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Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada T6G 2P5; * Animal Sciences Department, University of Misssouri, Columbia, MO 65211
2To whom correspondence should be addressed. E-mail: john.kennelly{at}ualberta.ca.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • leptin • glucose • lipid • dairy cows
Leptin, a hormone secreted primarily from adipose tissue, has been shown to play an important role in regulating feed intake in both ruminants and monogastrics (1), and in influencing carbohydrate and lipid metabolism in monogastric species (2). In the long term, circulating leptin concentrations are strongly associated with the degree of adiposity and the plane of nutrition (3). In the short term, feed deprivation is reported to reduce plasma leptin concentrations in beef cattle (4,5) and sheep (6,7) independent of changes in body weight. We have recently shown that the response of plasma leptin concentration to the feed deprivation is dependent on the physiological stage of the animal; feed deprivation sharply reduced leptin levels in early-lactating dairy cows, but this response was blunted in nonlactating dry cows and postpubertal heifers (8). We also found a positive correlation of leptin with glucose, insulin and insulin-like growth factor-1 (IGF-1),2 and a negative correlation with nonesterified fatty acids (NEFA) and growth hormone (GH), suggesting that these plasma variables might play a role in the short-term regulation of leptin in dairy cattle. However, the role of specific macronutrients in the short-term regulation of leptin secretion in ruminants has received little attention.
The stimulatory effect of dietary carbohydrate and fat on leptin secretion in rodents is well documented (9). We have recently reported that either feeding or abomasal infusion of canola oil had no significant effect on plasma leptin concentration in dairy cattle (10). In that study the animals were relatively thin, in late lactation, and the treatments did not affect body weight and body condition score (BCS). If the leptin response to fat supplementation is dependent on body fat reserves, it may be reasoned that cows with a high BCS will exhibit a robust response compared with cows with a low BCS.
As part of the homeorhetic adaptations that occur in cows during early lactation, the adipose tissue develops resistance to insulin-mediated glucose and acetate uptake, and concomitantly becomes sensitized to the lipolytic effects of an elevated concentration of plasma GH (11). The ability of GH to attenuate the stimulatory effects of insulin or dexamethasone on leptin gene expression in bovine adipose tissue explants has also been reported recently (12). Based on these observations, we hypothesized that plasma leptin concentration would exhibit a strong response to energy supplementation in late-lactation cows with adequate fat reserves compared with thin cows in early lactation. To test this hypothesis, and to minimize the potential metabolism of energy supplements in the gastrointestinal tract, we compared the effects of parenteral infusions of glucose and lipid in this study. Our specific objectives were to determine the effects of isoenergetic jugular infusions of dextrose and lipid on dry matter intake (DMI), milk yield and composition and plasma concentrations of leptin, insulin, IGF-1, GH, glucose, NEFA and ß-hydroxybutyrate (BHBA) in cows in early and late lactation.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The experiments were conducted at the Dairy Research and Technology Centre, University of Alberta, with all animal procedures approved by the University of Alberta Animal Policy and Welfare Committee (protocol number 2000–75C). Experiments were performed between March and October 2001, when the cows were in early lactation (32 ± 3 d in milk) and again in late lactation (249 ± 3 d in milk; 187 ± 7 d pregnant). The six multiparous cows used in this study were housed in tie-stalls, fed at about 0900 h to ensure 5% orts and had free access to water at all times. To minimize the potential confounding effects of diets on hormonal and metabolite response to infusion at different stages of lactation, the cows were fed a common total mixed ration during both stages of lactation over a 10-d adaptation period (Table 1).
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1200 g) and Intralipid (400 g soybean oil) infused in this study were calculated to be isocaloric and to provide 16.74 MJ/d. The day before initiation of the experiment, the cows were fitted with BD Angiocath catheters (catalog no. 382269, 2.1 mm x 133 cm, Becton Dickinson, Franklin Lakes, NJ) into both jugular veins, one for infusion of solutions and the other for blood sampling. Patency of the catheters was maintained overnight with 200,000 IU heparin/L sterile saline. The solutions were continuously infused for 6 h from 0900 to 1500 h for two consecutive days in each period by means of a Masterflex peristaltic pump (Labcor, Anjou, QC). Measurements and sampling.
The amount of feed consumed was determined daily. Samples of total mixed ration, ingredients and orts were collected on both days of each period and combined by cow within each period. At the end of each period, body weight was recorded and BCS (1–5 scale) was assessed by three individuals. Energy balance was calculated as described previously (8). Animal health was monitored frequently by checking body temperature, heart rate and urinary ketones (Clini-2K Reagent strips, URI-Quick, Stanbio, Boerne, TX). The cows were milked twice daily, between 0400 and 0600 h and between 1600 and 1800 h, milk yield was recorded, and samples were taken for milk fat, protein and lactose analyses. Samples were sent to the Alberta Central Milk Testing Laboratory (Edmonton, AB) for analysis.
Relative to the beginning of infusions (0900 h), blood samples were collected at -1, -0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10 12 and 24 h on the second day of each period. Samples were collected on ice in 10-mL vacutainer tubes (Becton Dickinson, Franklin Lakes, NJ) containing EDTA or sodium heparin. Prior to collecting blood samples, the catheters were flushed with 10 to 20 mL of heparin solution (20,000 IU heparin/L sterile saline). Within 2 h of sampling, plasma was separated by centrifugation (1500 x g) and stored at -20°C until it was analyzed for hormones and metabolites.
Chemical analyses.
Samples of feed, ingredients and orts were dried at 60°C for 72 h, and ground through a 1-mm screen (Thomas-Wiley laboratory mill model 4, Philadelphia, PA). Dry matter weight was calculated by drying samples at 110°C overnight, and the organic matter component was calculated as weight loss upon ashing for at least 6 h at 500°C. Samples were analyzed for crude protein (6.25 x N; Leco FP-428 nitrogen determinator, Leco, St. Joseph, MI), neutral detergent fiber, acid detergent fiber and lignin (Ankom filter bag technique, Ankom, Macedon, NY).
Hormone and metabolite assays.
Plasma concentrations of leptin (13), insulin (8), GH (14) and IGF-1 (8) were determined by RIA validated for bovines. Assay sensitivity and intraassay CV for leptin, insulin, IGF-1 and GH were 0.03 nmol/L and 3.1%, 1.67 pmol/L and 5.1%, 4.78 nmol/L and 6.6% and 2.25 pmol/L and 2.7%, respectively. Plasma glucose and NEFA concentrations were determined as described previously (8), with intraassay CV of 3.5 and 2.5% and interassay CV of 5.9 and 5.1%, respectively. Plasma BHBA concentrations were determined using enzymatic assay kits (Procedure 310-UV, Sigma Chemical, St. Louis, MO). The BHBA analysis was done only on samples collected at 0, 3, 6 and 12 h since the beginning of infusion. The volume of reagent and sample was modified to allow the assays to be conducted in 96-well ELISA plates and absorbance to be measured with a SPECTRAmax 190 Microplate spectrophotometer (Molecular Devices, Sunnyvale, CA). The intra- and interassay CV for BHBA were 1.4% and 2.7%, respectively.
Statistical analyses.
Data were analyzed by ANOVA for a replicated Latin square design using the MIXED procedure of SAS (version 8.2, SAS Institute, Cary, NC). Repeated measures on plasma hormones and metabolites, and other performance parameters, were analyzed using the following univariate linear mixed model:
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where µ is the population mean; 
i is the fixed effect of treatment i; ßj is the fixed effect of period j; 
k is the fixed effect of time k; 
l is the fixed effect of lactational stage l; 
m is the fixed effect of square, (ß)ij is the interaction of treatment and period; ()ik is the interaction of treatment and time; ()il is the interaction of treatment and stage; ()im is the interaction of treatment and square; (ß)ijl is the interaction of treatment, period and stage; ()ikl is the interaction of treatment, time and stage; and eijklm is the residual error. The Kenward-Roger procedure was used for approximating the denominator degrees of freedom. Animal nested in treatment, period and square was the random variable, and was considered as the subject on which repeated measures were taken and covariance structures were modeled. Based on the smallest values of fit statistics for AICC and BIC criteria, the covariance structure of the unequally spaced repeated measurements for each variable was modeled either as compound symmetry, heterogenous compound symmetry, first-order antedependence or spatial power law (15). Discrete data on feed intake, energy balance and milk production and composition were analyzed by a similar model as described above, except that time and interactions with time were excluded. One cow in early lactation developed signs of severe ketosis and was removed from the trial; the data from this animal were not considered for analysis. Preplanned treatment comparisons among individual time points were made with the PDIFF option. Comparisons with P < 0.01 were declared highly significant, P < 0.05 significant, and 0.05 < P < 0.10 were considered to indicate trends.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In general, cows in late lactation had lower DMI and yields of milk and milk components, but greater body weight, energy balance and BCS, compared with early-lactation cows (Table 2; P < 0.05). Treatment x stage interaction tended to be significant for DMI (P = 0.06); treatments significantly influenced DMI in late (P < 0.05) but not in early (P > 0.10) lactation. In late-lactation cows, LIP treatment reduced DMI by 14 and 16% compared with CON and GLU, respectively (P < 0.05); there was no difference between CON and GLU treatments (P > 0.10). The yields of milk and milk components were similar among treatments at both stages of lactation (P > 0.10); however, treatment x stage interaction was significant for milk fat percentage (P < 0.05). Relative to CON, GLU reduced and LIP increased the percentage of milk fat in early lactation (P < 0.05), but there were no treatment differences in late lactation (P > 0.10).
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As expected, GLU treatment sharply increased plasma glucose concentration (Fig. 1) at both stages of lactation. The treatment x time x stage interaction for glucose was highly significant (P < 0.001; Table 3); GLU treatment increased plasma glucose concentrations over CON levels more than fourfold by 3 h and fivefold by 4 h in early and late lactation cows, respectively (Fig. 1). This hyperglycemia persisted for 7 and 8 h in early- and late-lactation cows, respectively. Plasma glucose concentrations were similar (P > 0.10) in CON and LIP treatments at both stages of lactation (Fig. 1). Overall glucose concentrations in cows treated with CON tended to be greater in late compared to early lactation (stage effect; P = 0.10).
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Plasma insulin concentrations were nearly 36% greater in late compared to early lactation CON cows (stage effect; P < 0.001). The treatment x time x stage interaction was highly significant for insulin (P < 0.001; Table 3). In early lactation, 4 h of GLU treatment increased plasma insulin concentrations threefold over CON levels (P < 0.001), and they remained elevated for the duration of infusion (Fig. 4). The insulin response to GLU treatment was quite rapid and strong in late-lactation cows; concentrations increased fivefold over CON levels within 1 h, reaching a maximum 28-fold increase by 6 h of infusion (P < 0.001; Fig. 4). The GLU-induced hyperinsulinemia persisted for 8 and 10 h in early- and late-lactation cows, respectively. There was no difference between CON and LIP on plasma insulin concentrations at either stage of lactation (P > 0.10).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The hyperglycemia induced by GLU treatment relative to CON levels was greater and prolonged in late-compared with early-lactation cows. This suggests an enhanced clearance of plasma glucose in early- relative to late-lactation cows, which concurs with other reports (17,18). The increase in plasma NEFA with LIP, relative to CON, at both stages of lactation is in agreement with the report of Bareille and Faverdin (16). Intralipid particles are similar in size to chylomicrons and are hydrolyzed by peripheral tissues to a similar extent, resulting in an increase in plasma NEFA (19). A similar mechanism could be operating in the cows in this study, because both the early- and late-lactation cows exhibited a massive NEFA response to LIP treatment. Although the relative contribution of lipoprotein lipase activity in mammary tissue, adipose tissue and muscle to the observed increase in plasma NEFA might vary with the stage of lactation, a lower mammary drain of plasma NEFA in late-lactation cows probably explains the high NEFA response in late-lactation cows. However, the higher basal NEFA levels coupled with a greater overall response to LIP treatment in early-lactation cows might have overwhelmed the capacity of the liver to completely oxidize the fatty acids, leading to an increase in plasma BHBA concentrations. The sharp increase in plasma NEFA and BHBA with LIP treatment, in the absence of any changes in daily DMI, suggest that these metabolites do not have a persistent hypophagic effect in early lactation cows; however, the transient effects of these metabolites on DMI during the period of infusion cannot be discounted.
Compared with cows in early lactation, the insulin concentrations of CON cows were greater, and GLU induced a massive insulin response in late-lactation cows similar to those reported elsewhere in dairy cattle (20–22). In addition to an attenuated insulinotropic effect of glucose, insulin-mediated glucose uptake is also reported to be reduced in nonmammary tissues (adipose and muscle) of cows in early lactation, thereby facilitating an increased utilization of glucose by the mammary gland (11). In late-lactation cows, however, insulin-dependent utilization of glucose in adipose tissue is believed to be increased (17). Therefore, it is plausible that our early-lactation cows were insensitive to insulin despite a marginal increase in plasma insulin concentrations. However, the dramatic increase in plasma insulin concentrations coupled with an enhanced tissue sensitivity might have synergized the metabolic effects of insulin in late-lactation cows. Despite marked elevation in plasma NEFA concentrations, LIP treatment did not affect plasma insulin concentrations in this study.
It is well documented that a chronic hyperinsulinemic–euglycemic clamp increases plasma IGF-1 concentrations in early- (18,23) and midlactation Holstein cows (24). Further, a significant increase in IGF-1 was detectable only 12 h after initiation of the clamp (23) whereas infusion of glucose alone did not affect plasma IGF-1 concentrations in early lactation cows (25). The lack of an effect of hyperglycemia on plasma IGF-1 in our early-lactation cows is likely a consequence of the relatively short duration of hyperinsulinemia produced by GLU infusion and/or the antagonistic effects of the elevated plasma GH on insulin action. However, the increase in plasma IGF-1 concentrations with GLU treatment in late-lactation cows could be a combination of the hyperinsulinemic response, lower basal GH concentrations in plasma and removal of the inhibitory influence of GH on insulin action. Despite a numerical increase, LIP infusion did not significantly affect plasma IGF-1 concentrations in late-lactation cows. As expected, plasma GH concentrations were greater in early- compared with late-lactation cows. We provide here the first evidence of a direct inhibitory effect of LIP on plasma GH concentrations in early-lactation cows, which is consistent with a similar report in sheep (26). It is likely that the low plasma GH concentrations observed in late-lactation cows masked any inhibitory effect of LIP on plasma GH levels.
A novel finding of this study is the differential leptin response to short-term energy supplementation in early- and late-lactation cows. In support of our hypothesis, cows in late lactation were in positive energy balance, had relatively higher BCS and greater basal leptin concentrations and exhibited a significant leptin response to short-term infusions of both GLU and LIP. In contrast, early-lactation cows were in negative energy balance, had lower BCS and had relatively lower basal leptin concentrations, which were unresponsive to energy supplementation. The significant increase in plasma leptin concentrations by 6 h of GLU infusion is consistent with studies in rats (27,28) and humans (29–31) demonstrating that 4 to 6 h of glucose or insulin infusion is required to stimulate leptin secretion. Leptin production is regulated at the level of transcription (32), translation (33) and/or secretion (34). If glucose directly stimulates leptin secretion, then an earlier rise in circulating leptin might be expected. That the rise in insulin preceded an increase in plasma leptin suggests that insulin-mediated glucose metabolism in adipocytes coordinates the increase in leptin secretion. In support of our results, studies show that insulin stimulates leptin expression in bovine adipose tissue explants (12), and insulin-induced glucose metabolism, rather than insulin per se, stimulates leptin secretion in rats (35) and humans (36). The glucose flux through the hexosamine biosynthetic pathway (37) and/or the increased intracellular energy from glucose metabolism (38) may be involved in the acute stimulation of leptin secretion. However, in contrast to our results, Gabai et al. (22) observed that plasma leptin concentrations were unresponsive to jugular glucose infusions in cows in late pregnancy. The discrepancy between studies could be attributable to the total amount of glucose infused (723 vs. 1200 g) and the specificity of the assay system used to measure circulating concentrations of leptin (multispecies leptin RIA kit vs. bovine-specific leptin RIA). The lack of an effect of GLU on plasma leptin concentrations in early-lactation cows might be due to a lower hyperglycemic and hyperinsulinemic response, reduced adipose tissue sensitivity to insulin (11), low BCS or negative energy balance.
Compared with the delayed temporal response of leptin to GLU, the leptin response to LIP treatment was more rapid in late-lactation cows, which suggests potential differences in the mechanisms of action of the two macronutrients on leptin secretion. The relatively acute increase in plasma leptin concentrations in late-lactation cows occurred in the absence of any significant change in plasma glucose and insulin concentrations, and may play a role in mediating the satiety observed in these animals. It is unlikely that hyperglycemia or hyperinsulinemia mediated the stimulatory effect of LIP on leptin secretion. Intravascular infusion of Intralipid increases leptin mRNA expression in adipose tissue of humans (39) and rats (37,40), and it increases plasma leptin concentrations within 3 h in rats (40). Further, feeding safflower oil (high in linoleic acid) increases leptin gene expression (41) and plasma leptin concentrations (42) in rats, and it increases plasma leptin concentrations in dairy cattle (43). Therefore, it is likely that the rapid induction of leptin secretion by LIP treatment in our study is due to the direct stimulatory effect of linoleic acid. The effect of LIP on leptin secretion could also be mediated by the hexosamine pathway. It has been shown recently that the bovine leptin gene promoter contains functional binding sites for the transcription factor specificity protein-1 (Sp1) (44); and that increased activity of the hexosamine pathway in bovine endothelial cells increases Sp1 activity (45). Further, basal content of UDP-N-acetylglucosamine (UDP-GlcNAc), the end product of the hexosamine pathway, was found to be lower in adipocytes of lean individuals compared with obese individuals; UDP-GlcNAc was found to induce a 21 and 74% increase in leptin production in adipocytes of lean and obese humans, respectively (46); and infusion of lipid was found to increase UDP-GlcNAc in rats (37). Although it remains to be proven, it is likely that a similar mechanism occurs in cows, with the basal and lipid-stimulated increase in UDP-GlcNAc, and hence of leptin production, being greater in late- than in early-lactation cows.
Based on the observations in this study, and from other recent reports, we propose a mechanism through which glucose and lipid stimulate leptin secretion in dairy cattle. Glucose could stimulate leptin secretion directly, or indirectly through insulin-induced glucose metabolism in adipocytes. The increase in plasma IGF-1 concentrations might either be caused by a direct effect of glucose or be mediated by hyperinsulinemia. Given the strong correlation between leptin and IGF-1 expression in adipocytes (12), and the potential role for IGF-1 in regulating leptin secretion (47), IGF-1 could directly stimulate leptin release from adipocytes, or it might have a permissive role in leptin secretion by attenuating the inhibitory effect of GH on leptin. Unlike the effects of glucose, the stimulatory effects of lipid on leptin secretion are independent of insulin, and might be caused by a direct effect of linoleic acid and/or be mediated through the hexosamine pathway. Although this scenario might hold true in late-lactation cows, in early-lactation cows a strong inhibitory effect of GH on leptin expression and release, in concert with low energy balance and/or adipose reserves, might override any stimulatory effect of glucose or lipid on leptin secretion.
In summary, this study demonstrates for the first time that plasma leptin response to isoenergetic glucose or lipid supplementation is dependent on the stage of lactation. Holstein cows in late lactation exhibited a robust leptin response to parenteral glucose or lipid administration, whereas early-lactation cows did not respond. Both macronutrients, however, had a differential effect on leptin secretion. Compared with the rapid effect of lipid infusion on leptin secretion in late-lactation cows, the glucose-induced increase in plasma leptin concentration was delayed and was preceded by a strong insulin response. We speculate that insulin-mediated glucose metabolism may be involved in the stimulatory effect of glucose on leptin secretion but that the stimulatory effect of lipid is independent of insulin and might be mediated through a direct effect of fatty acids and/or through the hexosamine pathway. Future studies using hyperinsulinemic and hyperglycemic clamps should be useful in delineating the functional importance of glucose metabolism in leptin regulation in ruminants. Studies are also needed to unravel the molecular events involved in the regulation of leptin secretion by lipid and glucose in ruminants.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BCS, body condition score; BHBA, ß-hydroxybutyrate; CON, control; DMI, dry matter intake; GH, growth hormone; GLU, glucose infusion; IGF-1, insulin-like growth factor-1; LIP, lipid infusion; NEFA, nonesterified fatty acids; Sp1, specificity protein-1; UDP-GlcNAc, UDP-N-acetylglucosamine.
Manuscript received 20 June 2003. Initial review completed 1 August 2003. Revision accepted 25 August 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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