Impaired lipogenesis in mammary glands of lactating rats fed on a cafeteria diet. Reversal of inhibition of glucose metabolism in vitro by insulin.
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ABSTRACT:
SUBMITTER: Agius L
PROVIDER: S-EPMC1161742 | biostudies-other | 1980 Mar
REPOSITORIES: biostudies-other
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Project description:Dietary malpractice is a risk factor for obesity. This study tested the hypothesis that consumption of a high-fat diet alters mammary metabolome in pubertal mice. We performed untargeted metabolomic analysis of primary metabolism on mammary glands from pubertal mice fed the AIN93G standard diet or a high-fat diet (HFD) for 3 weeks. We identified 97 metabolites for statistical comparisons. The HFD altered the amino acid metabolism considerably. This included elevated expression of branched-chain amino acids, non-essential amino acids (aspartic acid and glutamic acid), and methionine sulfoxide (oxidized methionine) and an alteration in the aminoacyl-tRNA biosynthesis pathway. Furthermore, elevations of fumaric acid and malic acid (both are citrate cycle intermediates) and glyceric acid (its phosphate derivatives are intermediates of glycolysis) in HFD-fed mice suggest an acceleration of both citrate cycle and glycolysis. Lower expression of glycerol, oleic acid, and palmitoleic acid, as well as decreased mammary expression of genes encoding lipid metabolism (Acaca, Fads1, Fasn, Scd1, and Srebf1) in HFD-fed mice indicate an attenuated lipid metabolism in the presence of adequate dietary fat. In conclusion, consumption of the HFD for 3 weeks alters metabolic profile of pubertal mammary glands. This alteration may affect mammary development and growth in pubertal mice.
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Project description:Arteriovenous glucose difference across the mammary gland of the lactating rat was used as an 'instantaneous' monitor of mammary glucose uptake. Plasma [glucose] and arteriovenous glucose difference varied according to whether Halothane, diethyl ether or sodium pentobarbitone anaesthesia was used. In pentobarbitone-treated rats a 60% glucose extraction in the fed state decreased to 5% after 18 h starvation, and recovered to 40% and 59% after 15 min and 60 min re-feeding respectively. The increase and decrease in plasma [fatty acids] and the depletion and restoration of hepatic glycogen mostly followed similar time courses. Re-feeding was accompanied by a brief surge of plasma [insulin]. Starved lactating rats showed a markedly greater capacity than age-matched virgin rats in the oral and intraperitoneal glucose tolerance tests. Mammary glucose uptake in the starved rat was significantly restored by oral or intraperitoneal glucose or by insulin, but not by acetoacetate or by heparin-induced elevation of plasma [fatty acids]. The role of insulin and of possible changes in mammary sensitivity to insulin in the return of mammary glucose uptake on re-feeding is discussed.
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Project description:BackgroundThe local supply of energy-yielding nutrients such as glucose seems to affect the synthesis of milk components in the mammary gland (MG). Thus, our study was conducted to investigate the effects of locally available MG glucose supply (LMGS) on amino acid (AA) sensing and utilization in the MG of lactating dairy goats. Six dosages of glucose (0, 20, 40, 60, 80, and 100 g/d) were infused into the MG through the external pudendal artery to investigate the dose-dependent changes in mammary AA uptake and utilization (Exp.1) and the changes in mRNA and protein expression of the AMPK-mTOR pathway (Expt.2).ResultsIn Exp.1, total milk AA concentration was highest when goats were infused with 60 g/d glucose, but lower when goats were infused with 0 and 100 g/d glucose. Increasing LMGS quadratically changed the percentages of αS2-casein and α-lactalbumin in milk protein, which increased with infusions from 0 to 60 g/d glucose and then decreased with infusions between 60 and 100 g/d glucose. The LMGS changed the AA availability and intramammary gland AA utilization, as reflected by the mammary AA flux indexes. In Exp.2, the mRNA expression of LALBA in the MG increased quadratically with increasing LMGS, with the highest expression at dose of 60 g/d glucose. A high glucose dosage (100 g/d) activated the general control nonderepressible 2 kinase, an intracellular sensor of AA status, resulting in a reduced total milk AA concentration.ConclusionsOur new findings suggest that the lactating MG in dairy goats may be affected by LMGS through regulation of the AA sensory pathway, AA utilization and protein synthesis, all being driven by the AMPK-mTOR pathway.
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Project description:Ectopic tertiary lymphoid organs (TLOs) have been identified in many organs, such as the lungs, nasal cavities, and kidneys of both mice and humans. Although lymphocyte aggregates have been observed in the mammary glands of ruminants, the details remain unclear. In this study, we investigated the mammary glands of lactating goats for the presence of TLOs. The localization of CD20 (B cells), CD3 (T cells), MECA79 (high endothelial venules), CD40 (follicular dendritic cells), BCL6 (germinal center), and IgA was examined by immunohistochemistry. The concentrations of IgG, IgA, lactoferrin, β-defensin-1, cathelicidin-2, cathelicidin-7, S100A7, and S100A8 in milk were measured by ELISA. The localization and amount of tight junction (TJ) proteins (claudin-3 and claudin-4) were examined using immunofluorescence and western blotting. We found that 19 out of 30 udders contained lymphocyte aggregates, which showed positive reactions against CD20, CD3, CD40, and MECA79. In addition, large-sized aggregations showed separate localization of B cells and T cells and a positive reaction against BCL6, although BCL6 was sparsely localized in the aggregations. These results indicate that mammary glands of lactating goats contain TLOs. The IgG and IgA concentrations in the milk of TLO-positive goats and the number of IgA-positive cells were higher than those in negative goats. Furthermore, claudin-4 was localized in the TJ region and the amount was higher in TLO-positive mammary glands than that in the negative group, indicating the presence of leakages at TJs. In conclusion, a majority of lactating goat udders have TLOs, which contribute to local immunity by producing immunoglobulins.
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Project description:BackgroundHexabromocyclododecane (HBCD) is an additive flame retardant used in the textile industry and in polystyrene foam manufacturing. Because of its lipophilicity and persistency, HBCD accumulates in adipose tissue and thus has the potential of causing metabolic disorders through disruption of lipid and glucose homeostasis. However, the association between HBCD and obesity remains unclear.ObjectivesWe investigated whether exposure to HBCD contributes to initiation and progression of obesity and related metabolic dysfunction in mice fed a normal diet (ND) or a high-fat diet (HFD).MethodsMale C57BL/6J mice were fed a HFD (62.2 kcal% fat) or a ND and treated orally with HBCD (0, 1.75, 35, or 700 μg/kg body weight) weekly from 6 to 20 weeks of age. We examined body weight, liver weight, blood biochemistry, histopathological changes, and gene expression profiles in the liver and adipose tissue.ResultsIn HFD-fed mice, body and liver weight were markedly increased in mice treated with the high (700 μg/kg) and medium (35 μg/kg) doses of HBCD compared with vehicle. This effect was more prominent in the high-dose group. These increases were paralleled by increases in random blood glucose and insulin levels and enhancement of microvesicular steatosis and macrophage accumulation in adipose tissue. HBCD-treated HFD-fed mice also had increased mRNA levels of Pparg (peroxisome proliferator-activated receptor-γ) in the liver and decreased mRNA levels of Glut4 (glucose transporter 4) in adipose tissue compared with vehicle-treated HFD-fed mice.ConclusionsOur findings suggest that HBCD may contribute to enhancement of diet-induced body weight gain and metabolic dysfunction through disruption of lipid and glucose homeostasis, resulting in accelerated progression of obesity.CitationYanagisawa R, Koike E, Win-Shwe TT, Yamamoto M, Takano H. 2014. Impaired lipid and glucose homeostasis in hexabromocyclododecane-exposed mice fed a high-fat diet. Environ Health Perspect 122:277-283; http://dx.doi.org/10.1289/ehp.1307421.
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Project description:The proportion of medium-chain fatty acids (C8:0, C10:0 and C12:0) in rat milk increased significantly between day 4 and day 8 of lactation and for the remainder of lactation these acids comprised 40-50mol% of the total fatty acids. The milk fatty acid composition from day 8 was markedly dependent on the presence of dietary fat and altered to include the major fatty acids of the fats (peanut oil, coconut oil and linseed oil). The distribution of fatty acids made within the gland, however, was independent of dietary lipid and C8:0, C10:0 and C12:0 acids accounted for over 70% of the fatty acids made. The rates of lipogenesis in both the mammary gland and liver determined in vivo after the administration of 3H2O were affected by the presence of dietary lipid. In the mammary gland the rate for rats fed a diet containing peanut oil for 7 days was only one fifth that for rats fed a fat-free diet. Coconut oil also suppressed lipogenesis. Both dietary fats also suppressed lipogenesis in the liver.
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Project description:Administration of acetoactate to fed lactating rats rapidly decreases glucose uptake by the mammary gland, and causes an output of pyruvate, whereas lactate uptake remains unchanged. Similar changes, though not identical, occur in starved lactating rats, which suggests that the increased acetoacetate concentration in this situation may be one of the factors responsible for the alterations in glucose metabolism.
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Project description:BackgroundMicroRNAs (miRNAs) have been implicated in the regulation of milk protein synthesis and development of the mammary gland (MG). However, the specific functions of miRNAs in these regulations are not clear. Therefore, the elucidation of miRNA expression profiles in the MG is an important step towards understanding the mechanisms of lactogenesis.ResultsTwo miRNA libraries were constructed from MG tissues taken from a lactating and a non-lactating Holstein dairy cow, respectively, and the short RNA sequences (18-30 nt) in these libraries were sequenced by Solexa sequencing method. The libraries included 885 pre-miRNAs encoding for 921 miRNAs, of which 884 miRNAs were unique sequences and 544 (61.5%) were expressed in both periods. A custom-designed microarray assay was then performed to compare miRNA expression patterns in the MG of lactating and non-lactating dairy cows. A total of 56 miRNAs in the lactating MG showed significant differences in expression compared to non-lactating MG (P<0.05). Integrative miRNA target prediction and network analysis approaches were employed to construct an interaction network of lactation-related miRNAs and their putative targets. Using a cell-based model, six miRNAs (miR-125b, miR-141, miR-181a, miR-199b, miR-484 and miR-500) were studied to reveal their possible biological significance.ConclusionOur study provides a broad view of the bovine MG miRNA expression profile characteristics. Eight hundred and eighty-four miRNAs were identified in bovine MG. Differences in types and expression levels of miRNAs were observed between lactating and non-lactating bovine MG. Systematic predictions aided in the identification of lactation-related miRNAs, providing insight into the types of miRNAs and their possible mechanisms in regulating lactation.
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Project description:Feeding lactating rats on high-fat cheese crackers in addition to laboratory chow increased the dietary intake of fat from 2 to 20% of the total weight of food eaten and decreased mammary-gland lipogenesis in vivo by approx. 50%. This lipogenic inhibition was also observed in isolated mammary acini, where it was accompanied by decreased glucose uptake. These inhibitions were completely reversed by incubation with insulin. Insulin had no effect on the rate of glucose transport into acini, nor on pyruvate dehydrogenase activity as estimated by the accumulation of pyruvate and lactate, suggesting that these are not the sites of lipogenic inhibition. Insulin stimulated the incorporation of [1-14C]acetate into lipid in acini from high-fat-fed rats. In the presence of alpha-cyanohydroxycinnamate, a potent inhibitor of mitochondrial pyruvate transport, and with glucose as the sole substrate, neither [1-14C]glucose incorporation into lipid nor glucose uptake were stimulated by insulin. Insulin did stimulate the incorporation of [1-14C]acetate into lipid in the presence of alpha-cyanohydroxycinnamate, and this was accompanied by an increase in glucose uptake by the acini. This indicated that increased glucose uptake was secondary to the stimulation of lipogenesis by insulin, which therefore must occur via activation of a step in the pathway distal to mitochondrial pyruvate transport. Insulin stimulated acetyl-CoA carboxylase activity measured in crude extracts of acini from high-fat-fed rats, restoring it to values close to those of chow-fed controls. The effects of insulin on acetyl-CoA carboxylase activity and lipogenesis were not antagonized by adrenaline or dibutyryl cyclic AMP.
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