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Department of Diabetes-INSERM U341, Hôtel-Dieu Hospital, 75181 Paris Cedex 04, France and * INSERM U465, 75006 Paris, France
3To whom correspondence should be addressed. E-mail: salwa.rizkalla{at}htd.ap-hop-paris.fr.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • (n-3) polyunsaturated fatty acids • leptin • insulin-resistant rats • glucose transporters
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), suggesting that adipose tissue size is a major regulator of leptin production. In a stable situation, plasma leptin is thought to signal a set point at which energy intake and energy expenditure are balanced (2
). This set point reflects a level of leptin sensitivity, which might vary with genetic, nutritional and/or environmental factors.
Dietary regulation of leptin levels has been demonstrated by some investigators. Restriction and refeeding regulate plasma leptin levels and ob gene expression in rodents and humans (1
,3
). Under these conditions, leptin concentrations are down- and up-regulated, respectively (4
,5
).
The effect of increased dietary fat on circulating leptin has been assessed in several models. A high fat diet increased plasma leptin levels and body fat mass in male Sprague-Dawley rats (6
) as well as in normal and transgenic mice models after ablation of brown adipose tissue (7
). However, the effects of the type of dietary fats on plasma leptin are unknown.
Because we previously found (8
) that fish oil in the diet of insulin-resistant sucrose-fed rats decreased both adiposity and adipocyte size, we designed this study to evaluate in the same model the effects of dietary (n-3) polyunsaturated fatty acids (PUFA)4
on a lipostatic regulator factor such as leptin (plasma and adipose tissue leptin). This model of insulin resistance is characterized by early hyperinsulinemia after 2–4 wk and normoinsulinemia after 5–15 wk (9
). Later, insulin resistance is manifested by hypertriglyceridemia and decreased insulin action in several target tissues (8
,10
). Moreover Lombardo et al. (9
) demonstrated that insulin resistance due to long-term sucrose consumption could be reversed by long-term fish oil intake but without any change in circulating insulin levels.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Male Sprague-Dawley rats (n = 48; Centre d’élevage R. Janvier, Le Genest-Saint-Isle, France), 3 wk old, were housed in polypropylene cages (four/cage) and maintained at 24°C with a 12-h light:dark cycle. Rats were initially fed standard laboratory diet and had free access to water. After a 2-wk acclimation period, rats were randomly assigned for 3 or 6 wk to one of two purified powder diets (INRA, Jouy-en-Josas, France) containing (g/100 g) 57.5 sucrose, 21 protein and 14 fat, as either fish oil (SF) or a mixture of vegetable and animal extractive oils (SC). Fish oil (MAXEPA) was donated by Pierre Fabre Medicaments Laboratory, Castres, France. The third group, the reference group (R), was fed a standard powdered commercial diet (semipurified diet no. 210, INRA) containing (g/kg diet) 575 g carbohydrate, 230 g protein and 55 g lipid (corn oil, 11; peanut oil, 11; lard, 33). The other constituents of the diet were 10 g/kg vitamin mixture, 70 g/kg mineral components and 60 g/kg cellulose as described previously (11
). The composition of the experimental diets is given in Table 1
, and the fatty acid content of the diets is presented in Table 2
. The SC diet was high in (n-6) PUFA, whereas the SF diet was rich in (n-3) PUFA. Daily food intake was determined by weighing the food remaining in the cage. Rats were weighed once weekly. Rats (n = 24) were decapitated in the fed state between 0830 and 0930 h in the morning, (n = 8/ diet group) after 3 wk and 24 rats (n = 8/diet group) after 6 wk. Food was withdrawn 1 h before decapitation. Blood was collected and plasma was immediately separated by centrifugation (10 min at 900 x g) and stored at -20°C to measure glucose, insulin, lipid and leptin concentrations. Epididymal and retroperitoneal fat pads were removed, weighed, immediately minced (to mix the different parts of a pad), frozen in liquid nitrogen and stored at -80°C.
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Approval to use laboratory animals was given by the French Ministry of Agriculture and the protocol complied with the NIH guidelines for the care and use of laboratory animals.
Measurement of total fat mass.
At the end of the nutritional period, total lean and fat mass were measured for each rat by the method of dual-energy X-ray absorptiometry (DEXA) using a Hologic QDR 2000 instrument (Hologic, Waltham, MA) with specific software (version V8–19a) and an internal standard adapted for rat measurements (12
). The X-ray beam passes through a calibration disk and scans the rat longitudinally. A detector passing simultaneously under the rat feeds a computer with the absorption data recorded as pixel by pixel. For each pixel corresponding to a surface of 0.151 cm length x 0.064 cm width, weight, lean mass, fat mass and mineral bone mass are determined from beam attenuation analysis, which depends on the relevant tissue composition. The sum of all pixel values gives the whole-body composition in terms of fat mass, boneless lean mass and mineral bone mass.
Membrane preparation and Western-blot analysis of glucose transporter (Glut)-4.
The frozen epididymal and retroperitoneal adipose tissues were homogenized in a buffer containing sucrose 250 mmol/L, EDTA 1 mmol/L, Tris-HCl 20 mmol/L, pH 7.4, and protease inhibitors, including phenylmethylsulfonyl fluoride (PMSF) 0.1 mol/L and pepstatin 0.036 mmol/L. The homogenate was centrifuged at low speed (800 x g) at 4°C for 10 min to separate the nuclei, blood cells and fat, then centrifuged again for 60 min, at 200,000 x g at 4°C to separate total membranes. Total membrane proteins were determined (Bradford Bio-Rad, Richmond, CA). Membrane proteins were subjected to SDS-PAGE using a 12% polyacrylamide resolving gel and then transferred to nitrocellulose membranes. The membranes were incubated with antiserum (1:1000 dilution) specific for the COOH-terminal segment of the Glut-4 transporter, followed by 125I-protein A. Immunolabeled bands were visualized by autoradiography and scanning densitometry. A control sample was run on every gel and used for comparing samples from different gels. Results were adjusted to the control sample in the same gel.
Leptin concentration within adipose tissue.
The frozen epididymal and retroperitoneal adipose tissue samples (50 mg) were homogenized in TES buffer (20 mmol/L TRIS-HCL, 1 mmol/L EDTA, 225 mmol/L sucrose, 0.1 mmol/L PMSF and protease inhibitor: 0.036 mmol/L pepstatin). Cell homogenates were centrifuged (10 min at 12,000 x g) and the leptin content of the cytosolic phase was measured (Linco’s Rat Leptin RIA kit, Clinisciences, Montrouge, France). Data are presented as leptin concentrations of epididymal or retroperitoneal adipose tissue adjusted for body weight.
Biological assays.
Plasma glucose was measured by the glucose oxidase method (Glucose Analyser 2, Beckman, Fullerton, CA), plasma insulin by RIA (Bi-insulin RIA Diagnostic, Pasteur, Paris, France). Plasma triacylglycerols (Triglycerides Enzymatiques kits, BioMérieux, Marcy-l’Etoile, France), plasma cholesterol (Labintest Cholesterol kits, Labintest, Aix-en-Provence, France), plasma phospholipids (Phospholipids Enzymatiques kits, BioMérieux), free fatty acids (Nefa C* kit, Unipath, Dardilly, France) and leptin (Linco’s Rat Leptin RIA kit, Clinisciences, Montrouge, France) concentrations were determined.
Statistical analysis.
Overall comparisons were done by a two-way ANOVA followed by Fisher’s least significant difference (LSD) post-hoc test. A comparison was made between the SC-fed rats and the R group to characterize the sucrose model. Another comparison was made between the two experimental groups (SC, SF). When the variances associated with each experimental mean were heterogeneous, a logarithmic transformation was performed as in the case of accumulated leptin within adipose tissue. Linear regression analysis was applied to determine the correlation between leptin, body weight and total fat mass in all of the experimental rats (SC, SF) at 3 and 6 wk. All analyses were carried out with StatView 512+ software program (Brainpower, Calabasas, CA). Results are given as means ± SEM. Differences were considered significant when P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Sucrose-fed rats (SC) had slightly lower food intake than R rats (3 wk, 21.2 ± 0.2 vs. 25.5 ± 0.1 g/d; 6 wk, 23.6 ± 1.2 vs. 27.0 ± 0.9 g/d; P < 0.0005), but similar energy intake. Body weight tended (P = 0.07) to be higher in the SC group than in the R group (3 wk, 303 ± 6 vs. 297 ± 6 g; 6 wk, 418 ± 12 vs. 386 ± 14 g). The SC-fed rats had greater total fat mass (3 wk, 54.1 ± 2.4 vs. 47.7 ± 2.4 g; 6 wk, 87.1 ± 9.8 vs. 58.3 ± 2.4 g; P < 0.05) as well as greater retroperitoneal and epididymal fat pad weights (P < 0.005, P < 0.05, respectively) than R rats. Sucrose-fed rats were hypertriglyceridemic (P < 0.005), hyperglycemic (P < 0.05) and hyperinsulinemic at 3 wk (P < 0.05) but not at 6 wk, as expected (9
). These modifications were associated with greater plasma leptin levels in the SC-fed rats than in the R rats (3 wk, 4.1 ± 0.2 vs. 3.4 ± 0.3 µg/L; 6 wk, 5.5 ± 0.8 vs. 3.6 ± 0.5 µg/L; P < 0.005). Rats in the 6-wk experiment had greater food and energy intakes (P < 0.05), with heavier body weight (P < 0.0005) and retroperitoneal and total fat mass (P < 0.0005) than younger rats in the 3-wk experiment.
Effects of dietary (n-3) PUFA in sucrose-fed rats
Food and energy intakes, body and organ weights.
The characteristics of the two sucrose-fed groups (SC and SF) at the end of the nutritional periods are shown in Table 3
. There were significant interactions (P < 0.05) between diet and duration on food and energy intakes. At 3 and 6 wk, food and energy intakes were higher in the SF-fed rats than SC-fed rats, whereas body weight and total fat mass did not differ at any time point. The epididymal and retroperitoneal fat pad weights were significantly lower in SF-fed rats than in the SC-fed rats (P < 0.0005 and 0.005, respectively). Rats in the 6-wk experiment had greater food intake and were heavier because they had greater total lean and fat masses than those in the 3-wk experiment.
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, fish oil feeding induced more total membrane Glut-4 protein in both epididymal and retroperitoneal adipose tissue compared with SC-fed rats. Rats fed the diets for 6 wk had more Glut-4 protein in epididymal adipose tissue than did rats fed the diets for 3 wk.
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). In the SC group, adipose tissue leptin concentration was higher at 6 wk than after the 3-wk dietary period. This was not the case in the SF group.
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). When plasma leptin was adjusted to total fat mass, the concentration was also greater in the SF group than in the SC group (P < 0.0005), but the duration of feeding had no effect.
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Correlations. When all SC- and SF-fed rats (both diets and feeding durations) were considered, strong positive correlations were found between plasma leptin and both body weight (r = 0.5, P < 0.0001) and total fat mass (r = 0.5, P < 0.0005). When these correlations were examined in each diet group, positive correlations were found in the SC group (leptin and body weight, r = 0.7, P < 0.01; leptin and total fat mass, r = 0.85, P < 0.001), but not in the SF group.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), in this study, dietary fish oil increased plasma leptin without any effect on total fat mass or body weight. However, both epididymal and retroperitoneal adipose tissue weights were reduced, consistent with a site-specific effect of dietary fish oil (13
,14
,15
). Despite secretion (plasma leptin), the quantity of leptin accumulated within these adipose tissue sites was greater in the SF group than in the SC group at 3 wk, suggesting enhanced leptin synthesis. At 6 wk, the increased plasma leptin was not associated with elevated leptin in adipose tissue, indicating that leptin secretion was more active than intracellular leptin turnover. Data in the fish oil–fed rats suggest a dissociation between changes in plasma leptin, body weight and adipose tissue mass. This dissociation was demonstrated in another study after 10 wk of fish oil feeding in normal, but not in sucrose-fed rats (16
). Two recent studies, however, found that fish oil feeding for 3 wk (17
) or 3 mo (18
) might reduce leptin mRNA in normal rats. Unfortunately, the authors did not give sufficient information on food intake and body weight to clarify the cause of these results. Nevertheless, in the study by Reseland et al. (17
) a nonsignificant decrease of 11% in body weight was found to parallel a nonsignificant decrease of 18% in plasma leptin levels. A slight decrease in body weight might explain the reduction in plasma leptin or leptin mRNA levels. Moreover, in vitro, some investigators demonstrated that (n-3) PUFA inhibit leptin mRNA concentrations in different cell lines (17
,18
). Results in vitro, however, cannot be extrapolated to results in vivo for which there are additional environmental factors.
In the present study, fish oil feeding might have resulted in a relative leptin resistance, manifested by high plasma leptin levels without a decrease in food intake or total fat mass. However, this was not the case because these high leptin levels (which remained within the physiologic range) maintained body weight at a constant level and limited the increase of some body fat stores, especially retroperitoneal and epididymal adipose tissue. In the SF-fed rats, the high leptin levels were followed by an increased food intake. These data suggest that the effect of leptin on regulating body weight and fat mass cannot always be explained on the basis of food intake alone, but might also suggest that energy expenditure increased. This is compatible with the finding that leptin treatment could increase energy expenditure through enhanced thermogenesis in brown adipose tissue (19
,20
).
In this study, we could not ignore the known effect of age (21
,22
). Older rats were heavier and their increased total fat mass was associated with an increase in plasma leptin levels. This is strengthened by the presence of positive correlations between plasma leptin concentrations and both body weight and total fat mass when all sucrose-fed rats (both diets and feeding durations) were analyzed. Thus, factors involved in the regulation of leptin by age might be totally different from those implicated in the regulation of leptin by dietary lipids at any given time.
The results with fish oil feeding are not in opposition to the lipostatic hypothesis, but rather, emphasize that biological factors other than adipose tissue size are involved in determining leptin levels. Insulin or some components of insulin resistance could be possible candidates. Although not consistently found (23
–25
), a stimulatory effect of insulin on ob gene expression was reported by several groups (4
,26
). In the present study, however, fish oil feeding induced high plasma leptin levels in the absence of high plasma insulin measured in food-deprived rats. This apparent contradiction might be due to increased insulin sensitivity in these rats. Indeed, dietary fish oil prevented the sucrose-induced insulin resistance as in this study (normalization of plasma triglycerides and free fatty acids and (Glut)-4 proteins quantity) and as demonstrated previously (9
,10
,27
,28
). This hypothesis is likely and is strengthened by other findings in humans (29
) and animals (30
). Moreover, a role for glucose transport and/or metabolism in regulating leptin secretion might be also considered in the present study because fish-oil feeding was found to increase glucose transport proteins (Glut-4) and activity (10
). On the other hand, in a primary culture of rat adipocytes, Mueller et al. (30
) demonstrated that the increase in insulin-stimulated leptin secretion was more closely related to the amount of glucose taken up by the adipocytes than to the insulin concentration per se. Nyholm et al. (31
) found that insulin-stimulated glucose uptake contributed significantly to leptin level increments as assessed by multiple regression analyses, indicating an association between the rise in leptin and the increase in insulin sensitivity. Thus, increasing glucose flux into adipocytes as well as increasing insulin sensitivity of adipocytes as shown previously (8
,10
) might be the major cause of enhancing leptin secretion in the SF-fed rats.
An alternative explanation might be that the rise in leptin levels in the SF-fed rats was the cause of increased insulin sensitivity and glucose transport. In fact, chronic leptin administration has been shown to increase whole-body glucose disposal (32
). Moreover, microinjections of leptin into the ventromedial hypothalamus dramatically increased glucose uptake in certain peripheral tissues through the mediation of a ß-adrenergic mechanism for the sympathetic nerves innervating the tissues (33
). Therefore, all of the effects found after ingestion of fish oil might be explained simply by the increase in leptin levels, which improved insulin sensitivity and hyperinsulinemia. Moreover, increased leptin levels might contribute to the reduction of retroperitoneal and epididymal fat pads by enhancing thermogenesis and energy expenditure, through sympathetic stimulation (34
).
Nevertheless, the inclusion of fish oil in a starch diet might be of interest (16
) but this was not the aim of the present study in which we evaluated leptin regulation in a model characterized by increased adiposity and insulin resistance.
Thus, in the present model, dietary fish oil prevented adiposity induced by sucrose feeding and up-regulated plasma leptin levels via possible improvement in both insulin sensitivity and glucose uptake into adipocytes. Thus, plasma leptin could be high for a given fat mass in insulin-sensitive rats. Understanding the regulation of leptin levels by (n-3) PUFA might be a tool in preventing adiposity and consequently the enhanced risk of developing diabetes and cardiovascular diseases.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Supported by a grant from the National Institute of Health and Medical Research (INSERM) and by Pierre and Marie Curie University.
4 Abbreviations used: DEXA, dual-energy X-ray absorptiometry; Glut, glucose transporter; PMSF, phenylmethylsulfonyl fluoride; PUFA, polyunsaturated fatty acids; R, reference group; SC, sucrose-control oil diet; SF, sucrose-fish oil diet.
Manuscript received 4 January 2002. Initial review completed 30 January 2002. Revision accepted 24 April 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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