| | Effects of dexamethasone, glucose infusion, adrenocorticotropin, and propylthiouracil on plasma leptin concentrations in horses☆Received 15 March 2002; accepted 1 June 2002. Abstract In experiment 1, nine light horse geldings (three 3×3 Latin squares) received dexamethasone (DEX; 125 μg/kg BW, i.m.), glucose (0.2g/kg BW, i.v.), or nothing (control) once per day for 4 days. DEX increased (P<0.001) glucose, insulin, and leptin concentrations and resulted in a delayed increase (P<0.001) in IGF-I concentrations. In experiment 2, mares were similarly treated with DEX (n=6) or vehicle (n=6). DEX again increased (P<0.01) glucose, insulin, and leptin concentrations; the delayed elevation in IGF-I concentrations occurred on day 10, 12, and 19, relative to the first day of treatment. In experiment 3, six light horse geldings received either 200IU of adrenocorticotropin (ACTH) i.m. or vehicle twice daily for 4 days. ACTH increased (P<0.001) cortisol concentrations. Further, ACTH resulted in increases (P<0.01) glucose, insulin, and leptin concentrations. In experiment 4, plasma samples from four light horse stallions that were fed 6-n-propyl-2-thiouracil (PTU) at 6mg/kg BW for 60 days to induce hypothyroidism were compared to samples from control stallions. On day 52, stallions receiving PTU had lower concentrations of thyroxine (P<0.05) and triiodothyronine (P<0.01) and higher (P<0.01) concentrations of TSH. Leptin concentrations were higher (P<0.01) in PTU-fed stallions from day 10 through 52. In conclusion, circulating concentrations of leptin in horses was increased by administering DEX. Treatment with ACTH increased cortisol and resulted in lesser increases in leptin, glucose, and insulin. In addition, PTU feeding results in lesser increases in leptin concentrations.
1. Introduction  Dexamethasone (DEX) and insulin have been reported to stimulate leptin secretion in various nonequine species [1], [2], [3]. In adipocytes cultured in vitro, DEX stimulates leptin production and secretion [4], [5] as well as mRNA content [6], [7]. Hypothyroidism has been reported to increase leptin secretion in humans [8], [9], [10]; however, others have reported that hypothyroidism is associated with decreased leptin concentrations [11], [12]. Treatment with thyroxine (T4; [13]) or T4 plus triiodothyronine (T3; [14]) decreased circulating concentrations of leptin. In horses, 24h of feed restriction reduced leptin concentrations but had no effect on gonadotropin secretion [15]. Due to the lack of information on the effect of glucocorticoids on leptin secretion in equine species and the controversial effects of thyroid hormones on leptin secretion in nonequine species we designed the following experiments. The series of experiments reported herein were designed to assess the effects of DEX, glucose infusion, adrenocorticotropin (ACTH), and 6-n-propyl-2-thiouracil (PTU; an inducer of hypothyroidism) on leptin secretion in horses. 2. Materials and methods 2.1. Experiment 1 Nine light horse geldings (462–577kg BW) were used in three replicates of a 3×3 Latin square with repeated measures. They were maintained on native grass pasture and provided grass hay as needed to maintain good body condition (scores of 6–8; [16]). The three geldings within each replicate were assigned randomly to the three treatments: (1) i.m. injection of DEX in vegetable oil (125μg/kg BW; Sigma Chemical Co., St. Louis, MO, USA); (2) i.v. infusion of glucose (0.2g/kg BW as a 50% solution in 0.155M saline); or (3) no injection (controls). The three replicates were performed simultaneously. Treatments were administered in the morning at approximately 8:00h for 4 days consecutively (day 1–4). Samples of jugular blood were drawn via jugular venipuncture into evacuated, heparinized tubes at 0 and 12h relative to treatments on these days. Weekly blood samples were subsequently collected on day 12, 19, 26, and 33. The successive periods (2 and 3) of the Latin square were begun on day 34 after the initial treatment injection of the previous period. All blood samples were immediately centrifuged at 1200×g at 5°C and the plasma was harvested and stored at −15°C. Plasma concentrations of leptin were measured by RIA using commercially available reagents (Multi-species leptin kit, Linco Research Inc., St. Charles, MO, USA). Similar to reported previously by McManus and Fitzgerald [15], human leptin standards from the kit, human recombinant leptin (0.16–10ng/tube), and three horse plasma pools (two mares and one gelding; 6.2–100μL/tube) produced parallel inhibition curves in the assay. Moreover, five levels of human recombinant leptin (0.3–5ng) added to a pool of horse plasma were quantitatively recovered with an average of 111% and a R2 value of 0.995. The intra and interassay coefficients of variation and assay sensitivity were 4 and 8%, and 0.8ng/mL. Insulin [17], insulin-like growth factor-1 (IGF-I; [18]), and growth hormone (GH; [19]) were determined by RIA previously validated for horse samples. Intra and interassay coefficients of variation and assay sensitivities were 5 and 8%, and 0.1ng/mL for insulin; 5 and 12%, and 8ng/mL for IGF-I; and 8 and 11%, and 0.5ng/mL for GH. Glucose concentrations were determined spectrophotometrically (method no. 315; Sigma Chemical Co., St. Louis, MO, USA). 2.2. Experiment 2 Twelve light horse mares (465–560kg BW; body condition scores of 6–8) were used. Six mares were assigned randomly to each of two groups, and then groups were selected randomly to receive either: (1) DEX in oil (125μg/kg BW i.m.); or (2) a similar volume of oil i.m. Injections were administered at approximately 8:00h each morning for 4 days beginning on day 1. Blood samples were collected just prior to injections and 12h later during the first 4 days. Additional samples were collected in the morning on day 5, 6, 7, 8, 10, 12, 19, 26, and 33. Samples were immediately centrifuged and plasma frozen for later determination of glucose, insulin, leptin, and IGF-I concentrations as described for experiment 1. 2.3. Experiment 3 Six light horse geldings (490–600kg BW) not used in experiment 1 were used in a completely randomized design with repeated measures. They were in good body condition (6–8) and were assigned randomly to receive either: (1) 200IU i.m. of porcine ACTH (Sigma Chemical Co., St. Louis, MO, USA; A6303) in saline containing 0.1g/mL gelatin (n=3); or (2) an equivalent volume of vehicle (n=3) i.m. at 12-h intervals for 4 days consecutively (0, 12, 24, 36, 48, 60, 72, and 84h). Blood samples were collected via jugular venipuncture at −1, 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 30, 36, 42, 48, 54, 60, 66, 72, 74, 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, and 96h. Additional blood samples were collected on day 12, 19, 26, and 33 relative to the first day of treatment. All blood samples were immediately centrifuged and the plasma harvested for later determination of cortisol (ICN Pharmaceuticals, Inc., Costa Mesa, CA, USA; kit no. 07-221102), insulin, glucose, leptin, and IGF-I concentrations. 2.4. Experiment 4 Plasma samples selected from a previous experiment [20] were used for the measurement of leptin. In that experiment, eight adult light horse stallions (390–550kg BW; body condition scores 5–7) were used. Stallions were on a diet of commercially available pelleted feed plus grass hay to maintain body condition. To induce hypothyroidism, four randomly selected stallions received PTU (Sigma Chemical Co., St. Louis, MO, USA; P3755) at 6mg/kg BW administered in 250g of a top dressing of a molasses-containing balanced grain ration; four control stallions were given the top dressing with no addition. Stallions were fed their rations daily at 8:00h and were allowed to eat throughout the day; hay and water were available ad libitum throughout the experiment. Plasma samples drawn on day 1, 6, 13, 20, 27, 31, 36, 41, 45, and 52 relative to the start of treatment were selected for determination of leptin concentrations; in addition, samples from day 52 were assessed for T3 and T4 (ICN Pharmaceuticals, Inc., Costa Mesa, CA, USA; kit no. 07-290102 and 07-292102, respectively) and TSH [21] concentrations. Intraassay coefficients of variation and assay sensitivities were 5% and 0.02ng/mL for TSH; 5% and 5ng/mL for T4; and 5% and 40pg/mL for T3. 2.5. Statistical analyses Data were analyzed via the GLM procedure of SAS (SAS Institute Inc., Cary, NC, USA). Data from repetitive sampling over time were analyzed in a split-plot ANOVA [22] for a replicated Latin square (experiment 1) or a completely randomized design (experiment 2, 3, and 4; [23]). In experiment 1, the main effects of squares, treatments, horses, and days were tested by the square, treatment, horse, and day interaction term; the time factor and its interaction with treatment were tested with residual error. In experiment 2, 3, and 4, the main effect of treatment was tested with the horse within treatment term; the time factor and its interaction with treatment were tested with residual error. Differences between treatment groups in each time period in the treatment-day interactions were assessed by the least significant difference (LSD)-test [23] for experiment 2, 3, and 4; differences among the three treatments in each time period in experiment 1 were compared with Tukey’s honest significant difference (HSD) test [23]. In all cases, the LSD or HSD calculated for P<0.01 was used. 3. Results 3.1. Experiment 1 Treatment with DEX increased (P=0.0001) concentrations of plasma glucose and insulin (Fig. 1a) within 24h, and concentrations were at their highest on day 4. These elevated glucose and insulin concentrations persisted through day 12 (P<0.01) but returned to concentrations similar (P>0.05) to those in controls by day 19. Given the blood sampling schedule in this experiment, any effects of glucose infusion on the mornings of day 1 through 4 on glucose and insulin concentrations were not evident after 12h (the next blood sample), and there was no effect (P>0.1) in the ANOVA (Fig. 1a and b). Treatment with DEX also increased (P=0.001) plasma leptin concentrations (Fig. 2a) within 24h, and concentrations were at their highest on day 3. These elevated leptin concentrations persisted through day 12 (P<0.01) but returned to concentrations similar to those in controls by day 19 (P>0.05). There was no effect (P>0.1) of glucose infusion on leptin concentrations. There was an increase (P<0.001) in plasma IGF-I concentrations in DEX-treated geldings on days 12 and 19 (Fig. 2b), which well after treatment had ended (day 12 and 19). Glucose treatment did not affect (P>0.1) plasma IGF-I concentrations. Neither DEX nor glucose treatment affected (P>0.10) plasma GH concentrations (data not shown). 3.2. Experiment 2 Treatment with DEX increased (P<0.01) concentrations of glucose and insulin (Fig. 3a and b) in a manner similar to that in geldings in experiment 1. Plasma glucose and insulin concentrations in DEX-treated mares were elevated by day 2, were highest around day 6, and remained elevated above that of controls until day 12. Plasma leptin concentrations (Fig. 4a) following DEX administration were increased (P<0.01) by day 2, were highest on day 3.5, and remained elevated relative to controls through day 12. Plasma IGF-1 concentrations (Fig. 4b) following DEX treatment were also increased (P<0.01), again only after the end of treatment, on day 10, 12, and 19. 3.3. Experiment 3 Treatment with ACTH increased (P<0.01) plasma cortisol concentrations (Fig. 5a) 4–6h after injections on day 1, 2 and 4, but not day 3. In each case, cortisol concentrations in ACTH-treated geldings immediately before the next injection were not different (P>0.10) from controls. Plasma glucose concentrations (Fig. 5b) increased (P<0.01) in both groups from day 1–5, and were higher (P<0.01) in geldings receiving ACTH than in controls on day 2. Similarly, there was a transient increase (P<0.01) in insulin concentrations (Fig. 5c) in ACTH-treated geldings on day 3.5. There was no effect (P>0.10) of ACTH treatment on plasma concentrations of GH or IGF-I (data not shown). Plasma leptin concentration differed between groups (P<0.05) before onset of ACTH treatment (Fig. 6a), thus the residual values relative to time 0 were calculated and analyzed separately (Fig. 6b). For the residuals, treatment with ACTH increased (P<0.01) leptin concentrations relative to controls from day 2.5 through 4. Unlike previous experiments, leptin concentrations in control geldings tended to decrease from day 1–4, and gradually rebounded thereafter. 4. Discussion The hyperglycemia and hyperinsulinemia observed in the geldings in experiment 1 and the mares in experiment 2 are characteristic of excessive glucocorticoid exposure [24] and confirm the biological potency of this dose of DEX in horses. The results from experiment 1 and 2 also demonstrate that DEX at this dosage is a potent stimulator of plasma leptin concentrations in horses, which is assumed to be due to an increase in leptin secretion. This is in agreement with previous reports in humans [1], [2], [25] and rats [26] in which DEX was shown, at varying doses and routes of administration, to stimulate leptin secretion. In humans, circulating plasma leptin concentrations are higher in women than in men, even after correction for body fat [27], [28]. Moreover, Blache et al. [29] reported that plasma concentrations of leptin were higher in female sheep than in castrated or intact male sheep. Pretreatment leptin concentrations were similar for geldings in experiment 1 and mares in experiment 2, however the leptin response in mares was almost twice as large as that in the gelding, even though their body condition scores were similar. Thus, a sexual dichotomy may exist in horses for leptin responsiveness to DEX stimulation. In both experiments, leptin concentrations peaked on day 3 (experiment 1) or 3.5 (experiment 2) and had begun a gradual decline even though treatment was continued through day 4. Thus, although DEX at this dose stimulates leptin secretion within 24h, apparently the stimulatory effects are transient, or alternatively, continued exposure to DEX becomes inhibitory. The extra blood samples on day 5, 6, 7, 8, and 10 in experiment 2 were added to better define this decline, which was fairly abrupt to day 5 and gradual thereafter. The fact that leptin concentrations in DEX-treated horses returned to, but did not go below, pretreatment levels may indicate that the decline was not due to an inhibitory effect. Although our 12-h blood sampling regimen in experiment 1 did not characterize the short-term (first few hours) glucose and insulin responses to the glucose infusions, we have previously reported such responses in geldings [30] and mares [31]. In each case, insulin concentrations increased about 2ng/mL above baseline within 10min, and the elevated concentrations returned to preglucose levels within 3h. We chose to use glucose infusion in experiment 1 to elevate insulin concentrations rather than insulin injections per se due to the possible side effects of insulin injection. Given the temporary nature of the insulin elevations, the lack of effect of glucose infusion on leptin concentrations may have been due to insufficient insulin stimulation. In vitro studies with insulin and equine adipocytes are needed to directly test the hypothesis that insulin increases leptin production and secretion. The involvement of insulin in the DEX-induced increase in leptin secretion cannot be ruled out in vivo due to the fact that glucose and insulin concentrations increased rapidly at the same time as leptin concentrations. Several previous reports indicated that DEX has direct effects on leptin production and secretion [4], [5] as well as mRNA content [6], [7] in adipocytes cultured in vitro. Thus, it is likely that DEX stimulated leptin secretion in these horses directly, although an interaction with the elevated insulin and/or glucose concentrations was possible. The elevation in IGF-I concentrations on day 12 and 19 in the DEX-treated geldings in experiment 1 was unexpected, particularly given that GH concentrations were unaltered by treatment. The same increase was noted in the mares in experiment 2, except that by day 19 concentrations had begun to decrease back to pretreatment levels. The increase occurred 6–8 days after the end of DEX injections, and it is possible that IGF-I concentrations rose in response to the earlier elevation in insulin concentrations [32], [33]. Another possibility is that increased concentrations of leptin resulted in the elevation in IGF-I. Houseknecht et al. [34] observed a high correlation between IGF-I mRNA and leptin mRNA after incubation of bovine adipose tissue with GH in vitro. In addition, it has been suggested that excess GH/IGF-I reduces serum leptin concentrations [35]. Therefore, the possibility that an IGF-I/leptin feedback mechanism exists cannot be ruled out at this time. In experiment 3, ACTH was used to elevate plasma cortisol concentrations within physiologic limits for the horse. At this dose and frequency of injection, ACTH had a transient stimulatory effect on leptin concentrations. The magnitude of the leptin response in ACTH-treated geldings was considerably less than for the DEX-treated horses, which probably reflects the difference in degree of glucocorticoid stimulation in the three experiments. Others have reported adrenal–leptin associations [36]. Spinedi and Gaillard [37] observed decreased concentrations of leptin in adrenalectomized rats. Moreover, serum immunoreactive leptin levels are increased in human patients with Cushing’s syndrome [38], which some have attributed to the direct effect of glucocorticoids on adipocytes [39] but others to the associated hyperinsulinemia and(or) impaired insulin sensitivity [40]. The decrease in leptin concentrations observed in control geldings may be attributed to the abrupt change in feeding regime. Prior to the sampling times the geldings were kept on native pastures and grazed ad libitum. During the 4 days of sampling the geldings were kept in stalls and fed hay. The elevated concentrations of TSH and the decreased concentrations of T3 and T4 in the stallions in experiment 4 confirmed their status as hypothyroid relative to controls. The increase in leptin concentrations in those PTU-treated stallions, albeit small, is in agreement with reports in several species. Leonhardt et al. [9] reported an elevation in concentrations of leptin following methimazole-induced hypothyroidism in rats, with the greatest concentrations noted after 28 days of treatment. Escobar-Morreale et al. [14] reported that thyroidectomized rats had increased concentrations of leptin compared to controls and animals treated with T3 and T4. Similarly, in humans, hypothyroid subjects had elevated levels of leptin compared to controls and hyperthyroid subjects [8], [10], [13]. In contrast to these reports, some have reported lower leptin concentrations in human hypothyroid patients [11], [12]. The decrease in leptin concentrations in control stallions observed in this experiment may have been due to the effect of season (samples were collected during September and October). A seasonal pattern in circulating leptin concentrations has been previously reported [41] in both young and mature mares, with leptin being greatest in the summer and lowest in the winter. 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Department of Animal Science, Louisiana Agricultural Experiment Station, Louisiana State University Agricultural Center, Baton Rouge, LA 70803, USA  Corresponding author. Tel.: +1-225-578-3445; fax: +1-225-578-3279.
☆ Approved for publication by the Director of the Louisiana Agricultural Experiment Station as manuscript no. 02-11-0066. PII: S0739-7240(02)00183-2 © 2002 Elsevier Science Inc. All rights reserved. | |
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