Evidence for critical-period programming of intestinal transport function: variations in the dietary ratio of polyunsaturated to saturated fatty acids alters ontogeny of the rat intestine

2-week isocaloric modifications in the dietary ratio of polyunsaturated/saturated fatty acids (P/S) alters intestinal transport in rats. This study was undertaken to test the hypotheses that (1) the fatty acid composition of a nutritionally adequate diet in early life has lasting consequences for active and passive intestinal transport processes; and (2) early life feeding experiences with diets of varying fatty acid composition influence the intestines' ability to adaptively up- or down-regulate intestinal transport in later life. Female Sprague-Dawley rats were weaned onto S or P and were maintained on these diets for 2, 10 or 12 weeks. An in vitro uptake technique was used in which the bulk phase was vigorously stirred to reduce the effective resistance of the intestinal unstirred water layer. P decreased and S increased the uptake of glucose, and this effect was progressive from 2 to 12 weeks. Switching from a P to an S diet decreased jejunal but increased ileal uptake of glucose, whereas switching from an S to a P diet was associated with a decline in both the jejunal and the ileal uptake of glucose. The ileal uptake of galactose increased as the animals grew on either P or S. Switching from P to S resulted in a decline in ileal uptake of galactose, whereas the opposite effect was observed when switching from S to P. The effect of feeding P or S on hexose uptake was influenced by the animals' dietary history: ileal glucose and galactose uptake was lower in animals fed P at an early age (PSP) than in animals fed P for the first time in later life (SSP). Jejunal glucose and galactose uptake was also lower in animals fed S at an early age (SPS) than in those fed S for the first time in later life (PPS). The alterations in the uptake of long-chain saturated and unsaturated fatty acids and cholesterol did not progress with longer periods of feeding, and in the jejunum, lipid uptake did not change when switching from P to S or S to P. Early feeding with P (PSP vs. SSP) was associated with lower jejunal uptake of 18:3 and lower ileal uptake of 12:0, whereas previous feeding with S (SPS vs. PPS) was associated with lower ileal uptake of cholesterol. The changes in uptake of hexoses and lipids was not explained by differences in the animals' food consumption, body or intestinal weight or mucosal surface area.(ABSTRACT TRUNCATED AT 400 WORDS)     

Spectrum of effects of dietary long-chain fatty acids on rat intestinal glucose and lipid uptake

Isocaloric modification in the ratio of dietary polyunsaturated-to-saturated fatty acids influences intestinal uptake of actively and passively transported nutrients. This study was undertaken to determine which dietary fatty acid was responsible for these alterations in absorption. Adult female rats were fed isocaloric semisynthetic diets high in palmitic and stearic acids (SFA), oleic acid (OA), linoleic acid (LA), or linolenic acid (LNA). An in vitro technique was used to measure the uptake of varying concentrations of glucose as well as a series of fatty acids and cholesterol. Jejunal uptake of 40 mM glucose was highest in rats fed SFA and lowest in those fed LA; ileal glucose uptake was similar in OA, LA, and LNA, but was lowest in SFA. Jejunal uptake of medium-chain fatty acids (8:0-12:0) was higher in OA than in other diet groups; ileal uptake of medium-chain fatty acids was unaffected by diet. Jejunal and ileal uptake of 18:2 was higher in LNA than in SFA or OA; the uptake of the other long-chain saturated or unsaturated fatty acids was unchanged by diet. The ileal but not the jejunal uptake of cholesterol was increased in LA as compared with SFA or OA, and reduced in LNA as compared with LA. These transport changes were not explained by differences in the animals' food consumption, body weight gain, intestinal mass, or mucosal surface area. We postulate that these diet-induced transport alterations may be mediated via changes in brush border membrane phospholipid fatty acyl composition. Thus, intestinal transport of nutrients may be varied by isocaloric changes in the dietary content of individual fatty acids.     

The level of dietary protein and carbohydrate has a different effect on intestinal uptake of hexoses and lipids in rabbits with an ileal resection than in those with an intact intestinal tract

Either high protein, low carbohydrate (HP) or low protein, high carbohydrate (LP) diets were fed for 6 weeks to rabbits with or without resection of the distal half of the small intestine. Control and resected rabbits fed HP consumed more food and gained more weight than the animals fed LP. The level of dietary protein has a different effect on intestinal transport in animals with an ileal resection than in those with an intact small intestine. With 0.5 mM glucose, the in vitro uptake in control rabbits was greater for the LP than HP diet but was unchanged in resected rabbits; uptake of 0.5 mM galactose and 3-O-methyl glucose was unaffected by HP and LP, whereas in rabbit uptake was lower in LP than HP. The uptake of 40 mM glucose was greater with the LP than HP diet in control rabbits, but lower with LP than HP in resected rabbits. In control rabbits, the uptake of aluric acid was lower on the LP than HP diet; the uptake of octanoic acid, decanoic acid, and cholesterol was unchanged; and the uptake of each fatty acid and cholesterol was greater in resected rabbits fed LP than HP. Feeding a low protein diet to animals with an ileal resection is associated with lower jejunal uptake of high concentrations of glucose, but the higher uptake of galactose and enhanced permeability to fatty acids result in superior weight gain. Thus, recommendations for alterations in dietary protein and carbohydrate levels following ileal resection must be made with the knowledge that these changes may influence intestinal transport function as well as body weight gain.     

Fish oil prevents effect of high cholesterol diet on active intestinal transport of galactose

We tested the hypothesis that diets containing fish oils prevent the effects of a high cholesterol diet on the morphology and nutrient uptake of the intestine. Isocaloric semisynthetic diets were supplemented with beef tallow or fish oil containing low or high amounts of cholesterol and were fed to growing female Wistar rats for 14 days, after which the in vitro jejunal and ileal uptake of glucose, galactose, long-chain fatty acids, and cholesterol was determined. Feeding cholesterol with beef tallow was associated with a 12% decrease in the jejunal mucosal surface area. Feeding fish oil decreased jejunal mucosal surface area by 24%, as compared with the beef tallow diet, but the reduction was increased to 42% when fish oil and cholesterol were fed together. Ileal surface area was unaffected by varying the major source of dietary lipid, or by adding cholesterol. Despite the effect of fish oil on the mucosal surface area, the jejunal and ileal uptake of saturated as well as unsaturated long-chain fatty acids and cholesterol was similar in the four diet groups. Cholesterol supplementation enhanced the jejunal uptake of high concentrations of galactose only when fed with beef tallow, i.e., feeding fish oil prevented the enhancing effect of cholesterol on galactose uptake observed when beef tallow was fed. Thus, (i) a fish oil diet prevents the enhancing effect of cholesterol on jejunal active transport of galactose, an effect not explained by the reduction in jejunal mucosal surface area observed with the fish oil diet; (ii) these dietary manipulations result in a clear dissociation of the morphological from the transport adaptation of the intestine; and (iii) substitution of fish oil for beef tallow as the major source of lipid in the diet prevents the influence of cholesterol on the active intestinal transport of galactose.     

Feeding rats a diet enriched with saturated fatty acids prevents the inhibitory effects of acute and chronic ethanol exposure on the in vitro uptake of hexoses and lipids

Chow-fed rats were given 15% ethanol in their drinking water for 4 weeks, and then for the next 2 weeks of ethanol exposure they were fed isocaloric semisynthetic diets enriched in either saturated (S) or polyunsaturated (P, linoleic acid) fats. Food intake was lower in ethanol-fed (ETH) than in control (C) rats, but the average body weight gain was similar in ETH and C fed S or P. Intestinal dry weight and the percentage of the intestinal wall comprised of mucosa were more than 2-fold higher in ETH than C fed P, whereas these values were 50% lower in ETH than C fed S. The in vitro jejunal uptake of glucose and galactose was higher in ETH than C fed S, whereas the converse was true when feeding P. These effects were due to differences in the values of the maximal transport rate (Vmax), the Michaelis constant (Km), and the contribution of passive permeation. The relative permeability of the intestine to lipids was unchanged by giving ethanol or by feeding S or P, but the individual rates of uptake of most medium- and long-chain fatty acids and cholesterol were lower in ETH fed P as compared with S. In a second series of studies the acute effect of ethanol exposure was examined: animals were fed S or P for 2 weeks and the intestine was then removed: when 5% ethanol was added directly to the test solutions, there was lower in vitro jejunal and ileal uptake of glucose and higher jejunal uptake of 18:2 when rats were previously fed P, but not in those fed S. In summary; (1) feeding an isocaloric polyunsaturated fatty acid diet has a trophic effect on the intestinal mucosa of animals chronically drinking ethanol; and (2) feeding rats a diet enriched with saturated fatty acids prevents the inhibitory effects of acute and chronic ethanol exposure on the in vitro jejunal uptake of glucose, galactose and lipids observed in animals fed a polyunsaturated diet. Thus, the effect of chronic consumption of ethanol on the active and passive jejunal uptake of nutrients is influenced by the type of lipids in the animal's diet.     

Feeding long-chain n-3 polyunsaturated fatty acids during gestation increases intestinal glucose absorption potentially via the acute activation of AMPK

The current study utilized Ussing chambers to examine the impact of supplementing maternal gestation and/or lactation diets with n-3 polyunsaturated fatty acids (PUFA) provided via a protected fish oil (PFO) product on intestinal fatty acid profiles and ex vivo glucose uptake in the jejunum of weanling piglets. Jejunum tissues were enriched with n-3 PUFA as a result of feeding the sows the PFO during gestation and/or lactation (P<.05). Glucose uptake improved by twofold (P<.042) in intestinal preparations obtained from the offspring of sows fed PFO during gestation or throughout gestation/lactation versus lactation alone. This was also reflected in the jejunum protein expressions of glucose transporter 2 (GLUT2) and sodium-dependent glucose transporter 1 (SGLT1). Furthermore, adding docosahexaenoic acid (DHA) or an AMP-activated protein kinase (AMPK) agonist to the chamber buffer improved glucose uptake (P<.05) in intestinal preparations obtained from the offspring fed the control diet, devoid of the PFO product and containing minimal concentrations of n-3 PUFA. Collectively, these data indicate two important points. First, long-term exposure to n-3 PUFA via the maternal gestation diet effectively enhances glucose uptake in the weanling piglet, and the underlying mechanism may be associated with changes in the intestinal fatty acid profile. Secondly, there is an apparent direct and acute effect of DHA that is achieved within a time frame that precludes substantial changes in the intestinal fatty acid profile. Additionally, both mechanisms may involve activation of AMPK. Thus, n-3 PUFA delivered in utero and postnatally via the maternal diet may help the offspring adapt quickly to rapidly changing diets early in life and allow optimal nutrient uptake.     

Treatment of the enhanced intestinal uptake of glucose in diabetic rats with a polyunsaturated fatty acid diet

Intestinal absorption of most nutrients is enhanced in diabetic rats. We wished to test the hypothesis that manipulation of dietary fatty acids will modify enhanced uptake of glucose in rats with established streptozotocin-diabetes. Chow-fed control rats or animals with one week of streptozotocin-diabetes were continued on chow or were fed ad libitum for three weeks with semisynthetic isocaloric diets containing a high content of either essential polyunsaturated or non-essential saturated fatty acids. The jejunal and ileal in vitro uptake of varying concentrations of glucose was much higher in diabetic than control rats fed chow or the saturated fatty acid diet. In contrast, the enhanced uptake of this sugar was reduced or normalized in diabetic rats fed the polyunsaturated fatty acid diet. Feeding the polyunsaturated fatty acid diet was associated with increased brush-border membrane activity of alkaline phosphatase in diabetic jejunum and ileum, but neither the saturated fatty acid diet nor the polyunsaturated fatty acid diet altered brush-border membrane cholesterol or phospholipids in control or in diabetic rats. Mucosal surface area was similar in diabetic rats fed the saturated fatty acid diet or the polyunsaturated fatty acid diet. Thus, (1) feeding the polyunsaturated fatty acid diet diminishes the enhanced jejunal and ileal uptake of glucose in diabetic rats, and (2) the influence of the polyunsaturated fatty acid diet on uptake in diabetic rats was not explained by alterations in intestinal morphology or brush-border membrane content of cholesterol or phospholipids. This study suggests that manipulation of dietary lipids may play a role in the normalization of the enhanced intestinal glucose uptake in rats with established diabetes.     

Dietary lipids modify the age-associated changes in intestinal uptake of fructose in rats

Because reduced nutrient absorption may contribute to malnourishment in the elderly, age and diet modulate fructose uptake in mice, and alterations in fructose uptake may be paralleled by changes in the abundance of fructose transporters, the objectives of this study were to determine 1) the effects of aging on fructose absorption in rats, 2) the effect of feeding diets enriched with saturated fatty acids (SFA) vs. polyunsaturated fatty acids (PUFA), and 3) the mechanisms of these age-and diet-associated changes. Male Fischer 344 rats aged 1, 9, and 24 mo received isocaloric diets enriched with SFA or PUFA. The uptake of (14)C-labeled D-fructose was determined in vitro using the intestinal sheet method. Northern and Western blot analyses and immunohistochemistry were used to determine the abundance of sodium-independent glucose and fructose transporters (GLUT)2 and GLUT5. When expressed on the basis of mucosal surface area, jejunal fructose uptake was increased in 9 and 24 mo compared with 1-mo-old animals fed SFA. PUFA-fed animals demonstrated increased fructose uptake at 24 mo compared with younger animals. Ileal fructose uptake was increased with SFA vs. PUFA in 9-mo-old rats but was reduced with SFA in 1- and 24-mo-old rats. Variations in GLUT2 and GLUT5 abundance did not parallel changes in uptake. These results indicate that 1) age increases fructose uptake when expressed on the basis of mucosal surface area, 2) age influences the adaptive response to dietary lipid modifications, and 3) alterations in fructose uptake are not explained by variations in GLUT2 or GLUT5.     

Involvement of CD36 and intestinal alkaline phosphatases in fatty acid transport in enterocytes, and the response to a high-fat diet

The vertebrate intestine is notable for its plasticity in response to environmental, pathologic, reproductive, and dietary challenges. The molecular mechanisms of intestinal adaptations typically involve both morphologic and functional changes. In response to chronic ingestion of a high-fat diet, for example, the mammalian small intestine quickly adapts to efficiently accommodate increased transport of long-chain fatty acids across the mucosa. Whereas this may be adaptive in the short term, in the long term it may contribute to the pathologies associated with chronic high-fat diets in humans and other mammals. This review focuses on some of the known and putative mechanisms by which fatty acids are transported across the intestinal epithelium in addition to simple diffusion, and how these mechanisms may be regulated in part by a high-fat diet. A model is proposed in which two key proteins, CD36 and the enzyme intestinal alkaline phosphatase, work in a coordinated manner to optimize fatty acid transport across enterocytes in mice.     

Fat absorption in essential fatty acid deficiency: a model experimental approach to studies of the mechanism of fat malabsorption of unknown etiology

Male rats were made deficient in essential fatty acids by feeding them a fat-free diet supplemented with 4% tripalmitin for 8-12 wk from the time of weaning. After feeding 0.5 ml of [(14)C]triolein or [(3)H]oleic acid, 72-hr stool recoveries of radioactivity were significantly greater in deficient rats than in chow-fed controls. Essential fatty acid deficiency did not reduce the absorptive capacities for triolein or for a medium-chain fat, trioctanoin, measured after 3 and 2 hr of maximal-rate duodenal infusion. In everted jejunal slices from essential fatty acid-deficient rats, uptake of micellar [(14)C]oleic acid at 0-1 degrees C was similar to that of controls, but the rate of incorporation of fatty acid into triglyceride after rewarming to 37 degrees C was significantly reduced. The specific activities of the microsomal esterifying enzymes, acyl CoA:monoglyceride acyltransferase and fatty acid CoA ligase in jejunal mucosa were 30% lower in essential fatty acid-deficient rats. However, the total microsomal enzyme activity adjusted to constant weight did not differ significantly in deficient rats compared with controls. After intraduodenal perfusion of triolein, accumulation of lipid in the intestinal wall was increased in the deficient rats. Because over 90% of the absorbed mucosal lipid was present as triglyceride, essential fatty acid deficiency appears to affect the synthesis or release of chylomicron lipid from the intestine. Analysis of regions of intestine showed that this delay in transport was most marked in the midportion of the small intestine.     

Uptake of hexoses and lipids into rabbit jejunum and colon following ileal resection: effect of variations in the cholesterol and fat content of the diet

After 6 weeks feeding on either a high-cholesterol/fat (H) or a low-cholesterol/fat (L) diet, jejunal and colonic uptake was measured using a previously validated in vitro technique in control rabbits with an intact intestinal tract (C) and in animals submitted to the surgical removal of the distal half of the small intestine (R). The uptake of hexoses and fatty acids was influenced by ileal resection and by diet. Dietary manipulation altered the passive and active transport properties of the intestine and had a different effect on intestinal transport in animals with an ileal resection than in animals with an intact small intestine.     

Influence of dietary partially hydrogenated fat high in trans fatty acids on lipid composition and function of intestinal brush border membrane in rats

The effect of dietary hydrogenated fat (Indian vanaspati) high in trans fatty acids (6 en%) on lipid composition, fluidity and function of rat intestinal brush border membrane was studied at 2 and 8 en% of linoleic acid. Three groups of weanling rats were fed rice-pulse based diet containing 10% fat over a ten week period: Group I (groundnut oil), Group II (vanaspati), Group III (vanaspati + safflower oil). The functionality of the brush border membrane was assessed by the activity of membrane bound enzymes and transport of D-glucose and L-leucine. The levels of total cholesterol and phospholipids were similar in all groups. The data on fatty acid composition of membrane phospholipids showed that, at 2 en% of linoleic acid in the diet, trans fatty acids lowered arachidonic acid and increased linoleic acid contents indicating altered polyunsaturated fatty acid metabolism. Alkaline phosphatase activity was increased while the activities of sucrase, gamma-glutamyl transpeptidase and transport of D-glucose and L-leucine were not altered by dietary trans fatty acids. However at higher intake of linoleic acid in the diet, trans fatty acids have no effect on polyunsaturated fatty acid composition and alkaline phosphatase activity of intestinal brush border membrane. These data suggest that feeding dietary fat high in trans fatty acids is associated with alteration in intestinal brush border membrane polyunsaturated fatty acid composition and alkaline phosphatase activity only when the dietary linoleic acid is low.     

Glucose and lipid metabolism in the pancreas of rainbow trout is regulated at the molecular level by nutritional status and carbohydrate intake

Glucose and lipid metabolism in pancreatic islet organs is poorly characterized. In the present study, using as a model the carnivorous rainbow trout, a glucose-intolerant fish, we assessed mRNA expression levels of several genes involved in glucose and lipid metabolism (including ATP-citrate lyase; carnitine palmitoyltransferase-1 isoforms, CPT; the mitochondrial isoform of the phosphoenolpyrutave carboxykinase, mPEPCK and pyruvate kinase, PK) and glucosensing (glucose transporter type 2, Glut2; glucokinase, GK and the potassium channel, K_ATP) in Brockmann bodies. We evaluated the response of these parameters to changes in feeding status (food deprived vs. fed fish) as well as to changes in the amount of carbohydrate (dextrin) in the diet. A general inhibition of the glycolytic (including the glucosensing marker GK) and β-oxidation pathways was found when comparing fed versus food-deprived fish. When comparing fish feeding on either low- or high-carbohydrate diets, we found that some genes related to lipid metabolism were more controlled by the feeding status than by the carbohydrate content (fatty acid synthase, CPTs). Findings are discussed in the context of pancreatic regulation of glucose and lipid metabolism in fish, and show that while trout pancreatic metabolism can partially adapt to a high-carbohydrate diet, some of the molecular actors studied seem to be poorly regulated (K_ATP) and may contribute to the glucose intolerance observed in this species when fed high-carbohydrate diets.     

Liver composition and lipid metabolism in NZB/W F1 female mice fed dehydroisoandrosterone

The beneficial effects obtained with dehydroisoandrosterone (DHA) feeding in the treatment of murine systemic lupus erythematosus are similar to those obtained with caloric restriction or with dietary manipulation of essential fatty acid availability. In this study, the fatty acid composition of selected tissues was examined in NZB/W F1 mice fed a diet containing 0.4% DHA. The effect of the DHA diet on liver composition and the activity of key hepatic enzymes involved in fatty acid synthesis and glucose metabolism was also investigated. The content of the essential fatty acid, arachidonate, was decreased in plasma cholesteryl esters and liver and kidney phospholipids in mice fed the DHA diet, yet no significant decrease in arachidonate content was observed in plasma phospholipid. The most striking change in both plasma and liver phospholipid was an increase in palmitic acid and a decrease in stearic acid, which could result from a decreased ability for fatty acid elongation. The liver mass was dramatically increased in the mice fed DHA, primarily from parenchymal cell hypertrophy, and contained little lipid. Significant changes in the activities of malic enzyme, glucose-6-phosphate dehydrogenase and pyruvate kinase, similar to those changes which occur with fasting, were observed during the initial adaptation to the DHA diet. The pyruvate kinase activity remained low, suggesting a decrease in liver glycolysis. These results are consistent with the concept that diets containing DHA result in an altered metabolism with a decreased dependence on carbohydrate metabolism and an increased metabolism of lipids.     

Luminal nutrient signals for intestinal adaptation in pythons

Python intestine responds rapidly to luminal nutrients by increasing mass and upregulating nutrient transport. Candidates for luminal signals triggering those responses include mechanical stimulation, single or several dietary nutrients, and endogenous secretions. To identify signals, we infused into the python's small intestine either a nonnutrient solution (saline) or a single- or multinutrient solution. Python intestine failed to respond trophically or functionally to luminal infusions of saline, glucose, lipid, or bile. Infusion of amino acids and peptides, with or without glucose, induced an intermediate response. Infusion of nutritionally complete liquid formula or natural diet induced full intestinal response. Intact meals triggered full intestinal responses without pancreatic or biliary secretions, whereas direct cephalic and gastric stimulation failed to elicit any response. Hence neither physical stimulation (cephalic, gastric, or intestinal) nor the luminal presence of glucose, lipids, or bile can induce intestinal response; instead, a combination of nutrients is required (even without pancreaticobiliary secretions), the most important being amino acids and peptides. This is understandable because pythons, as carnivores, have a high-protein diet.     

Late effects of abdominal radiation on intestinal uptake of nutrients

The late effects of variable doses of abdominal irradiation on in vitro jejunal uptake were examined. The uptake of glucose, galactose, cholic acid, medium-chain length fatty acids, and decanol was studied 6 and 33 weeks following 300, 600, or 900 cGy abdominal irradiation. The intestinal morphological characteristics were similar 6 and 33 weeks after radiation. The uptake of cholic acid was unaffected by abdominal irradiation, but for glucose, galactose, and four fatty acids the direction and magnitude of the changes in uptake were influenced by the dose of irradiation and by the interval following exposure. The greater uptake of decanol at 6 weeks but lower uptake of decanol at 33 weeks reflected changes in the resistance of the intestinal unstirred water layer. These absorption changes suggest that the intestine may not be capable of correcting the transport abnormalities arising from sublethal doses of abdominal irradiation.