Fatty Acids In Rats Research Articles

Whole-body synthesis-secretion rates of long-chain n-3 PUFAs from circulating unesterified α-linolenic acid in unanesthetized rats

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), long-chain n-3 PUFAs important for brain and heart function, can be obtained from dietary fish products or by liver synthesis from alpha-linolenic acid (alpha-LNA). Their daily human dietary requirements are not clear, and their liver synthesis rates in humans and nonhumans are unknown. We estimated whole-body (presumably liver) synthesis rates in unanesthetized rats by infusing [U-(13)C]alpha-LNA intravenously for 2 h and measuring labeled and unlabeled n-3 PUFA in arterial plasma using negative chemical ionization GC-MS. Newly synthesized esterified [(13)C]DHA, [(13)C]EPA, and [(13)C]docosapentaenoic acid (DPA) appeared in arterial plasma after 60 min of infusion, then their concentrations rose in an S-shaped manner. Esterified concentration x plasma volume data were fit with a sigmoidal equation, whose peak first derivatives provided synthesis rates of unlabeled EPA, DPA, and DHA equal to 8.40, 6.27, and 9.84 mumol/day, respectively. The DHA synthesis rate exceeded the published daily rat brain DHA consumption rate by 30-fold, suggesting that liver synthesis from alpha-LNA could maintain brain DHA homeostasis were DHA absent from the diet. This stable isotope infusion method could be used to quantify whole-body DHA synthesis rates in human subjects.

Interactions of ethanol drinking withn-3 fatty acids in rats: potential consequences for the cardiovascular system

Moderate ethanol drinking (ED) and n-3 fatty acids have both been associated with low cardiac mortality. However, there are few data evaluating the interactions of ED with n-3. We recently reported that moderate ED results in increased n-3 in cardiac patients. The main aim of the present study was, through a well-controlled experimental model, to confirm that chronic ED actually results in increased n-3. Secondary aims were to examine the effects of chronic ED on cardiac mitochondria, cardiac function and experimental myocardial infarction. We studied the fatty acid profiles of plasma, cell membranes and cardiac mitochondria phospholipids in a rat model of chronic ED. In plasma and cell membranes, ED actually resulted in higher n-3 (P = 0.005). In mitochondria phospholipids of ED rats, n-3 were also increased (P < 0.05) but quite modestly. Cardiac mitochondrial function and left ventricular function were not significantly different in ED and control rats, while infarct size after 30 min ischaemia and reperfusion was smaller (P < 0.0001) in ED rats. This is the first animal study confirming interaction of alcohol drinking with n-3. We found no harmful effect of chronic ED on the heart in that model but a significant cardioprotection. Further studies are warranted to investigate the mechanisms by which moderate ED alters the metabolism of n-3 and whether n-3 are the mediators of the ED-induced cardioprotection.

N-3 fatty acids (eicosapentanoic and docosahexanoic acids) in epilepsy and for the prevention of sudden unexpected death in epilepsy

As described in this journal, Bromfield et al. and Yuen et al. tested the hypothesis that n-3 fatty acids may reduce seizures [ 1 Bromfield E. Dworetzsky B. Huwitz S. et al. A randomized trial of polyunsaturated fatty acids for refractory epilepsy. Epilepsy Behav. 2008; 12: 187-190 Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar , 2 Yuen A.W. Sander J.W. Fluegel D. et al. Omega-3 fatty acid supplementation in patients with chronic epilepsy: a randomized trial. Epilepsy Behav. 2005; 7: 253-258 Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar ]. This is important work, founded in sound science. It is known that eicosapentanoic acid reduces the frequency of hippocampal pyramidal neuron firing rates [ [3] Xiao Y. Li X. Polyunsaturated fatty acids modify mouse hippocampal neuronal excitability during excitotoxic or convulsant stimulation. Brain Res. 1999; 846: 112-121 Crossref PubMed Scopus (114) Google Scholar ]. Furthermore, n-3 fatty acids reduce the number and increase the latency of pentylenetetrazole- and FeCl3-induced seizures, reduce seizure severity in rodents, and improve cognitive recovery after acute seizures [ 4 Yehuda S. Carasso R. Mostofsky D. Essential fatty acid preparation (SR-3) raises the seizure threshold in rats. Eur J Pharmacol. 1994; 254: 193-198 Crossref PubMed Scopus (121) Google Scholar , 5 Voskuyl R. Vregdenhil M. Kang J. et al. Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol. 1998; 341: 145-152 Crossref PubMed Scopus (121) Google Scholar , 6 Rabinovitz S. Mostofsky D. Yehuda S. Anticonvulsant efficiency, behavioral performance, and cortisol levels: a comparison of carbamazepine (CBZ) and a fatty acid compound (SR-3). Psychoneuroendocrinology. 2004; 29: 113-124 Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar ]. Moreover, in an important discovery recently reported in this journal, Ferrari et al. found that n-3 fatty acids prevent or reduce hippocampal neuronal injury after status epilepticus [ [7] Ferrari D. Cysneiros R.M. Scorza C. et al. Neuroprotective activity of omega-3 fatty acids against epilepsy-induced hippocampal damage: quantification with immunohistochemical for calcium-binding proteins. Epilepsy Behav. 2008; 13: 36-42 Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar ].

Effect of acute lindane and alcohol intoxication on serum concentration of enzymes and fatty acids in rats

This study examines possible synergistic effects of lindane and ethanol on inducing liver injury and serum fatty acid derangement in adult male Wistar rats. When administered together, ethanol and lindane-induced even more pronounced increase of alanine aminotransferase (165±10U/L) and gamma-glutamyltranspeptidase activity (10.3±0.6U/L) than after isolated administration of either substance. In addition, separate administration of lindane and ethanol was followed by a significant decrease of linoleic acid level in the serum (301±38mg/L, 276±35mg/L vs. 416±48mg/L). However, when ethanol administration was followed by lindane injection, serum linoleic acid was at the similar level found in the control group (516±62mg/L). Ethanol-treated rats that received lindane 30min after ethanol administration have shown a marked increase of palmitic (421±27mg/L) and linolic acid level (43±5mg/L) in comparison with rats that have been treated only with ethanol (316±26mg/L for palmitic and 32±2mg/L for linolic acid) or lindane (295±26mg/L for palmitic and 301±38mg/L for linolic acid). Linolic acid level was significantly greater in comparison with control group (29±1mg/L). In conclusion, this study found enough evidence to support the hypothesis that acute ethanol intoxication potentiates lindane-induced liver injury and enhances lipid derangement.

The vagal afferent pathway does not play a major role in the induction of satiety by intestinal fatty acid in rats

Intestinal infusion of long-chain fatty acids (LCFAs) strongly suppresses food intake and gut motility. Vagal afferents and cholecystokinin (CCK) signaling pathway are considered to play important roles in intestinal LCFA-induced satiety. Here, we first investigated the influence of vagus nerve on satiety following intestinal LCFA infusion in rats. Jejunal infusion of linoleic acid (LA) at 200 microL/h for 7 h suppressed food intake and the effect lasted for 24 h. The satiety induced by jejunal LA infusion occurred in a dose dependent manner. In contrast, the anorectic effect induced by octanoic acid, a medium-chain fatty acid, was weaker than that induced by LA. The reduction in food intake induced by jejunal LA infusion was not attenuated in rats treated with vagotomy, the ablation of bilateral subdiaphragmatic vagal trunks. Jejunal LA-induced satiety could also be observed in rats with bilateral midbrain transections, which ablates fibers between the hindbrain and hypothalamus. These findings suggest that the vagus nerve and fibers ascending from the hindbrain to the hypothalamus do not play a major role in intestinal LCFA-induced satiety. Jejunal LA infusion also reduced food intake in CCK-A receptor-deficient OLETF rats, suggesting that CCK signaling pathway is not critical for intestinal LCFA-induced anorexia. In conclusion, this study indicates that the vagus nerve and the CCK signaling pathway do not play major roles in conveying satiety signals induced by intestinal LCFA to the brain in rats.

Whole body distribution of deuterated linoleic and α-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.

Artificial rearing with docosahexaenoic acid and n-6 docosapentaenoic acid alters rat tissue fatty acid composition

Docosahexaenoic acid (DHA; 22:6n-3) and n-6 docosapentaenoic acid (DPAn-6; 22:5n-6) are components of enriched animal feed and oil derived from Schizochytrium species microalgae. A one generation, artificial rearing model from day 2 after birth onward (AR) and a dam-reared control group (DAM) were used to examine DPAn-6 feeding on the fatty acid composition of various rat tissues at 15 weeks of age. Four AR diets were based on an n-3 fatty acid-deficient, 18:2n-6-based artificial milk with 22:6n-3 and/or 22:5n-6 added: AR-LA, AR-DHA, AR-DPAn-6, and AR-DHA+DPAn-6. The 22:6n-3 levels for the DAM, AR-DHA, and AR-DHA+DPAn-6 groups tended to be similar and higher than in the AR-LA and AR-DPAn-6 groups. The levels of 22:5n-6 tended to be higher only in the absence of dietary 22:6n-3. Adipose levels of 22:5n-6 was the only exception, as 22:5n-6 was significantly higher in AR-DHA+DPAn-6 than was observed in either the DAM or the AR-DHA group. There were no differences in 20:4n-6 levels within the tissues examined. In conclusion, 22:5n-6 replaces 22:6n-3 in the absence of 22:6n-3 only and does not appear to compete with 22:6n-3 in the presence of dietary 22:6n-3, suggesting that oils containing 22:5n-6 and 22:6n-3 may be a good dietary source of 22:6n-3.

Effect of radical stress and ageing on the occurrence of trans fatty acids in rats fed a trans-free diet

In a previous paper, we demonstrated that tissue trans fatty acids can not only derive from the diet but also be endogenously formed. The central focus of this study was to prove that the in vivo isomerization occurs via a radical process. Two different models of radical insult were used: CCl 4 and AAPH injection to rats fed a diet completely free of trans isomers. Following this acute radical stress, a significant increase in unnatural trans fatty acid content of erythrocyte, kidney, and heart, but not liver, was observed. These results can be mainly explained by the high content, particularly in the liver, of antioxidant vitamins A and E that exhibit also an “anti-isomerizing” effect. Since during ageing cellular components are exposed to increasing radical insults, the observation of a significant trans fatty acid accumulation in 30-month-old rats could confirm that the in vivo formation of unnatural isomers is due to a radical process. Trans fatty acids can influence the physical characteristics of bilayer microdomains, affecting membrane properties and functions; thus, knowledge of biological radical species responsible for cis/ trans isomerization and their possible sources can provide protective systems for preserving lipid geometry.

Markedly raised intake of saturated and monounsaturated fatty acids in rats on a high‐fat ketogenic diet does not inhibit carbon recycling of13C‐α‐linolenate

Under various dietary and physiological conditions, carbon from alpha-linolenic acid (ALA) is extensively recycled into saturated and monounsaturated fatty acids. In this study we investigated whether carbon is still recycled from ALA when a dietary source of saturated and monounsaturated fatty acids is provided in excess. 13C-labeled ALA was given to rats consuming a high-fat ketogenic diet and to rats consuming a low-fat control diet. In rats on the ketogenic diet, 13C recycling from alpha-linolenate into several, but not all, saturated and monounsaturated fatty acids matched or exceeded that in the controls (P < 0.05). We conclude that carbon recycling into saturated and monounsaturated fatty acids persists when the main end products of ALA recycling are provided in excess, using a ketogenic diet.

Ethanol and cardiac function

regular heavy ethanol consumption has been associated with a type of nonischemic dilated cardiomyopathy termed “alcoholic cardiomyopathy” (ACM), which is clinically expressed as an impairment of left ventricular function (nonsymptomatic stage) and occasionally as overt heart failure (symptomatic

Occurrence of trans fatty acids in rats fed a trans-free diet: A free radical-mediated formation?

Trans isomers of unsaturated fatty acids are absorbed from the diet, due to their presence in diary fat and hydrogenated vegetable oils, and health concern has risen due to their effects on lipid risk factors in cardiovascular diseases. On the basis of the efficiency of the thiyl-radical-catalyzed cis/ trans isomerization in vitro and the presence of many sulfur-containing compounds in the cell, the aim of this study was to demonstrate that trans geometry of lipid double bonds can be endogenously generated within membrane phospholipids. The study reports trans fatty acids occurrence in tissue and erythrocyte phospholipids of young adult rats fed a diet completely free of trans isomers. Results show that tissues are differently prone to the endogenous isomerization and that, following a free radical attack, trans fatty acids can reach very high amounts. The effectiveness of this process is considerably inhibited in the presence of all- trans retinol, confirming previous data in model membranes. Our results suggest that geometrical isomerization of unsaturated fatty acids, which causes a structural modification of membrane lipids and may influence basic membrane properties and vital biochemical functions, can occur under radical stress conditions and could be efficiently prevented by vitamin A.

Keeping cool in acute liver failure: Rationale for the use of mild hypothermia

Encephalopathy, brain edema and intracranial hypertension are neurological complications responsible for substantial morbidity/mortality in patients with acute liver failure (ALF), where, aside from liver transplantation, there is currently a paucity of effective therapies. Mirroring its cerebro-protective effects in other clinical conditions, the induction of mild hypothermia may provide a potential therapeutic approach to the management of ALF. A solid mechanistic rationale for the use of mild hypothermia is provided by clinical and experimental studies showing its beneficial effects in relation to many of the key factors that determine the development of brain edema and intracranial hypertension in ALF, namely the delivery of ammonia to the brain, the disturbances of brain organic osmolytes and brain extracellular amino acids, cerebro-vascular haemodynamics, brain glucose metabolism, inflammation, subclinical seizure activity and alterations of gene expression. Initial uncontrolled clinical studies of mild hypothermia in patients with ALF suggest that it is an effective, feasible and safe approach. Randomized controlled clinical trials are now needed to adequately assess its efficacy, safety, clinical impact on global outcomes and to provide the guidelines for its use in ALF.

Simultaneous quantitative determination of deuterium- and carbon-13-labeled essential fatty acids in rat plasma

This study reports methods for the quantitative determination of stable isotope-labeled essential fatty acids (EFAs) as well as an experiment in which deuterium-labeled linoleic acid (18:2n-6) and alpha-linolenic acid (18:3n-3) were compared with those labeled with carbon-13 in rat plasma in vivo. Standard curves were constructed to compensate for concentration and plasma matrix effects. It was observed that endogenous pools of fatty acids had a greater suppressing effect on the measurements of 13C-U-labeled EFAs relative to those labeled with 2H5. Using these methods, the in vivo metabolism of orally administered deuterated-linolenate, 13C-U-labeled linolenate, deuterated-linoleate, and 13C-U-labeled linoleate was compared in adult rats (n = 11). There were no significant differences in the concentrations of the 2H versus 13C isotopomers of 18:2n-6, 18:3n-3, arachidonic acid (20:4n-6), and docosahexaenoic acid (22:6n-3) in rat plasma samples at 24 h after dosing. Thus, there appears to be little isotope effect for 2H5- versus 13C-U-labeled EFAs when the data are calculated using the conventional standard curves and corrected for endogenous fatty acid pool size and matrix effects.

In vivo conversion of 18- and 20-C essential fatty acids in rats using the multiple simultaneous stable isotope method

An important question for mammalian nutrition is the relative efficiency of C18 versus C20 essential fatty acids (EFAs) for supporting the tissue composition of n-3 and n-6 pathway end products. One specific question is whether C22 EFAs are made available to tissues more effectively by dietary alpha-linolenic acid (18:3n-3) and linoleic acid (18:2n-6) or by dietary eicosapentaenoic acid (20:5n-3) and dihomo-gamma-linolenic acid (20:3n-6). To address this question in a direct manner, four stable isotope compounds were given simultaneously in a novel paradigm. A single oral dose of a mixture of 2H5-18:3n-3, 13C-U-20:5n-3, 13C-U-18:2n-6, and 2H5-20:3n-6 was administered to rats given a defined diet. There was a preferential in vivo conversion of arachidonic acid (20:4n-6) to docosatetraenoic acid (22:4n-6) and of 22:4n-6 to n-6 docosapentaenoic acid (22:5n-6) when the substrates originated from the C18 precursors. However, when the end products docosahexaenoic acid (22:6n-3) or 22:5n-6 were expressed as the total amount in the plasma compartment divided by the dosage, this parameter was 11-fold greater for 20:5n-3 than for 18:3n-3 and 14-fold greater for 20:3n-6 than for 18:2n-6. Thus, on a per dosage basis, the total amounts of n-3 and n-6 end products accreted in plasma were considerably greater for C20 EFA precursors relative to C18.

Biochemical Intestinal Parameters in Germ‐free Minipigs and Rats and in Ex‐germ‐free Minipigs and Rats Monoassociated with Escherichia coli

Intestinal contents of newborn and young germ-free minipigs and germ-free rats were investigated for the following biochemical parameters - conversion of cholesterol to coprostanol, degradation of beta-aspartylglycine, level of tryptic activity, formation of urobilinogen and the profile of short-chain fatty acids. Additionally, germ-free minipigs and germ-free rats were monoassociated with non-pathogenic strains of Escherichia coli and were investigated for the same biochemical parameters. The conversion of cholesterol to coprostanol, degradation of beta-aspartylglycine, tryptic activity and the short-chain fatty acid profile were similar to those found in previous studies in germ-free animals. Slightly higher amounts of urobilinogen than in the other species investigated so far were found in samples from germ-free and monoassociated minipigs. Except for the total amount of short-chain fatty acids in rats, monoassociation with E. coli did not alter any of the parameters either in the minipigs or in the rats.

Effect of Supplementation with Docosahexaenoic Acid Ethyl Ester and sn-2 Docosahexaenyl Monoacylglyceride on Plasma and Erythrocyte Fatty Acids in Rats

Background/Aims: Docosahexaenoic acid (C22:6, DHA) is an omega-3 fatty acid required for the normal development of the mammalian nervous and visual system. DHA is provided by the mother during pregnancy and lactating period. Mother’s DHA supplementation during pregnancy, and even before pregnancy, has been suggested. DHA can be provided by marine oils, egg’s yolk phospholipids, single cell algae oils, the pure fatty acid, or by the ethyl ester derivative (DHA-EE). Another way to provide DHA can be by sn-2 docosahexaenyl monoacylglyceride (DHA-MG), obtained by the treatment of fish oil with stereospecific lipases. sn-2 Fatty acid monoacylglycerides can be more easily absorbed at the intestine than other fatty acid derivatives. Methods: Female rats fed with a synthetic, which provided essentially no DHA, received a 40-day supplementation of either DHA-EE or DHA-MG. Plasma and erythrocyte fatty acid composition were assessed by gas chromatography at day 0 and 40 of supplementation. Results: DHA-EE increased plasma and erythrocyte DHA by 15 and 11.9%, respectively, with no modification of arachidonic acid (AA) content. DHA-MG supplementation increased plasma and erythrocyte DHA by 24 and 23.8%, respectively, but reduced AA by 5.5 and 3%, respectively. Conclusions: We conclude that in the rat, DHA-MG supplementation allows a higher plasma and erythrocyte DHA content than DHA-EE with minor modification of AA content.

Effect dietary inulin on microbial ecosystem and concentrations of volatile fatty acids in rat's caecum

Department of Human Nutrition and Hygiene Wolynska 33, 60-637 Poznan, Poland(Received 24 March 2004; revised version 25 October 2004; accepted 31 January 2005)ABSTRACTThe effect of inulin on diet intake, excreta output, microbial ecosystem and concentrations of short chain fatty acids in rat’s caecum was investigated on twenty one, 8-week old male Wistar rats. The animals were divided randomly into three experimental groups of 7 rats each, which were kept in individual cages. Three experimental isoprotein and isoenergetic diets were prepared providing different source and amount of fermentable carbohydrate. The control diet contained 5% of potato starch, while the IN-5 and the IN-10 diet contained 5 and 10% of inulin, respectively. Rats were fed these diets and provided distilled water ad libitum for 10 weeks. Dietary intake was monitored daily, weight gain was recorded twice a week. Between 30 and 41 day of experiment 10-day balance study was performed to determine diet intake and excreta output. Transit time was determined with the help of chlorophiline (0.5% diet weight) as a colour marker. At the end of experiment, after 12-h starvation, rats were sacrificed by thiopental injection and dissected to obtain samples of caecal digesta. Inclusion of 5 and 10% of inulin in the rat’s diet did not affect significantly feed intake, excreta output, its water content and transit time. However, in rats fed high-inulin diet a tendency to a higher water content of excreta and decrease of transit time was observed. Concentration of the volatile fatty acids in caecum, specially the butyrate, was significantly higher in rats fed inulin supplemented diets, however without changing their mutual proportions. Inulin inclusion in the diet, led to changes in caecal microflora populations, total counts of the coli form and anaerobic bacteria dropped. Comparing to control group the 10% inclusion of inulin led lowered the number of total coli form and anaerobic bacteria.KEYWORDS: rat, inulin, intake, excreta, caecum, microflora, volatile fatty acids

Chemopreventive Effects of Dietary Flaxseed Oil on Colon Tumor Development

: Fatty acid composition of dietary fat, primarily the levels of ω-3 and ω-6 polyunsaturated fatty acids, has shown profound effect on colon tumor development in animal studies. Fats containing ω-6 fatty acids (for example, corn oil) enhanced and ω-3 fatty acids (for example, fish oil and mustard oil) reduced chemically induced colon tumors in rats. The purpose of this study was to investigate the effects of dietary flaxseed oil (containing α-linolenic acid, an ω-3 polyunsaturated fatty acid) on azoxymethane-induced colon tumor in rats and how it compared with the dietary corn oil-treated group. Male Fischer rats, separated into 2 groups of 30, were assigned to the AIN-93M diet, which was supplemented with either 15% corn oil or 15% flaxseed oil. Carcinogenesis was initiated with subcutaneous injections of azoxymethane (15 mg/kg) once a week for three consecutive weeks. Thirty-five weeks after initiation, the rats were sacrificed under ether anesthesia. Blood was collected by cardiac puncture. The gastrointestinal tract was isolated and flushed with ice-cold normal saline. The site, size, and number of tumors were recorded. The incidence and multiplicity of the tumors in the colon were determined. The fatty acid composition in the serum, colon, and tumors was estimated by using gas chromatography-flame ionization detection. Colon tumor incidence was found to be 100% and 54%, whereas multiplicity was found to be 3.1 and 0.7 tumors per rat in corn oil- and flaxseed oil-treated groups, respectively. Tumor size was significantly larger in the corn oil-treated group than in the flaxseed oil group. Colon and serum samples of the corn oil group showed an increase in the ω-6 fatty acid levels, whereas the flaxseed oil group exhibited an increase in the ω-3 fatty acid levels. The results indicate that dietary flaxseed oil, containing high levels of ω-3 fatty acids, is effective in preventing colon tumor development when compared with dietary corn oil containing ω-6 fatty acids in rats.

Improvement of Colonic Healing by Preoperative Rectal Irrigation With Short-Chain Fatty Acids in Rats Given Radiotherapy

We investigated the effect of preoperative rectal irrigation with short-chain fatty acids on irradiated colonic anastomosis in rats. Sixty male Wistar rats were divided into four groups. Group I (control group, n = 15) underwent left colon resection and primary anastomosis. Group II (Short-chain fatty acids pretreatment group, n = 15) had short-chain fatty acids rectal irrigation for five days preoperatively. Group III (preoperative radiotherapy group, n = 15) underwent irradiation to the whole pelvis eight and four days before the operation, for a total dose of 20 Gy. Group IV (preoperative radiotherapy group + short-chain fatty acids pretreatment group, n = 15) had rectal irrigation with short-chain fatty acids for five days after the second irradiation. Within each group, animals were anesthetized to assess the clinical, mechanical, histologic, and biochemical parameters of anastomotic healing on either the third or seventh postoperative days. The mean bursting pressure was significantly low in Group III on Day 3 and was significantly high in Group IV on Day 7 (P = 0.001, P = 0.021). The burst occurred at the anastomoses in all animals tested on the third postoperative day, and outside of the anastomoses in all animals tested on the seventh postoperative day. The histologic parameters of anastomotic healing, such as epithelial regeneration and formation of granulation tissue, were significantly improved by use of preoperative rectal irrigation with short-chain fatty acids on Day 7. The amount of total and salt-soluble collagen concentrations significantly increased in Group IV compared with the control group on Day 3 (P = 0.008, P = 0.004). Some mechanical and histologic aspects of colonic anastomotic healing can be adversely affected by preoperative radiotherapy, but rectal irrigation with short-chain fatty acids may improve anastomotic healing.

Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin.

Thiazolidinediones can enhance clearance of whole-body non-esterified fatty acids and protect against the insulin resistance that develops during an acute lipid load. The present study used [(3)H]-R-bromopalmitate to compare the effects of the thiazolidinedione, rosiglitazone, and the biguanide, metformin, on insulin action and the tissue-specific fate of non-esterified fatty acids in rats during lipid infusion. Normal rats were treated with rosiglitazone or metformin for 7 days. Triglyceride/heparin (to elevate non-esterified fatty acids) or glycerol (control) were then infused for 5 h, with a hyperinsulinaemic clamp being performed between the 3rd and 5th hours. Rosiglitazone and metformin prevented fatty-acid-induced insulin resistance (reduced clamp glucose infusion rate). Both drugs improved insulin-mediated suppression of hepatic glucose output but only rosiglitazone enhanced systemic non-esterified fatty acid clearance (plateau plasma non-esterified fatty acids reduced by 40%). Despite this decrease in plateau plasma non-esterified fatty acids, rosiglitazone increased fatty acid uptake (two-fold) into adipose tissue and reduced fatty acid uptake into liver (by 40%) and muscle (by 30%), as well as reducing liver long-chain fatty acyl CoA accumulation (by 30%). Both rosiglitazone and metformin increased liver AMP-activated protein kinase activity, a possible mediator of the protective effects on insulin action, but in contrast to rosiglitazone, metformin had no significant effect on non-esterified fatty acid kinetics or relative tissue fatty acid uptake. These results directly demonstrate the "lipid steal" mechanism, by which thiazolidinediones help prevent fatty-acid-induced insulin resistance. The contrasting mechanisms of action of rosiglitazone and metformin could be beneficial when both drugs are used in combination to treat insulin resistance.