Nanoparticulate tablet dosage form of lisofylline-linoleic acid conjugate for type 1 diabetes: in situ single-pass intestinal perfusion (SPIP) studies and pharmacokinetics in rat.

Lisofylline (LSF) is an anti-inflammatory molecule with high aqueous solubility and rapid metabolic interconversion to its parent drug, pentoxifylline (PTX) resulting in very poor pharmacokinetic (PK) parameters, necessitating high dose and dosing frequency. In the present study, we resolved the physicochemical and pharmacokinetic limitations associated with LSF and designed its oral dosage form as a tablet for effective treatment in type 1 diabetes (T1D). Self-assembling polymeric micelles of LSF (lisofylline-linoleic acid polymeric micelles (LSF-LA PLM)) were optimized for scale-up (6 g batch size) and lyophilized followed by compression into tablets. Powder blend and tablets were evaluated as per USP. LSF-LA PLM tablet so formed was evaluated for in vitro release in simulated biological fluids (with enzymes) and for cell viability in MIN-6 cells. LSF-LA PLM in tablet formulation was further evaluated for intestinal permeability (in situ) along with LSF and LSF-LA self-assembled micelles (SM) as controls in a rat model using single-pass intestinal perfusion (SPIP) study. SPIP studies revealed 1.8-fold higher oral absorption of LSF-LA from LSF-LA PLM as compared to LSF-LA SM and ~5.9-fold higher than LSF (alone) solution. Pharmacokinetic studies of LSF-LA PLM tablet showed greater Cmax than LSF, LSF-LA, and LSF-LA PLM. Designed facile LSF-LA PLM tablet dosage form has potential for an immediate decrease in the postprandial glucose levels in patients of T1D.

The FADS1 Genotype Modifies Metabolic Responses to the Linoleic Acid and Alpha-linolenic Acid Containing Plant Oils-Genotype Based Randomized Trial FADSDIET2.

SCOPE: The article investigates the FADS1 rs174550 genotype interaction with dietary intakes of high linoleic acid (LA) and high alpha-linolenic acid (ALA) on the response of fatty acid composition of plasma phospholipids (PLs), and of markers of low-grade inflammation and glucose-insulin homeostasis. METHODS AND RESULTS: One-hundred thirty homozygotes men for FADS1 rs174550 SNP (TT and CC genotypes) were randomized to an 8-week intervention with either LA- or ALA-enriched diet (13 E% PUFA). The source of LA and ALA are 30-50 mL of sunflower oil (SFO, 62-63% LA) and Camelina sativa oil (CSO, 30- are randomized to an 35% ALA), respectively. In the SFO arm, there is a significant genotype x diet interaction for the proportion of arachidonic acid in plasma phospholipids (p < 0.001), disposition index (DI30 ) (p = 0.039), and for serum high-sensitive c-reactive protein (hs-CRP, p = 0.029) after excluding the participants with hs-CRP concentration of >10 mg L-1 and users of statins or anti-inflammatory therapy. In the CSO arm, there are significant genotype x diet interactions for n-3 polyunsaturated fatty acids, but not for the clinical characteristics. CONCLUSIONS: The FADS1 genotype modifies the response to high PUFA diets, especially to high-LA diet. These findings suggest that approaches considering FADS variation may be useful in personalized dietary counseling.

Therapeutic efficacy of lipid emulsions of docetaxel-linoleic acid conjugate in breast cancer.

Docetaxel (DTX) solution is among the most widely-used parenteral formulations used in advanced breast cancer therapy. However, severe side effects have been observed due to the use of ethanol and polysorbate 80. Herein, a novel DTX-based prodrug, docetaxel-linoleic acid conjugate (DTX-LA) was successfully synthesized. The high lipid solubility of DTX and DTX-LA resulted in a tendency for them to become entrapped in the oil core of the emulsions. As anticipated, nano-sized, sterically stabilized oil-in-water lipid emulsions (LMs) of DTX-LA LMs and DTX LMs were successfully constructed. Unlike DTX solution, LMs exhibited high colloidal stability and sustained-release behavior, having a narrow size distribution that was ∼220 nm in diameter. Compared with DTX LMs, DTX-LA LMs had a greater drug-loading capacity. Although the cytotoxicity of DTX-LA LMs was reduced in comparison with DTX solution, the pharmacokinetic study demonstrated increased bioavailability (p < 0.001) and half-life (p < 0.01). Finally, DTX-LA LMs displayed significant antitumor efficacy with reduced side effects in a 4T1 breast cancer xenograft model. Thus, the novel lipid emulsion-based docetaxel prodrug delivery system may be a promising strategy for improving intravenous administration for breast cancer treatment.

Anti-inflammatory effects of α-linolenic acid in M1-like macrophages are associated with enhanced production of oxylipins from α-linolenic and linoleic acid.

Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA α-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion. We find that ALA treatment leads to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α production. Although ALA is known to be converted to longer-chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins. In contrast, we observed profound increases in oxylipins directly derived from ALA. Lipoxygenase products of linoleic acid were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. These results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those used by the long-chain omega-3 fatty acids EPA and DHA. Thus, there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents.

Fatty acid vesicles acting as expanding horizon for transdermal delivery.

The body is protected against the external environment by the skin due to its physical barrier nature. Stratum corneum composed of corneocytes surrounded by lipid region performs a major barrier function as it lies in the uppermost area of skin. Alteration in barrier function, increase in permeability, and disorganization of stratum corneum represent diseased skin. Drugs applied to the diseased skin should induce a local effect at the site of application or area close to it along with cutaneous absorption rather than percutaneous absorption. Conventional formulations like ointments, gels, and creams suffer from the drawback of limited local activity. For the enhancement of drug penetration and localization of the drug at the site of action approaches explored are liposomes, niosomes, ethosomes microparticles, and solid lipid nanoparticles. Vesicles composed of fatty acids like oleic acid and linoleic acid represent the new approach used for transdermal penetration and localization. In this review article, our major aim was to explore the applications of fatty acid vesicles for transdermal delivery of various bioactives.

Fate of orally administered radioactive fatty acids in the late-pregnant rat.

To investigate the biodisponibility of placental transfer of fatty acids, rats pregnant for 20 days were given tracer amounts of [(14)C]palmitic (PA), oleic (OA), linoleic (LA), α-linolenic (LNA), or docosahexaenoic acid (DHA) orally and euthanized at 0.5, 1.0, 2.0, or 8.0 h thereafter. Maternal plasma radioactivity in lipids initially increased only to decline at later times. Most of the label appeared first as triacylglycerols (TAG); later, the proportion in phospholipids (PhL) increased. The percentage of label in placental lipids was also always highest shortly after administration and declined later; again, PhL increased with time. Fetal plasma radioactivity increased with time, with its highest value at 8.0 h after DHA or LNA administration. DHA initially appeared primarily in the nonesterified fatty acids (NEFA) and PA, OA, LA, and LNA as TAG followed by NEFA; in all cases, there was an increase in PhL at later times. Measurement of fatty acid concentrations allowed calculation of specific (radio)activities, and the ratio (fetal/maternal) of these in the plasmas gave an index of placental transfer activity, which was LNA > LA > DHA = OA > PA. It is proposed that a considerable proportion of most fatty acids transferred through the placenta are released into the fetal circulation in the form of TAG.

Australia's nutrition transition 1961-2009: a focus on fats.

Since the 1960s, Australian diets have changed considerably, influenced by a burgeoning multicultural cuisine, increase in urbanisation and food technology advances. This has been described as a 'nutrition transition', resulting in the adoption of a Western diet pattern, with a shift away from unrefined foods towards a diet higher in both plant-derived high PUFA and total fats and refined carbohydrates. Utilising the 1961-2009 annual food supply data from the UN FAO, the present study investigated changes in the intake of macronutrient and specific fatty acid in the Australian population, including that of the PUFA linoleic acid (LA), due to its hypothesised role in inflammation and risk for obesity. Cumulative change over time for the contribution of specific nutrients to total available energy (TAE) was calculated, as was linearity of change. Over the time period analysed, the cumulative change in TAE from carbohydrate was -9.35 and +16.67 % from lipid. The cumulative change in TAE from LA was +120.48 %. Moreover, the cumulative change in the contribution of LA to total PUFA availability was +7.1 %. Utilising the average g/d per capita of LA from selected dietary sources, the change in the contribution of specific foodstuffs was assessed, with total plant oils having a cumulative change of +627.19 % to LA availability, equating to a cumulative change of +195.61 % in contribution to total LA availability. The results of the present study indicate that LA availability in Australia has increased over the previous five decades as a result of the availability of increased plant oils, as has total fat, possibly contributing to the increasing rates of obesity and obesity-associated co-morbidities.

Nutrient-specific feeding and endocrine effects of jejunal infusions in obese animals.

Intestinal nutrient infusions result in variable decreases in food intake and body weight based on the nutrient type and the specific intestinal infusion site. We previously found that intrajejunal infusions of a fatty acid and glucose, but not casein hydrolysate, decreases food intake and body weight in lean chow-fed laboratory rats. To test whether obese, high fat-fed animals would show similar decreases in food intake and body weight in response to intrajejunal infusions of the same nutrients, equal kilocalorie loads of these nutrients (11.4 kcal) or vehicle were infused into the jejunum of obese, high fat-fed male Sprague-Dawley rats over 7 h/day for 5 consecutive days. Food intake was continuously monitored, and body weight was measured daily. After the infusion on the final day, rats were killed and plasma was collected. Similar to lean chow-fed rats, intrajejunal infusions of linoleic acid (LA) and glucose (Glu), but not casein hydrolysate (Cas), suppressed food intake with no compensatory increase in food intake after the infusion period. In contrast to lean chow-fed rats, only the LA, and not the Glu or Cas, produced decreases in body weight in the obese high fat-fed rat. There also were no differences in plasma glucagon-like peptide-1 levels in any of the nutrient infusion groups compared with saline infusion. These results suggest that there is a differential response to the same nutrients in lean vs. obese animals.

Cell penetrating peptide conjugated polymeric micelles as a high performance versatile nonviral gene carrier.

The major goal of this study is to design, synthesize, and evaluate linoleic acid and penetratin dual-functionalized chitosan (CS-Lin-Pen) as a nonviral gene carrier. The amphiphilic CS-Lin-Pen self-assembles to form cationic micelles in an aqueous environment. These polymeric micelles exhibited excellent hemocompatibility and cell viability, as evaluated by in vitro hemolysis and MTT assay, respectively. When CS-Lin-Pen micelles were added to plasmid DNA (pDNA) solution, the electrostatic interaction between the cationic micelles and anionic pDNA led to the formation of stable CS-Lin-Pen/pDNA polyplexes with ~100 nm in size. The resultant polyplexes demonstrated ~5-fold higher cellular uptake as compared to unmodified chitosan. Furthermore, CS-Lin-Pen micelles showed efficient protection of pDNA from DNase I attack and exhibited ~34-40-fold higher transfection in comparison with unmodified chitosan in HEK 293, CHO, and HeLa cells. These findings illustrate that the CS-Lin-Pen micelles could be exploited as a potential nonviral vector for efficient gene therapy.

ß-Lactoglobulin-linoleate complexes: In vitro digestion and the role of protein in fatty acid uptake.

The dairy protein ß-lactoglobulin (BLG) is known to bind fatty acids such as the salt of the essential longchain fatty acid linoleic acid (cis,cis-9,12-octadecadienoic acid, n-6, 18:2). The aim of the current study was to investigate how bovine BLG-linoleate complexes, of various stoichiometry, affect the enzymatic digestion of BLG and the intracellular transport of linoleate into enterocyte-like monolayers. Duodenal and gastric digestions of the complexes indicated that BLG was hydrolyzed more rapidly when complexed with linoleate. Digested as well as undigested BLG-linoleate complexes reduced intracellular linoleate transport as compared with free linoleate. To investigate whether enteroendocrine cells perceive linoleate differently when part of a complex, the ability of linoleate to increase production or secretion of the enteroendocrine satiety hormone, cholecystokinin, was measured. Cholecystokinin mRNA levels were different when linoleate was presented to the cells alone or as part of a protein complex. In conclusion, understanding interactions between linoleate and BLG could help to formulate foods with targeted fatty acid bioaccessibility and, therefore, aid in the development of food matrices with optimal bioactive efficacy.

Conjugated linoleic acid isomers and their precursor fatty acids regulate peroxisome proliferator-activated receptor subtypes and major peroxisome proliferator responsive element-bearing target genes in HepG2 cell model.

The purpose of this study was to examine the induction profiles (as judged by quantitative reverse transcription polymerase chain reaction (qRT-PCR)) of peroxisome proliferator-activated receptor (PPAR) α, ß, γ subtypes and major PPAR-target genes bearing a functional peroxisome proliferator responsive element (PPRE) in HepG2 cell model upon feeding with cis-9,trans-11-octadecadienoic acid (9-CLA) or trans-10,cis-12-octadecadienoic acid (10-CLA) or their precursor fatty acids (FAs). HepG2 cells were treated with 100 µmol/L 9-CLA or 10-CLA or their precursor FAs, viz., oleic, linoleic, and trans-11-vaccenic acids against bezafibrate control to evaluate the induction/expression profiles of PPAR α, ß, γ subtypes and major PPAR-target genes bearing a functional PPRE, i.e., fatty acid transporter (FAT), glucose transporter-2 (GLUT-2), liver-type FA binding protein (L-FABP), acyl CoA oxidase-1 (ACOX-1), and peroxisomal bifunctional enzyme (PBE) with reference to ß-actin as house keeping gene. Of the three housekeeping genes (glyceraldehyde 3-phosphate dehydrogenase (GAPDH), ß-actin, and ubiquitin), ß-actin was found to be stable. Dimethyl sulfoxide (DMSO), the common solubilizer of agonists, showed a significantly higher induction of genes analyzed. qRT-PCR profiles of CLAs and their precursor FAs clearly showed upregulation of FAT, GLUT-2, and L-FABP (~0.5-2.0-fold). Compared to 10-CLA, 9-CLA decreased the induction of the FA metabolizing gene ACOX-1 less than did PBE, while 10-CLA decreased the induction of PBE less than did ACOX-1. Both CLAs and precursor FAs upregulated PPRE-bearing genes, but with comparatively less or marginal activation of PPAR subtypes. This indicates that the binding of CLAs and their precursor FAs to PPAR subtypes results in PPAR activation, thereby induction of the target transporter genes coupled with downstream lipid metabolising genes such as ACOX-1 and PBE. To sum up, the expression profiles of these candidate genes showed that CLAs and their precursor FAs are involved in lipid signalling by modulating the PPAR α, ß, or γ subtype for the indirect activation of the PPAR-target genes, which may in turn be responsible for the supposed health effects of CLA, and that care should be taken while calculating the actual fold induction values of candidate genes with reference to housekeeping gene and DMSO as they may impart false positive results.

Reduced absorption of long-chain fatty acids during methotrexate-induced gastrointestinal mucositis in the rat.

BACKGROUND & AIMS: Patients with chemotherapy-induced gastrointestinal mucositis suffer from weight loss and possibly malabsorption. Since long-chain fatty acids serve important functions in the body, we aimed to determine the intestinal capacity of fat absorption in rats with and without methotrexate-induced mucositis. METHODS: Four days after intravenous injection with methotrexate (60 mg/kg) or saline, rats received saturated ([U-(13)C]palmitic acid) and unsaturated ([U-(13)C]linoleic acid) fatty acids dissolved in oil, either as a single bolus by oral gavage or by continuous intraduodenal infusion. We determined plasma and liver label concentrations at specific time points. RESULTS: We confirmed methotrexate-induced mucositis by villus atrophy using microscopy. Methotrexate treatment severely reduced the appearance of [U-(13)C]palmitic- and [U-(13)C]linoleic acid in plasma and liver, compared to controls, either when administered as a bolus or continuously (all at least -63%, P < 0.05). Liver [U-(13)C]palmitic acid appearance was higher than [U-(13)C]linoleic acid appearance, either when administered as a bolus (2.8-fold, P < 0.01) or continuously (5.7-fold, P < 0.01). CONCLUSIONS: The intestinal capacity to absorb long-chain fatty acids is severely reduced in rats with methotrexate-induced mucositis. Continuous administration does not overcome this impairment. The liver takes up and/or retains mainly saturated fatty acids during mucositis.

Species differences in toxicokinetic parameters of glycidol after a single dose of glycidol or glycidol linoleate in rats and monkeys.

Glycidol fatty acid esters (GEs) have been identified as contaminants in refined edible oils. Although the possible release of glycidol (G) from GEs is a concern, little is known about the conversion of GEs to G in the human body. This study addressed the toxicokinetics of glycidol linoleate (GL) and G in male Crl:CD(SD) rats and cynomolgus monkeys. Equimolar amounts of GL (341 mg/kg) or G (75 mg/kg) were administered by gavage to each animal. G was found in both species after the G and GL administration, while plasma GL concentrations were below the lower limit of quantification (5 ng/ml) in both species. In rats, the administration of GL or G produced similar concentration-time profiles for G. In monkeys, the C(max) and AUC values after GL administration were significantly lower than those after G administration. The oral bioavailability of G in monkeys (34.3%) was remarkably lower than that in rats (68.8%) at 75 mg/kg G administration. In addition, plasma G concentrations after oral administration at three lower doses of GL or G were measured in both species. In monkeys, G was detected only at the highest dose of G. In contrast, the rats exhibited similar plasma G concentration-time profiles after GL or G administration with significantly higher G levels than those in monkeys. In conclusion, these results indicate that there are remarkable species differences in the toxicokinetics of GEs and G between rodents and primates, findings that should be considered when assessing the human risk of GEs.

Enhanced anticancer activity of gemcitabine coupling with conjugated linoleic acid against human breast cancer in vitro and in vivo.

Gemcitabine (GEM) is a nucleoside analog agent against a wide variety of tumors. To overcome its limitation of rapid metabolism in vivo that results in short circulation time and poor antitumor efficacy, a novel prodrug (CLA-GEM conjugate) has been developed through the covalent coupling of conjugated linoleic acid (CLA) to N(4)-amino group of GEM. The chemical structure of CLA-GEM conjugate was identified by NMR, FTIR and other methods. From in vitro tests, it was demonstrated that the linkage with CLA increased the plasma stability of GEM as well as the antitumor activity against human breast tumor cells (MCF-7). Importantly, it also altered the transport pattern of GEM across cell membrane (MCF-7 and MDA-MB-231), evidenced by the little effect of nucleoside transporter inhibitors (NBMPR and dipyridamole) on the IC(50) values of CLA-GEM, instead of the great effect on that of unmodified GEM. In vivo pharmacokinetic study showed that the CLA-GEM conjugate had a longer plasma half-life and a higher bioavailability compared to that of unmodified GEM. Significant stronger antitumor activity was observed in the nude mice xenografted MCF-7 breast tumor after treated with CLA-GEM than that of unmodified GEM, while no significant body weight loss was found in all treatments. In conclusion, the novel CLA-GEM conjugate prepared in this study would be a promising prodrug of gemcitabine for future clinical use.

Healing fats of the skin: the structural and immunologic roles of the omega-6 and omega-3 fatty acids.

Linoleic acid (18:2omega6) and alpha-linolenic acid (18:3omega3) represent the parent fats of the two main classes of polyunsaturated fatty acids: the omega-6 (n-6) and the omega-3 (n-3) fatty acids, respectively. Linoleic acid and alpha-linolenic acid both give rise to other long-chain fatty acid derivatives, including gamma-linolenic acid and arachidonic acid (omega-6 fatty acids) and docosahexaenoic acid and eicosapentaenoic acid (omega-3 fatty acids). These fatty acids are showing promise as safe adjunctive treatments for many skin disorders, including atopic dermatitis, psoriasis, acne vulgaris, systemic lupus erythematosus, nonmelanoma skin cancer, and melanoma. Their roles are diverse and include maintenance of the stratum corneum permeability barrier, maturation and differentiation of the stratum corneum, formation and secretion of lamellar bodies, inhibition of proinflammatory eicosanoids, elevation of the sunburn threshold, inhibition of proinflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, and interleukin-12), inhibition of lipoxygenase, promotion of wound healing, and promotion of apoptosis in malignant cells, including melanoma. They fulfill these functions independently and through the modulation of peroxisome proliferator-activated receptors and Toll-like receptors.

Dermal targeting using colloidal carrier systems with linoleic acid.

In the basic therapy of chronic skin diseases characterized by xerosis, the local treatment is an essential strategy to reach ideal therapeutic effects. Suitable active ingredients for this aim are fatty acids, in particular linoleic acid, which is an essential component for the organization and perpetuation of the skin barrier. In the present work, the development of a well-tolerated colloidal carrier system (microemulsion) containing linoleic acid as active ingredient is described. A comprehensive physiochemical characterization of the novel microemulsion system was performed using different techniques. The potential of the developed microemulsion system compared to a cream as suitable carrier for the dermal delivery of linoleic acid was determined. Penetration studies showed higher linoleic acids concentrations after administration of the colloidal carrier system in all skin layers independent of the time of incubation. Up to 23% of applied dose reached the skin from the colloidal carrier system whereas at most 8% of the active ingredient could be detected after applying the cream. Particularly, the percentage of the linoleic acids penetrated through the microemulsion in the stratum corneum and the viable epidermis differed significantly (p<0.01) when compared to that through a standard cream. Furthermore, linoleic acids accumulated in the epidermis at longer incubation times. Using the microemulsion, the penetration of linoleic acids was enhanced significantly (p<0.01). Hence, the microemulsion might be an innovative vehicle for the delivery of linoleic acids to the epidermis improving its use as their barrier regeneration and providing possible anti-inflammatory effects.

Whole body distribution of deuterated linoleic and alpha-linolenic acids and their metabolites in the rat.

Little is known about the uptake or metabolism of essential fatty acids (EFAs) in various mammalian organs. Thus, the distribution of deuterated alpha-linolenic acid (18:3n-3) and linoleic acid (18:2n-6) and their metabolites was studied using a stable isotope tracer technique. Rats were orally administered a single dose of a mixture (20 mg each) of ethyl D5-18:3n-3 and D5-18:2n-6, and 25 tissues per animal were analyzed for D5-labeled PUFAs at 4, 8, 24, 96, 168, 240, 360, and 600 h after dosing. Plasma, stomach, and spleen contained the highest concentrations of labeled precursors at the earliest time points, whereas other internal organs and red blood cells reached their maximal concentrations at 8 h. The time-course data were consistent with liver metabolism of EFAs, but local metabolism in other tissues could not be ruled out. Brain, spinal cord, heart, testis, and eye accumulated docosahexaenoic acid with time, whereas skin accumulated mainly 20:4n-6. On average, approximately 16-18% of the D5-18:3n-3 and D5-18:2n-6 initial dosage was eventually accumulated in tissues, principally in adipose, skin, and muscle. Approximately 6.0% of D5-18:3n-3 and 2.6% of D5-18:2n-6 were elongated/desaturated and stored, mainly in muscle, adipose, and the carcass. The remaining 78% of both precursors was apparently catabolized or excreted.

[Is brown adipose tissue a store of long chain polyunsaturated fatty acids during postnatal developing brain?]. / Funciona el tejido adiposo marrón como un depósito de acidos grasos poliinsaturados de cadena larga durante el desarrollo postnatal del cerebro?

Mammals along their early postnatal period develop a substantial amount of a very active brown adipose tissue (BAT). Through this work we explored the possibility that BAT may function as a long chain polyunsaturated fatty acids reservoir (LC-PUFA) during the rapid growth of brain structures. In new born rats 1, 6, 12 and 20 days old, we analyzed fatty acid percentage of triglycerides (TG) and phospholipid fractions, and the absolute amount of TG. In 6 day old rats we also evaluated the extend of further desaturation of 1-14C linoleic acid administered by intraperitoneal injection. Results demonstrated a drastic increase of TG concentration during experimental period (1,5; 40; 118; 120 mg/g wet weight) and LC-PUFA percentage was higher in "1 and 6" than "12 and 20" days old rats (16-17% vs 5%). Our results showed that BAT stored important amounts of LC-PUFA. On the other hand, 1-14C linoleic acid incorporation was higher in liver than BAT. In contrast, the desaturated products of 1-14C linoleic acid /1-14C linoleic acid ratio was greater in BAT than liver (>4). This could indicate that BAT synthesizes LC-PUFA in addition to store it. In summary we demonstrated than BAT is an important reservoir of LC-PUFA during postnatal brain growth.

Funciona el tejido adiposo marrón como un depósito de acidos grasos poliinsaturados de cadena larga durante el desarrollo postnatal del cerebro? / [Is brown adipose tissue a store of long chain polyunsaturated fatty acids during postnatal developing brain?]

Mammals along their early postnatal period develop a substantial amount of a very active brown adipose tissue (BAT). Through this work we explored the possibility that BAT may function as a long chain polyunsaturated fatty acids reservoir (LC-PUFA) during the rapid growth of brain structures. In new born rats 1, 6, 12 and 20 days old, we analyzed fatty acid percentage of triglycerides (TG) and phospholipid fractions, and the absolute amount of TG. In 6 day old rats we also evaluated the extend of further desaturation of 1-14C linoleic acid administered by intraperitoneal injection. Results demonstrated a drastic increase of TG concentration during experimental period (1,5; 40; 118; 120 mg/g wet weight) and LC-PUFA percentage was higher in [quot ]1 and 6[quot ] than [quot ]12 and 20[quot ] days old rats (16-17% vs 5%). Our results showed that BAT stored important amounts of LC-PUFA. On the other hand, 1-14C linoleic acid incorporation was higher in liver than BAT. In contrast, the desaturated products of 1-14C linoleic acid /1-14C linoleic acid ratio was greater in BAT than liver (>4). This could indicate that BAT synthesizes LC-PUFA in addition to store it. In summary we demonstrated than BAT is an important reservoir of LC-PUFA during postnatal brain growth.

Los mamíferos como el hombre y la rata, poseen durante su desarrollo postnatal temprano un tejido adiposo marrón (TAM) muy activo. En este trabajo se exploró la posibilidad de que el TAM funcione como un depósito de ácidos grasos poliinsaturados de cadena larga (AGPI-CL), durante el período de máximo crecimiento postnatal del cerebro de rata. En el TAM de ratas de 1, 6, 12 y 20 días de edad analizamos la concentración de triglicéridos (TG) y la composición de ácidos grasos en los TG y fosfolípidos (FL). Además, en ratas de 6 días de edad evaluamos la capacidad del TAM para desaturar 1- 14C ácido linoleico administrado por vía intraperitoneal. Los resultados mostraron un rápido incremento en la concentración de TG durante el período experimental (1,5; 40; 118; 120 mg /g de peso húmedo). El porcentaje de AGPI-CL fue mayor en las ratas de 1 y 6 días de edad que en las de 12 y 20 días (16-17% vs 5%). Por otra parte, la incorporación de 1-14C ácido linoleico fue más alta en el hígado que en el TAM, aunque la relación "productos desaturados de 1-14C ácido linoleico / 1-14C ácido linoleico" fue mayor en el TAM que en el hígado (>4), lo cual podría indicar que este tejido además de almacenar AGPI-CL los sintetiza. En resumen, nuestros resultados demuestran que el TAM es depósito importante de AGPICL durante el período de máximo desarrollo postnatal del cerebro.