinal tract influences alone in the modulation of ghrelin. Supporting this speculation are data from many studies that have reported significant decreases in plasma ghrelin concentrations in humans in response to an oral glucose tolerance test (Nakagawa et al., 2002; Anderwald et al., 2003; Gottero et al., 2003) as well as experiments that examined the effects of hyperinsulinemic/euglycemic clamps on plasma ghrelin secretion (Anderwald et al., 2003; Flanagan et al., 2003; Mohlig et al., 2003). This inverse relationship between glucose/insulin and ghrelin was accentuated in the intravenous glucose trial of the present experiment, in which there was a more rapid and more pronounced decrease in ghrelin compared with the grain trial. This more pronounced response in the intravenous trial is consistent with one study in humans that demonstrated that ghrelin is decreased in a dose dependent fashion by insulin infusion (Anderwald et al., 2003). Data from the horses in the current study also agree with several studies in humans (Shiiya et al., 2002; Nakagawa et al., 2002) and rodents (McCowen et al., 2002) that demonstrate that intravenous glucose infusion significantly decreases plasma ghrelin concentration within 30 min. Mechanistically, Briatore et al. (2003) suggested that plasma ghrelin suppression resulting from glucose infusion may be due to the acute increase in plasma glucose concentration and not the resulting early insulin response. However, that notion is questionable because intravenous infusion of glucose did not suppress plasma ghrelin concentrations in studies of humans (Caixas et al., 2002; Schaller et al., 2003). In the latter study (Schaller et al., 2003), it was demonstrated that supraphysiologic insulin concentrations were needed to decrease plasma ghrelin concentrations. Therefore, it is unclear if alterations in glucose or insulin or a combination of both are responsible for alterations in ghrelin concentration in horses. Although glucose and insulin appear to play a modulatory role in the integrative regulation of plasma ghrelin secretion in the horses of the current study, the distinct mechanism responsible for this relationship is not clear.
The decrease in plasma leptin seen in the current study in response to the oral grain challenge was intriguing as several studies in humans and other mammals report either an increase in plasma leptin concentration (Dallongeville et al., 1998; Evans et al., 2001; Romon et al., 2003) or no change in plasma leptin concentration due to feeding (Korbonits et al., 1997; Asakuma et al., 2003). On the other hand, oral and intravenous administration of fat have been shown to decrease plasma leptin concentration in humans (Evans et al., 2001). Whereas the grain administered in the challenge given to the horses in the current study did contain a small amount of fat (determined to be ~3% by ether extract analysis), it does not seem likely that this very small amount of fat could mediate the decrease in plasma leptin concentration. Hence, the reasons behind the discrepancies between the current study in horses and the studies conducted in humans are not exactly clear but may lie in the amount, nutrient composition, blood sampling procedures, and individual subject variability associated with oral trials.
In contrast to the decrease in plasma leptin seen when the horses of the current study were given an oral carbohydrate challenge, the intravenous infusion of dextrose caused a marked increase in plasma leptin concentrations beginning at 180 min postinfusion. This finding is in agreement with studies in humans and rodents that also reported an increase in plasma leptin with intravenous glucose infusion (Levy et al., 2000; Sonnenberg et al., 2001). In light of these findings, some have suggested that plasma glucose or insulin concentrations or both may modulate plasma leptin concentration. Supporting this hypothesis are studies of humans and other mammals that have shown an increase in plasma leptin in response to varying methods of insulin infusion (Malmstrom et al., 1996; Saad et al., 1998) and hyperinsulinemic clamp (Malmstrom et al., 1996; Utriainen et al., 1996; Koopmans et al., 1998). However, short-term changes in glucose/insulin and physiologic doses of insulin do not appear to modulate plasma leptin concentrations (Gonzalez-Ortiz et al., 2000). The latter suggests that only pharmacological doses of glucose or insulin or some other mechanism may be responsible for the resulting alterations in plasma leptin concentration. Nevertheless, a preponderance of evidence suggests a few potential mechanisms supporting the relationship between plasma glucose, insulin, and leptin concentrations. These include activation of the hexosamine biosynthetic pathway (Wang et al., 1998; Considine et al., 2000) and the direct effect of glucose or insulin or both on adipocytes (Mueller et al., 1998). The descriptive nature of this study in horses does not elucidate the apparent connection between plasma glucose/insulin and plasma leptin concentrations. However, a recent paper by Cartmill et al. (2005) reports strong direct evidence for insulin stimulation of leptin concentration in horses.
Similar to the data on plasma ghrelin and leptin concentration, the effects of different carbohydrate challenges on plasma cortisol concentration have also yielded diverse and contradictory results. For example, in humans, oral glucose tolerance tests evoke decreases in plasma cortisol concentration (Rodman and Bleicher, 1973; Sober et al., 1977) that are similar to those seen with the oral grain challenge given to the horses of the current study. However, those results contrast with those obtained from a study in humans that shows an increase in plasma cortisol concentrations in response to a meal (Rosmond et al., 1998). It should be noted that it is not clear whether the decreases in plasma cortisol concentration in humans or horses were due to diurnal rhythm of the hormone or from the challenge itself. We, and others, have reported a diurnal variation in cortisol in horses (Zolovick et al., 1966; Gordon and McKeever, 2005), and data from a recent study conducted indicate a peak in plasma cortisol between 0630 and 0830. That peak coincided with a morning meal at 0730 but was followed by a decline in cortisol concentration until 1030 (Gordon and McKeever, 2005). Hence, it is not clear whether the decline in cortisol seen in the present experiment is due to a natural decrease from its morning peak, to the morning meal feeding, or both.
In contrast to the oral challenge, the intravenous dextrose challenge increased plasma cortisol concentrations at 210 min postinfusion. Giving an oral glucose load to humans also resulted in increased plasma cortisol concentrations (Reynolds et al., 2001), although glucose was given at small doses compared with the intravenous infusion given here. Furthermore, it cannot be discounted that changes in plasma glucose, insulin, leptin, or ghrelin concentrations may have an effect on plasma cortisol concentrations or vice versa. A time relationship among leptin, insulin, and cortisol has been described in humans by Wagner et al. (2000), but the descriptive nature of this study as well as the short sampling period does not allow for mechanistic explanations for altered cortisol concentrations.
Finally, there are few studies investigating changes in plasma adiponectin concentrations in response to either oral feeding or an IV glucose challenge. However, the results shown in the horses of the current study are in agreement with studies of lean humans, in which it was also reported that plasma adiponectin concentration did not change after a mixed meal (English et al., 2003; Imbeault et al., 2004). Interestingly, obese humans showed a 4-fold increase in plasma adiponectin concentrations after an overnight fast followed by a mixed breakfast. The authors speculated that the greater plasma insulin concentrations observed in the obese subjects in response to the meal mediated plasma adiponectin concentrations (Imbeault et al., 2004). Contrary to this speculation, hyperinsulinemic euglycemic clamp studies in humans and rats actually decrease plasma adiponectin concentrations (Yu et al., 2002), and the extremely high plasma insulin concentration resulting from the dextrose infusion in this study appears to have no effect on plasma adiponectin concentrations. Hence, at least in lean subjects, it appears that acute changes in plasma glucose and insulin concentrations, as well as changes in other energy homeostasis variables as a result of nutrient challenges, do not regulate plasma adiponectin concentrations on a short-term basis.
In conclusion, both oral and intravenous nutrient challenges affect plasma concentrations of hormones associated with energy metabolism. How alterations in plasma active ghrelin, leptin, and adiponectin relate to actual energy intake and expenditure in horses remains to be elucidated. Nevertheless, studies such as this one, describing modifications or stability of energy metabolism hormones in the face of nutrient challenges, set the groundwork for future studies looking at these parameters on a more mechanistic level.
|
Footnotes
|
|---|
1 Acknowledgments: The authors thank D. Todd Wilkinson, Helio C. Manso Filho, and the many undergraduate and graduate students who helped conduct this study. The authors also thank Jennifer McKeever for her help in preparing the manuscript. Support for this project provided by the New Jersey State Equine Initiative and the New Jersey Agricultural Experimentation Station. 
2 Corresponding author: mckeever{at}aesop.rutgers.edu
Received for publication August 31, 2005.
Accepted for publication February 6, 2006.
|
LITERATURE CITED
|
|---|
Anderwald, C., G. Brabant, E. Bernroider, R. Horn, A. Brehm, W. Waldhausl, and M. Roden. 2003. Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes 52:1792–1798.[Abstract/Free Full Text]
Asakuma, S., H. Morishita, T. Sugino, Y. Kurose, S. Kobayashi, and Y. Terashima. 2003. Circulating leptin response to feeding and exogenous infusion of insulin in sheep exposed to thermoneutral and cold environments. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 134:329–335.[CrossRef][Medline]
Berg, A. H., T. P. Combs, X. Du, M. Brownlee, and P. E. Scherer. 2001. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7:947–953.[CrossRef][Medline]
Berg, A. H., T. P. Combs, and P. E. Scherer. 2002. ACRP30/adiponectin: An adipokine regulating glucose and lipid metabolism. Trends Endocrinol. Metab. 13:84–89.[CrossRef][Medline]
Briatore, L., G. Andraghetti, and R. Cordera. 2003. Acute plasma glucose increase, but not early insulin response, regulates plasma ghrelin. Eur. J. Endocrinol. 149:403–406.[Abstract]
Caixas, A., C. Bashore, W. Nash, F. Pi-Sunyer, and B. Laferrere. 2002. Insulin, unlike food intake, does not suppress ghrelin in human subjects. J. Clin. Endocrinol. Metab. 87:1902–1906.[Abstract/Free Full Text]
Caro, J. F., M. K. Sinha, J. W. Kolaczynski, P. L. Zhang, and R. V. Considine. 1996. Leptin: The tale of an obesity gene. Diabetes 45:1455–1462.[Medline]
Cartmill, J. A., D. L. Thompson, L. R. Gentry, H. E. Pruett, and C. A. Johnson. 2003. Effects of dexamethasone, glucose infusion, adrenocorticotropin, and propylthiouracil on plasma leptin concentrations in horses. Domest. Anim. Endocrinol. 24:1–14.[CrossRef][Medline]
Cartmill, J. A., D. L. Thompson Jr., W. A. Storer, J. C. Crowley, N. K. Huff, and C. A. Waller. 2005. Effect of dexamethasone, feeding time, and insulin infusion on leptin concentrations in stallions. J. Anim. Sci. 83:1875–1881.[Abstract/Free Full Text]
Considine, R. V., R. C. Cooksey, L. B. Williams, R. L. Fawcett, P. Zhang, W. T. Ambrosius, R. M. Whitfield, R. Jones, M. Inman, J. Huse, and D. A. McClain. 2000. Hexosamines regulate leptin production in human subcutaneous adipocytes. J. Clin. Endocrinol. Metab. 85:3551–3556.[Abstract/Free Full Text]
Cummings, D. E., R. S. Frayo, C. Marmonier, R. Aubert, and D. Chapelot. 2004. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am. J. Physiol. Endocrinol. Metab. 287:E297–E304.[Abstract/Free Full Text]
Cummings, D. E., J. Q. Purnell, R. S. Frayo, K. Schmidova, B. E. Wisse, and D. S. Weigle. 2001. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714–1719.[Abstract/Free Full Text]
Dallongeville, J., B. Hecquet, P. Lebel, J. L. Edme, C. Le Fur, J. C. Fruchart, J. Auwerx, and M. Romon. 1998. Short term response of circulating leptin to feeding and fasting in man: Influence of circadian cycle. Int. J. Obes. Relat. Metab. Disord. 22:728–733.[CrossRef][Medline]
English, P. J., S. R. Coughlin, K. Hayden, I. A. Malik, and J. P. Wilding. 2003. Plasma adiponectin increases postprandially in obese, but not in lean, subjects. Obes. Res. 11:839–844.[Medline]
Evans, K., M. L. Clark, and K. N. Frayn. 2001. Carbohydrate and fat have different effects on plasma leptin concentrations and adipose tissue leptin production. Clin. Sci. (Lond.) 100:493–498.[Medline]
Flanagan, D. E., M. L. Evans, T. P. Monsod, F. Rife, R. A. Heptulla, W. V. Tamborlane, and R. S. Sherwin. 2003. The influence of insulin on circulating ghrelin. Am. J. Physiol. Endocrinol. Metab. 284:E313–E316.[Abstract/Free Full Text]
Freestone, J. F., K. J. Wolfsheimer, S. G. Kamerling, G. Church, J. Hamra, and C. Bagwell. 1991. Exercise induced hormonal and metabolic changes in Thoroughbred horses: Effects of conditioning and acepromazine. Equine Vet. J. 23:219–223.[Medline]
Gonzalez-Ortiz, M., E. Martinez-Abundis, and J. M. Mora-Martinez. 2000. Acute effect of physiologic hyperinsulinaemia on serum leptin concentration in healthy young people. Acta Diabetol. 37:83–86.[CrossRef][Medline]
Gordon, M. E., and K. H. McKeever. 2005. Diurnal variation of ghrelin, leptin, and adiponectin in Standardbred mares. J. Anim. Sci. 83:6365–6371.
Gordon, M. E., K. H. McKeever, C. L. Betros, and H. C. Manso Filho. 2005. Plasma leptin, ghrelin and adiponectin concentrations in young fit versus mature unfit Standardbreds. Vet. J. (doi: 10.1016/j.tvjl.2005.11.004)
Gottero, C., S. Bellone, A. Rapa, P. van Koetsveld, D. Vivenza, F. Prodam, A. Benso, S. Destefanis, C. Gauna, J. Bellone, L. Hofland, A. J. van der Lely, G. Bona, E. Ghigo, and F. Broglio. 2003. Standard light breakfast inhibits circulating ghrelin level to the same extent of oral glucose load in humans, despite different impact on glucose and insulin levels. Endocrinol. Invest. 26:1203–1207.
Henneke, D. R., G. D. Potter, J. L. Kreider, and B. F. Yeates. 1983. Relationship between condition score, physical measurements and body fat percentage in mares. Equine Vet. J. 15:371–372.[Medline]
Imbeault, P., M. Pomerleau, M. E. Harper, and E. Doucet. 2004. Unchanged fasting and postprandial adiponectin levels following a 4-day caloric restriction in young healthy men. Clin. Endocrinol. (Oxf.) 60:429–433.[CrossRef][Medline]
Kearns, C. F., K. H. McKeever, V. Roegner, S. M. Brady, and K. Malinowski. 2005. Adiponectin and leptin are related to fat mass in horses. Vet. J. (In press, doi:10.1016/j.tvjl.2005.05.002)
Koopmans, S. J., M. Frolich, E. H. Gribnau, R. G. Westendorp, and R. A. DeFronzo. 1998. Effect of hyperinsulinemia on plasma leptin concentrations and food intake in rats. Am. J. Physiol. 274:E998–E1001.[Medline]
Korbonits, M., P. J. Trainer, J. A. Little, R. Edwards, P. G. Kopelman, G. M. Besser, F. Svec, and A. B. Grossman. 1997. Leptin levels do not change acutely with food administration in normal or obese subjects, but are negatively correlated with pituitary-adrenal activity. Clin. Endocrinol. (Oxf.) 46:751–757.[CrossRef][Medline]
Levy, J. R., J. Lesko, R. J. Krieg Jr., R. A. Adler, and W. Stevens. 2000. Leptin responses to glucose infusions in obesity-prone rats. Am. J. Physiol. Endocrinol. Metab. 279:E1088–E1096.[Abstract/Free Full Text]
Malmstrom, R., M. R. Taskinen, S. L. Karonen, and H. Yki-Jarvinen. 1996. Insulin increases plasma leptin concentrations in normal subjects and patients with NIDDM. Diabetologia 39:993–996.[Medline]
McCowen, K. C., J. A. Maykel, B. R. Bistrian, and P. R. Ling. 2002. Circulating ghrelin concentrations are lowered by intravenous glucose or hyperinsulinemic euglycemic conditions in rodents. J. Endocrinol. 175:R7–11.[Abstract]
McManus, C. J., and B. P. Fitzgerald. 2000. Effects of a single day of feed restriction on changes in serum leptin, gonadotropins, prolactin, and metabolites in aged and young mares. Domest. Anim. Endocrinol. 19:1–13.[CrossRef][Medline]
Meier, U., and A. M. Gressner. 2004. Endocrine regulation of energy metabolism: Review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin and resistin. Clin. Chem. 50:1511–1525.[Abstract/Free Full Text]
Mohlig, M., J. Spranger, B. Otto, M. Ristow, M. Tschop, and A. F. Pfeiffer. 2003. Euglycemic hyperinsulinemia, but not lipid infusion, decreases circulating ghrelin levels in humans. J. Endocrinol. Invest. 25:RC36–RC38.
Mueller, W. M., F. M. Gregoire, K. L. Stanhope, C. V. Mobbs, T. M. Mizuno, C. H. Warden, J. S. Stern, and P. J. Havel. 1998. Evidence that glucose metabolism regulates leptin secretion from cultured rat adipocytes. Endocrinology 139:551–558.[Abstract/Free Full Text]
Nakagawa, E., N. Nagaya, H. Okumura, M. Enomoto, H. Oya, F. Ono, H. Hosoda, M. Kojima, and K. Kangawa. 2002. Hyperglycaemia suppresses the secretion of ghrelin, a novel growth-hormone-releasing peptide: Responses to the intravenous and oral administration of glucose. Clin. Sci. (Lond.) 103:325–328.[Medline]
Pratt, S. E., R. J. Geor, and L. J. McCutcheon. 2005. Repeatability of 2 methods for assessment of insulin sensitivity and glucose dynamics in horses. J. Vet. Intern. Med. 19:883–888.[CrossRef][Medline]
Reynolds, R. M., B. R. Walker, H. E. Syddall, C. B. Whorwood, P. J. Wood, and D. I. Phillips. 2001. Elevated plasma cortisol in glucose-intolerant men: Differences in responses to glucose and habituation to venepuncture. J. Clin. Endocrinol. Metab. 86:1149–1153.[Abstract/Free Full Text]
Rodman, H. M., and S. J. Bleicher. 1973. Plasma cortisol during normal glucose tolerance. Metabolism 22:745–748.[CrossRef][Medline]
Romon, M., P. Lebel, J. C. Fruchart, and J. Dallongeville. 2003. Postprandial leptin response to carbohydrate and fat meals in obese women. J. Am. Coll. Nutr. 22:247–251.[Abstract/Free Full Text]
Rosmond, R., M. F. Dallman, and P. Bjorntorp. 1998. Stress-related cortisol secretion in men: Relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities. J. Clin. Endocrinol. Metab. 83:1853–1859.[Abstract/Free Full Text]
Saad, M. F., A. Khan, A. Sharma, R. Michael, M. G. Riad-Gabriel, R. Boyadjian, S. D. Jinagouda, G. M. Steil, and V. Kamdar. 1998. Physiological insulinemia acutely modulates plasma leptin. Diabetes 47:544–549.[Abstract]
Schaller, G., A. Schmidt, J. Pleiner, W. Woloszczuk, M. Wolzt, and A. Luger. 2003. Plasma ghrelin concentrations are not regulated by glucose or insulin: A double-blind, placebo-controlled crossover clamp study. Diabetes 52:16–20.[Abstract/Free Full Text]
Scherer, P. E., S. Williams, M. Fogliano, G. Baldini, and H. F. Lodish. 1995. A novel serum protein similar to C1q, produced exclusively in adipocytes. J. Biol. Chem. 270:26746–26749.[Abstract/Free Full Text]
Shiiya, T., M. Nakazato, M. Mizuta, Y. Date, M. S. Mondal, M. Tanaka, S. Nozoe, H. Hosoda, K. Kangawa, and S. Matsukura. 2002. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J. Clin. Endocrinol. Metab. 87:240–244.[Abstract/Free Full Text]
Sober, A. J., H. J. Ruder, and J. Sode. 1977. Adrenal activity during normal glucose tolerance. Acta Endocrinol. (Copenh.) 84:115–118.[Abstract/Free Full Text]
Sonnenberg, G. E., G. R. Krakower, R. G. Hoffmann, D. L. Maas, M. M. Hennes, and A. H. Kissebah. 2001. Plasma leptin concentrations during extended fasting and graded glucose infusions: Relationships with changes in glucose, insulin, and FFA. J. Clin. Endocrinol. Metab. 86:4895–4900.[Abstract/Free Full Text]
Sugino, T., Y. Hasegawa, Y. Kikkawa, J. Yamaura, M. Yamagishi, Y. Kurose, M. Kojima, K. Kangawa, and Y. Terashima. 2002. A transient ghrelin surge occurs just before feeding in a scheduled meal-fed sheep. Biochem. Biophys. Res. Commun. 295:255–260.[CrossRef][Medline]
Tschop, M., C. Weyer, P. A. Tataranni, V. Devanarayan, E. Ravussin, and M. L. Heiman. 2001. Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707–709.[Abstract/Free Full Text]
Utriainen, T., R. Malmstrom, S. Makimattila, and H. Yki-Jarvinen. 1996. Supraphysiological hyperinsulinemia increases plasma leptin concentrations after 4 h in normal subjects. Diabetes 45:1364–1366.[Abstract]
Wagner, R., C. Oberste-Berghaus, S. Herpertz, W. F. Blum, B. Pelz, J. Hebebrand, W. Senf, K. Mann, and N. Albers. 2000. Time relationship between circadian variation of serum levels of leptin, insulin and cortisol in healthy subjects. Horm. Res. 54:174–180.[CrossRef][Medline]
Wang, J., R. Liu, M. Hawkins, N. Barzilai, and L. Rossetti. 1998. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393:684–688.[CrossRef][Medline]
Wren, A. M., L. J. Seal, M. A. Cohen, A. E. Brynes, G. S. Frost, K. G. Murphy, W. S. Dhillo, M. A. Ghatei, and S. R. Bloom. 2001b. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86:5992.[Abstract/Free Full Text]
Wren, A. M., C. J. Small, C. R. Abbott, W. S. Dhillo, L. J. Seal, M. A. Cohen, R. L. Batterham, S. Taheri, S. A. Stanley, M. A. Ghatei, and S. R. Bloom. 2001a. Ghrelin causes hyperphagia and obesity in rats. Diabetes 50:2540–2547.[Abstract/Free Full Text]
Wren, A. M., C. J. Small, H. L. Ward, K. G. Murphy, C. L. Dakin, S. Taheri, A. R. Kennedy, G. H. Roberts, D. G. Morgan, M. A. Ghatei, and S. R. Bloom. 2000. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141:4325–4328.[Abstract/Free Full Text]
Yu, J. G., S. Javorschi, A. L. Hevener, Y. T. Kruszynska, R. A. Norman, M. Sinha, and J. M. Olefsky. 2002. The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968–2974.[Abstract/Free Full Text]
Zolovick, A., D. W. Upson, and B. E. Eleftheriou. 1966. Diurnal variation in plasma gluco-corticosteroid levels in the horse (Equus caballus). J. Endocrinol. 35:249–253.[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
H. C. Manso Filho, K. H. McKeever, M. E. Gordon, H. E. C. Costa, W. S. Lagakos, and M. Watford
Changes in glutamine metabolism indicate a mild catabolic state in the transition mare
J Anim Sci,
December 1, 2008;
86(12):
3424 - 3431.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Gauna, P. Uitterlinden, P. Kramer, R. M. Kiewiet, J. A. M. J. L. Janssen, P. J. D. Delhanty, M. O. van Aken, E. Ghigo, L. J. Hofland, A. P. N. Themmen, et al.
Intravenous Glucose Administration in Fasting Rats Has Differential Effects on Acylated and Unacylated Ghrelin in the Portal and Systemic Circulation: A Comparison between Portal and Peripheral Concentrations in Anesthetized Rats
Endocrinology,
November 1, 2007;
148(11):
5278 - 5287.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
INTRODUCTION
