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Institute of Agricultural and Nutritional Sciences, Martin Luther University, D-06108 Halle (Saale), Germany
* To whom correspondence should be addressed. E-mail: klaus.eder{at}landw.uni-halle.de.
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ABSTRACT |
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 TOP ABSTRACT IntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Introduction |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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, which is associated with increased expression of genes involved in oxidation of fatty acids [e.g. acyl-CoA oxidase (ACO),2 L-type carnitin-palmitoyl transferase I (L-CPT I), medium-chain acyl-CoA dehydrogenase (MCAD), cytochrome P450 4A1 (CYP4A1) (lauric acid omega-hydroxylase)], reduced gene expression of enzymes involved in de novo-fatty acid synthesis [e.g. fatty acid synthase (FAS)], and strongly reduced concentrations of triacylglycerols in liver and plasma (4–7). In lactating rats, feeding oxidized fats caused a strong reduction of milk triacylglycerol concentration, which in turn led to reduced weight gains of suckling pups (8,9). The reason underlying the reduction of milk triacylglycerol concentration in lactating rats by oxidized fat, however, has not yet been clarified. Milk triacylglycerol synthesis depends on the availability of fatty acids in the mammary gland, which derive from 3 different sources. The first source represents de novo biosynthesis of fatty acids within the mammary gland by the activity of lipogenic enzymes. Medium-chain fatty acids with 8–14 carbon atoms are the main products of this process, which is controlled by the lipogenic transcription factor sterol regulatory element-binding protein (SREBP)-1c (10). Fatty acids released from triacylglycerol-rich lipoproteins by lipoprotein lipase (LPL) and taken up into the mammary gland are another important source for milk triacylglycerol synthesis (11). Those fatty acids reflect those of the diet and are typically long-chain fatty acids with 16–22 carbon atoms, either saturated or unsaturated (12,13). Nonesterified fatty acids (NEFA) in the plasma released from adipose tissue by hormone-sensitive lipase and taken up into the mammary gland by fatty acid transporters are the 3rd source of fatty acids available for milk triacylglycerol synthesis. We have recently shown that fatty acid synthesis in the mammary gland is not influenced by dietary oxidized fats in lactating rats (8). Therefore, we postulate that reduced milk triacylglycerol concentrations in lactating rats fed oxidized fats are due to a decreased uptake of fatty acids from triacylglycerol-rich lipoproteins and/or a reduced uptake of NEFA from plasma. The availability of fatty acids from triacylglycerol-rich lipoproteins for tissues depends on the concentrations of triacylglycerol-rich lipoproteins in plasma and on the activity of LPL (14). To determine whether oxidized fat could reduce the availability of fatty acids from triacylglycerol-rich lipoproteins for the mammary gland, we measured plasma triacylglycerol concentrations and gene expression of LPL in mammary gland. In growing rats, feeding an oxidized fat causes a strong reduction of triacylglycerols in plasma and VLDL by an increased ß-oxidation of fatty acids and a reduced de novo-fatty acid synthesis in the liver (6,7). To study whether such an effect also occurs in lactating rats, we determined messenger RNA (mRNA) expression of genes involved in hepatic fatty acid oxidation (ACO, L-CPT I, CYP4A1, and MCAD) and synthesis [SREBP-1c, FAS, stearoyl-CoA desaturase (SCD), cytosolic NADP+-dependent isocitrate dehydrogenase (IDH1)]. To further elucidate the effect of oxidized fat on the uptake of NEFA into the mammary gland, we determined plasma concentrations of NEFA and mRNA expression levels of fatty acid transporters, fatty acid translocase/CD36 (FAT/CD36), fatty acid transport protein (FATP), and mitochondrial aspartate aminotransferase [(mAspAT), also called plasma membrane fatty acid-binding protein (FABPpm)] in the mammary gland.
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Materials and Methods |
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Diets and feeding.
Semipurified diets, composed according to the recommendations of American Society for Nutritional Sciences for rats during reproduction (16), were used. The diet consisted of (g/kg diet): casein, 200; cornstarch, 390; saccharose, 198; cellulose, 50; fat, 100; mineral mixture, 40; vitamin mixture, 20; DL-methionine, 2. The type of fat was varied according to a 1-factorial design. The first group [fed fresh fat (FF)] received a mixture of sunflower oil and lard (60:40, wt:wt). We chose this ratio to equalize the concentration of PUFA, mainly C18:2(n-6), of the fresh fat with that of the oxidized fat, because the heating process caused a loss of PUFA. The second group was fed oxidized fat (OF; see "Preparation of the oxidized fat"). The vitamin E concentration of the diets was 50 mg -tocopherol equivalents per kilogram diet. To adjust the vitamin E concentration of the diets, the native concentrations of tocopherols of the fats were analyzed. Based on the native concentrations of the fats, diets were supplemented individually with all-rac--tocopheryl acetate (the biopotency of all-rac--tocopheryl acetate is considered to be 67% of that of -tocopherol). Diets were prepared by mixing the dry components with the fat and water and were subsequently freeze-dried. The residual water content of the diet was <5 g/100 g diet. Food was administered daily at 0800 in restricted amounts to standardize intake.
Experimental diets were fed during the suckling period from d 1 to d 20 of lactation. To standardize food intake, diets were fed in a controlled feeding regimen, whereby each rat received the same amount of diet. The food given was 20% less than the amounts of identical diets with fresh fats consumed ad libitum by rats in preliminary studies. The amount of food offered each day was increased continuously from 20 g at d 1 of lactation to 36 g at the end of the experiment (d 20 of lactation).
Rats consumed water ad libitum from nipple drinkers during the entire experiment.
Preparation of the oxidized fat. The oxidized fat was prepared by heating sunflower oil at 60°C for 25 d. Sunflower oil was poured into a glass beaker and placed into a drying oven set at the intended temperature. Throughout the heating process, air was continuously bubbled through the fat at a flow rate of 650 mL/min. This treatment caused a loss of PUFA and a complete loss of tocopherols and raised the concentrations of lipid peroxidation products in the fats. The extent of lipid peroxidation in the oxidized fat was estimated by assaying the peroxide value (POV) (17), concentration of TBARS (18), and concentration of conjugated dienes (19). To assess lipid peroxidation products in the oxidized fat after inclusion into the diet, the fat was extracted from aliquots of the diets with a mixture of hexane and isopropanol (3:2, v:v) and analyzed for POV, concentration of conjugated dienes, and TBARS.
Sample collection. At d 15 of lactation, milk samples were collected from the dams. After separation from the pups for 1 h, dams were anesthetized i.m. with ketamine (75 mg/kg body weight) and injected i.m. with 1 international units oxytocin to stimulate milk flow. Milking was performed at 1000 h with a milking machine. From each rat, 2–3 mL of milk was obtained from all teats within 10 min through below atmospheric pressure. Samples were stored at –20°C until analysis. At d 20 of lactation, rats were killed by decapitation under light anesthesia with diethyl ether. Blood was collected from the opened neck into heparinized polyethylene tubes (Sarstedt) by the use of heparinized plastic funnels. Plasma was separated from blood by centrifugation (1100 x g; 10 min) at 4°C. Liver and mammary gland were excised immediately and shock frozen with liquid nitrogen. All samples were stored at –80°C pending analysis.
Lipid analysis. Triacylglycerol concentrations in liver, milk, and plasma were determined using an enzymatic reagent kit obtained from Merck Eurolab (ref. No. 113009990314). For the measurement of liver and milk triacylglycerols, lipids of the extract, obtained with a mixture of hexane and isopropanol (3:2, v:v) (20), were dissolved in Triton X-100 prior to enzymatic measurement, as described by De Hoff et al. (21). Plasma NEFA concentrations were determined using the enzymatic NEFA C kit from Wako Chemicals (ref. no. 99975406). The fatty acid composition of dietary fats and milk total lipids was determined by GC-flame ionization detector as described recently (22).
RNA isolation and real-time detection PCR.
For the determination of mRNA expression levels of PPAR, CYP4A1, ACO, L-CPT I, MCAD, LPL, hepatic lipase (HL), FAT/CD36, FATP, mAspAT, SREBP-1c, FAT, SCD, and IDH1, total RNA was isolated from liver and mammary gland using TrizolP reagent (Invitrogen) according to the manufacturer's protocol. RNA concentration and purity were estimated from the OD at 260 and 280 nm, respectively. cDNA synthesis and relative quantification of target gene mRNA compared with the housekeeping gene mRNA was determined by real-time detection PCR as described previously (23). As housekeeping genes, we used glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the liver and ribosomal protein S9 (RPS9) in the mammary gland. RPS9, in contrast to GAPDH, is a suitable internal reference gene for normalization of gene expression data in mammary tissue (24). Relative quantification was performed using the 
cycle threshold (Ct)-method (25). Ct values of target genes and the reference gene were obtained using Rotorgene software 5.0. Relative expression ratios are expressed as fold-changes of mRNA abundance in the treatment group (OF) compared with the control group (FF). Sequences of gene-specific primers were as follows (forward, reverse; National Center for Biotechnology Information GenBank): GAPDH (GCA TGG CCT TCC GTG TTC C, GGG TGG TCC AGG GTT TCT TAC TC; NM_017008); PPAR (CCC TCT CTC CAG CTT CCA GCC C, CCA CAA GCG TCT TCT CAG CCA TG; NM_013196); CYP4A1 (CAG AAT GGA GAA TGG GGA CAG C, TGA GAA GGG CAG GAA TGA GTG G; M14972); ACO (CTT TCT TGC TTG CCT TCC TTC TCC, GCC GTT TCA CCG CCT CGT A; J02752); L-CPT I (GGA GAC AGA CAC CAT CCA ACA TA, AGG TGA TGG ACT TGT CAA ACC; NM_031559); SREBP-1c (GGA GCC ATG GAT TGC ACA TT, AGG AAG GCT TCC AGA GAG GA; XM_213329); FAS (AGG TGC TAG AGG CCC TGC TA, GTG CAC AGA CAC CTT CCC AT; NM_017332); MCAD (CAA GAG AGC CTG GGA ACT TG, CCC CAA AGA ATT TGC TTC AA; NM_016986); LPL (TCC CAC CAC AAC GAA GTA CA, TCA GCC AGG GCA TTA TTT TC; NM_012598); FAT/CD36 (TCG TAT GGT GTG CTG GAC AT, GGC CCA GGA GCT TTA TTT TC; L19658); FATP (GGT AGC AAA TGC ACC CTC AT, CTC CTG CTG TGA TGT GAG GA; U89529); mAspAT (ACC ATC CAC TGC CGT CTT AC, CCC CGA TGC GTA GGT ATT CT; M18467); SCD (CCG TGG CTT TTT CTT CTC TCA, CTT TCC GCC CTT CTC TTT GA; NM_139192); IDH1 (GCT TCA TCT GGG CCT GTA AG, GCT TTG CTC TGT GGG CTA AC; NM_031510); HL (TGC CAA TTT TGT GGA TGC TA, TTA AGC CAT GCT CTG CAA TG; NM_012597); and RPS9 (CAA ATT TAC CCT GGC GAA GA, TCA GGC CCA GAA TGT AAT CC; NM_031108).
Statistical analysis. Values presented in the text are means ± SD. Treatment effects were analyzed using 1-way ANOVA. For significant F-values, means were compared by Fisher's multiple range test. Differences with P < 0.05 were considered significant.
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Results |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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Development of litters during the suckling period. At d 8, 14, and 20 of lactation, litters, standardized to 7 pups/dam, of dams fed diets containing OF were lighter than those fed diets containing FF (P < 0.05; Table 2). Weight gains of litters from d 1 to d 20 were also lower in dams fed diets containing OF than in dams fed diets containing FF.
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, ACO, L-CPT I, CYP4A1, and MCAD in the liver of dams fed diets with OF were 1.8-, 5.3-, 2.3-, 5.2-, and 5.6-fold, respectively, of control (P < 0.05; Fig. 1). In contrast, PPAR mRNA was only barely detectable by real-time RT-PCR in lactating mammary gland. The relative mRNA concentrations of ACO, L-CPT I, CYP4A1, and MCAD in the mammary gland did not differ between both groups (data not shown).
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Discussion |
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TOPABSTRACTIntroductionMaterials and MethodsResultsDiscussionLITERATURE CITED |
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agonists (27–29). For technical reasons, we did not directly determine the concentrations of these oxidized fatty acids in the dietary fats, but the high POV and the high concentration of conjugated dienes indicate that the OF indeed had high concentrations of these fatty acids. To exclude effects of a different intake of PUFA, we equalized the concentration of linoleic acid of the FF to that of the OF. There were slight differences in the proportions of SFA and monounsaturated fatty acids in both fats, but we assume that these differences contributed less, if at all, to the effects observed in the rats fed the oxidized fat. Because the intake of OF could lead to a diminished food intake (30,31), we used a controlled feeding system in which each rat consumed the same amount of diet to exclude secondary food intake effects. The amount of food administered was 20% less than in preliminary studies but was sufficient to meet the high energy demand of lactating rats even in peak lactation (32). This study clearly confirmed the findings of our previous study (8) that reduced milk triacylglycerol concentrations by dietary OF are not the result of a reduced de novo-fatty acid synthesis in the mammary gland. This was evidenced by an unaltered mRNA abundance of genes encoding enzymes involved in de novo-fatty acid synthesis such as FAS, SCD, and IDH1 as well as of the lipogenic transcription factor SREBP-1c in the mammary gland of dams fed OF compared with control dams. Furthermore, the concentration of medium-chain fatty acids with 8–14 carbon atoms in the milk, which are mainly synthesized de novo within the mammary epithelial cell (14), did not differ between both groups of dams.
Our study shows that the dietary OF leads to a decreased mRNA abundance of LPL, which mediates utilization of fatty acids from circulating triacylglycerol-rich lipoproteins by the hydrolysis of triacylglycerols, and of fatty acid transporters, which mediate cellular uptake of albumin-bound NEFA, in the mammary gland. In addition, the decreased concentration of plasma triacylglycerols in rats fed OF indicates that the substrate for LPL was also reduced by feeding OF. Fatty acid analysis of milk lipids revealed that the concentrations of long-chain fatty acids with 18–22 carbon atoms, which are hydrolyzed from lipoprotein triacylglycerols by the activity of LPL and largely reflect those of the diet (12,13), were significantly lower in the milk of dams fed OF than in control dams. These findings strongly support our assumption that the reduced milk triacylglycerol concentration in dams fed OF is the consequence of both a diminished uptake of fatty acids from lipoproteins by LPL and a decreased uptake of free fatty acids by fatty acid transporters from plasma into the mammary gland.
Interestingly, in the liver, the mRNA abundance of HL and fatty acid transporters was increased in dams fed OF relative to control dams. This indicates that feeding OF to dams exerted a completely opposing effect on the expression of these genes in the liver compared with the mammary gland. Moreover, relative liver weights and mRNA abundance of PPAR-responsive genes involved in fatty acid catabolism such as ACO, CYP4A1, L-CPT I, and MCAD were increased in the liver of dams fed OF. These findings are in accordance with findings from several recent studies using nonlactating rats and are explained by the strong PPAR-activating effect of OF in the liver (4–6). This effect is also accompanied by induction of peroxisome proliferation contributing to the increase in liver weights in dams fed OF. The strongly reduced triacylglycerol concentrations in the liver of dams fed OF are probably largely explained by the upregulation of hepatic PPAR-responsive genes, which markedly enhances hepatic fatty acid ß-oxidation capacity. The latter effect presumably explains that the physiological lactation-induced increase in hepatic triacylglycerol concentrations as observed in lactating rats fed FF was considerably reduced by OF. Because the fatty acid transporters investigated are also PPAR target genes (33,34), we assume that upregulation of those genes in the liver of dams fed OF was also mediated by the PPAR activating effect of OF. Decreased plasma concentrations of NEFA in dams fed OF may be due to an increased uptake of circulating NEFA from the plasma into the liver. Normally, during lactation, the utilization of metabolic substrates such as fatty acids or glucose for the synthesis of milk in the mammary gland is increased and the utilization of substrates for oxidation in other tissues (e.g. liver, skeletal muscle) is reduced (35). The finding that uptake of fatty acids into the liver and their subsequent oxidation increased, whereas uptake of fatty acids into the mammary gland decreased, indicates that the OF impaired normal metabolic adaptations during lactation due to its PPAR-activating effect. Similar observations regarding an impairment of lactation-induced energy-sparing mechanisms (e.g. reduction in heat production by skeletal muscle) by the administration of PPAR activators have been reported from others (36). We cannot exclude the possibility that OF might have provoked similar changes in adaptative thermogenesis, which could be an explanation for the observation that dams fed OF had similar body weights as control dams, although the dams fed OF produced less milk and thus may have required less energy for milk production.
In the mammary gland, the mRNA expression of genes involved in intracellular fatty acid catabolism did not differ between dams of both groups, indicating that reduction in milk triacylglycerols by oxidized fat is not due to an altered rate of fatty acid oxidation in the mammary gland of dams fed OF. However, the PPAR gene shows only a negligible expression in the lactating mammary gland of rodents (37,38), because the physiological expression of PPAR is dramatically decreased in the mammary gland during lactation (38), indicating that oxidation of fatty acids in the lactating mammary gland might be limited. A possible effect of OF on mammary tissue development cannot be ruled out, because we did not perform histological analysis of mammary tissue or determine mammary tissue weights in lactating rats. However, future studies should also address a possible detrimental effect of OF on mammary gland development, because a recent study revealed that pharmacological activation of PPAR during pregnancy impairs mammary gland development and results in a defect of lactation and mortality of the pups (39).
In view of the physiological relevance of milk for the development of the offspring, we also investigated the effect of OF on the development of the suckling pups during lactation. Because maternal milk is the only source of nutrients for the suckling pups, it was not surprising that the reductions in triacylglycerols and, concomitantly, energy in the milk by oxidized fat were accompanied by reduced development of litters during lactation, as also shown previously (8,9). Because the litter weight of lactating rats fed OF was already reduced at d 8 of lactation and thereafter, we assume that the reduction of triacylglycerols in the milk occurred early during lactation, indicating that this effect of OF is mediated even after short-term administration of OF. Therefore, the uptake of oxidized fats by the lactating organism has to be considered critically with regard to the great biological importance of milk fat synthesis for the development of the offspring.
Taken together, this study demonstrates for the first time, to our knowledge, that feeding OF during lactation increases not only the mRNA abundance of genes involved in fatty acid oxidation but also of genes mediating fatty acid uptake in the liver. In contrast, in the mammary gland, the mRNA expression levels of LPL and fatty acid transporters were significantly downregulated by the administration of OF to dams, which was accompanied by significant milk fat reduction. Therefore, these findings suggest that the normal metabolic adaptations during lactation, which promote the utilization of substrates by the mammary gland for the synthesis of milk and reduce the use of substrates for oxidation in other tissues, are disturbed in lactating rats by OF and largely explain the milk fat reducing effect of OF.
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FOOTNOTES |
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2 Abbreviations used: ACO, acyl-CoA oxidase; CYP4A1, cytochrome P450 4A1; FABPpm, plasma membrane fatty acid-binding protein; FAS, fatty acid synthase; FAT/CD36, fatty acid translocase/CD36; FATP, fatty acid transport protein; FF, group fed fresh fat; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HL, hepatic lipase; IDH1, cytosolic NADP+-dependent isocitrate dehydrogenase; L-CPT I, L-type carnitin-palmitoyl transferase I; LPL, lipoprotein lipase; mAspAT, mitochondrial aspartate aminotransferase; MCAD, medium-chain acyl-CoA dehydrogenase; mRNA, messenger RNA; NEFA, nonesterified fatty acids; OF, group fed oxidized fat; POV, peroxide value; RPS9, ribosomal protein S9; SCD, stearoyl-CoA desaturase; SREBP-1c, sterol regulatory element-binding protein-1c.
Manuscript received 12 April 2007. Initial review completed 9 June 2007. Revision accepted 29 June 2007.
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