Treatment of suckling rats with GLP-2 plus dexamethasone increases the ileal uptake of fatty acids in later life
Claudiu Iordache,1
Laurie Drozdowski,1
M. Tom Clandinin,1
Gary Wild,2
Zoe Todd,1 and
Alan B. R. Thomson1
1Nutrition and Metabolism Group, University of Alberta, 2Division of Gastroenterology, Department of Medicine, McGill University, Edmonton, Canada
Submitted 26 January 2004
; accepted in final form 7 July 2004
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ABSTRACT
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Glucocorticosteroids such as dexamethasone (Dex) increase sugar and lipid uptake in adult animals and accelerate the development of the immature intestine. The effect of Dex on the ontogeny of lipid absorption is unknown. In adult rats, glucagon-like peptide-2 (GLP-2) has a trophic effect on the intestine and enhances nutrient absorption. This study was undertaken to determine the effect of GLP-2 and Dex on the intestine uptake of lipids in suckling rats and to determine whether any such effect persists into the postweanling period. Sixty-four suckling rats were randomized into four groups. They were treated from days 11 to 21 with GLP-2 (0.1 µg·g1·day1 sc), Dex (0.128 µg·g1·day1 sc), GLP-2 plus Dex (GLP-2 0.1 µg·g1·day1 sc + Dex 0.128 µg·g1·day1 sc), or placebo. One-half the pups were killed at days 1921 ("sucklings"), and one-half were killed 4 wk later ("weanlings"). The rate of intestinal uptake of six fatty acids (12:0, lauric; 16:0, palmitic; 18:0, stearic; 18:1, oleic; 18:2, linoleic; and 18:3, linolenic) and cholesterol was assessed using an in vitro ring technique. GLP-2 had no effect on lipid uptake. Dex increased the uptake of 18:3 in sucklings, and the ileal uptake of 18:0 was increased in weanlings. The combination of GLP-2 plus Dex had no effect in sucklings and increased the ileal uptake of 12:0, 18:0, 18:1, 18:2, and 18:3 in weanlings. The enhanced uptake of fatty acids with GLP-2 plus Dex was not explained by alterations in the animals' body or intestinal weights, intestinal morphology, or intestinal- or liver-fatty acid binding proteins. Unlike adults, GLP-2 does not enhance lipid uptake in sucklings. Dex has a modest enhancing effect on selected fatty acid uptake both in sucklings as well as weanlings. GLP-2 plus Dex has an enhancing effect on the ileal uptake of fatty acids in weanlings 4 wk after their previous injection with GLP-2 plus Dex. It remains to be established what is the nutritional importance of this late effect of prior exposure to Dex or GLP-2 plus Dex on the intestinal uptake of lipids.
adaptation; cholesterol; jejunum; ileum; late effects; lipid binding proteins; morphology
GENETIC PROGRAMMING IS THE main contributor to the development and maturation of the intestine (11, 17, 18, 27). Various stimuli influence intestinal ontogeny such as hormones, the enteric nervous system, the mesenchyme, and luminal factors including the luminal bacterial flora and animals' diet (23, 28, 30). The digestion and absorption of nutrients demonstrate age-dependent changes during the development of the gut due to alterations in the brush-border membrane (BBM) permeability and the BBM nutrient transporters or enzymes (6, 18, 34). A diet with a high content in lipids such as milk is well digested during the suckling period in rodents despite a low secretion of lipase and colipase by the newborn pancreas and lack of gastric lipases (14). The impaired pancreatic and gastric lipolytic process is compensated for by the lingual and milk lipases (17). Lipid absorption is a complex process involving the passive diffusion and protein-mediated transport of lipids across the BBM, their intracellular metabolism, as well as the subsequent transfer of the lipids into the lymphatics or into the portal circulation (2, 37). During suckling, the intestine is capable of an increased uptake of lipids compared with the weanling period (16, 15). This higher uptake results possibly from an increased fluidity of the BBM (19, 35) and/or a greater metabolism of fat in suckling compared with weanling or adult rats (15, 16). The age-dependent decrease of the BBM fluidity results from alterations in lipid composition of BBM. The suckling intestine contains greater amounts of cholesterol and phospholipids per milligram of protein compared with the mature intestine (35, 19). The decline in lipid uptake between the suckling and weaning period is associated with a change in the diet from a high uptake of fat in milk to a high intake of carbohydrates in rat chow.
In adult rats, glucagon-like peptide-2 (GLP-2) enhances the intestinal BBM and basolateral membrane (BLM) uptake of sugars (810) as well as triolein (4). Also, balance studies in human patients with the short bowel syndrome have shown that GLP-2 increases lipid uptake (24). It is not known whether this peptide influences the uptake of lipids in suckling animals. Glucocorticosteroids such as dexamethasone (Dex) increase the uptake of sugars and lipids in adult rats (39, 40) and accelerate the development of the transport and digestive functions of the young intestine (18, 30). Dex and GLP-2 may have a synergistic effect because Dex increases the activity of cAMP acting hormones, such as GLP-2, by altering the adenylyl cyclase catalyst (44). It is not known whether the combination GLP-2 plus Dex enhances the intestinal uptake of lipids in suckling rats or whether such an effect persists into the postweaning period.
Accordingly, this study was undertaken to determine 1) whether GLP-2 and Dex when administered alone or in combination to suckling rats enhance the intestinal in vitro uptake of lipids; 2) whether these changes in the uptake of lipids are due to variations in the intestinal mass or morphology or to changes in the abundance of selected intracellular lipid binding proteins in the enterocytes; and 3) whether the effects of GLP-2 and Dex on the intestine persist into the postweaning period.
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MATERIALS AND METHODS
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Animals.
The principles for the care and use of laboratory animals, approved by the Canadian Council on Animal Care and by the Council of the American Physiological Society, were observed in the conduct of this study. All experiments were approved by the Animal Ethics Board, University of Alberta. Eight nursing Sprague-Dawley rats with 64 suckling offspring were obtained from Bio Science Animal Services, University of Alberta.
The suckling rats were randomized into four groups that received treatment with GLP-2, Dex, GLP-2 plus Dex, or placebo. All animals received treatment for 10 days starting with the 11th day from time of their delivery. GLP-2 was administrated in a dose of 0.1 µg·g body wt1·day1 sc twice per day at 7 AM and 7 PM. Dex was administrated in a dose of 0.128 µg·g body wt1·day1 sc once per day at 7 PM. The regimen used for GLP-2 plus Dex group was GLP-2 0.1 µg·g body wt1·day1 sc twice per day at 7 AM and 7 PM plus Dex 0.128 µg·g body wt1·day1 sc once per day at 7 PM. The placebo group received 0.9% saline in a volume equal to the volume of GLP-2 administered daily per rat (depending on the weight of the rat, the volume ranged from 0.08 ml on the first day to 0.18 ml on the 10th day) subcutaneously twice per day at 7 AM and 7 PM.
There were eight animals in each group. After treatment, all sucklings were killed for uptake studies at 21 days of age, and all postweaning animals (weanlings) were killed for the uptake studies at 7 wk of age (Fig. 1).

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Fig. 1. Experimental design. Dex, dexamethasone; GLP-2, glucagon-like peptide-2. *Treatment with GLP02, Dex, GLP-2 + Dex, and Placebo was administrated each day during lactation. **Uptake studies were performed at day 21 ("suckling") and day 49 ("weaning").
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The animals were housed at a temperature of 21°C, and each day they were exposed to 12:12-h light-dark cycle. During the suckling period, the offspring received only the dam's milk. The weanlings were housed in pairs. Their water and food were supplied ad libitum. The dams and the weanlings were fed standard rat chow (PMI #5001; Nutrition International, Brentwood, MO). The diets were nutritionally adequate, providing for all known essential nutrient requirements. Body weights were recorded at the time of weanling and then weekly for the next 4 wk.
Uptake Studies
Probe and marker compounds.
The 14C-labeled probes included cholesterol (0.05 mM) and six fatty acids (0.1 mM): lauric acid (12:0), palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), and linolenic acid (18:3). The labeled probes were supplied by Amersham Biosciences (Piscataway, NJ). The lipid probes were prepared by solubilizing them in 10 mM taurodeoxycholic acid (Sigma, St. Louis, MO) in Krebs-bicarbonate buffer, with the exception of 12:0, which was solubilized only in Krebs-bicarbonate buffer. [3H]inulin was used as a nonabsorbable marker to correct for the adherent mucosal fluid volume (44).
Tissue preparation.
Eight animals per treatment group were killed by an intraperitoneal injection of Euthanyl (pentobarbital sodium, 240 mg/100 g body wt). The whole length of the small intestine was rapidly removed and rinsed with 150 ml cold saline. The intestine was divided into two parts: the proximal half of the intestine beginning at the ligament of Treitz was termed the "jejunum," and the distal half was termed the "ileum." A 2-cm piece of each segment of jejunum and ileum was gently scraped with a glass slide. The mucosal scrapings and the remaining wall of the intestine were dried overnight in an oven at 55°C. The percentage of the intestinal wall comprised of mucosa was calculated. The remaining intestine was everted and cut into small rings of
24 mm each. These intestinal rings were immersed in preincubation beakers containing Krebs buffer (pH 7.2) at 37°C, bubbled with oxygen plus bicarbonate (O2-CO2, 95:5 by volume), and were allowed to equilibrate for 5 min (32). Uptake was initiated by the timed transfer of the tissue rings from the preincubation buffer to a 5-ml plastic vial containing [3H]inulin and 14C-labeled lipids in Krebs buffer bubbled with oxygen plus bicarbonate that had been equilibrated to 37°C in a shaking water bath. The intestinal rings were incubated in the lipid substrates for 5 min.
Determination of uptake rates.
The rate of uptake of lipid was terminated by pouring the vial contents onto filters on an Amicon vacuum filtration manifold that was maintained under suction followed by washing the intestinal rings three times with ice-cold saline. The tissue rings were placed on a glass slide and were dried overnight in an oven at a constant temperature of 55°C. The dry weight of the tissue was determined, and the tissue was transferred to scintillation counting vials. The samples were saponified with 0.75 M NaOH, scintillation fluid was added, and radioactivity was determined by means of an external standardization technique to correct for variable quenching of the two isotopes. The rates of lipid uptake were determined as nanomoles of substrate absorbed per 100 mg dry weight of the mucosa per minute (Jm; nmol·100 mg mucosal tissue1·min1).
Morphological Analysis
To determine the morphological characteristics of the intestine, a vertical section was prepared from the jejunum and from the ileum. Hematoxylin and eosin-stained slides were prepared from paraffin blocks. Crypt depth, villous height, villous width, villous width at half height, and cell density were measured using the program MetaMorph 5.05r (Universal Imaging, Downingtown, PA). The group means were obtained based on 10 villi and 20 crypts per slide, with a minimum of four animals in each group.
Immunohistochemistry
Jejunal and ileal tissues were embedded in paraffin, and 4- to 5-µm sections were mounted on glass slides. The sections were heated and placed immediately in xylene (2x for 5 min each), followed by absolute ethanol (2x for 2 min each) and were then rinsed with tap water. The slides were incubated in a hydrogen peroxide/methanol solution and rinsed with tap water. Then they were rehydrated, and the tissue was encircled on the slides with a hydrophobic slide marker (PAP pen, BioGenex, San Ramon, CA). The slides were incubated for 15 min in blocking reagent (20% normal goat serum) followed by primary antibody to the intestinal fatty acid binding protein (I-FABP) or to the liver fatty acid binding protein L-FABP for 30 min. Both antibodies were a generous gift from Dr. L. B. Agellon, University of Alberta. The slides were incubated in LINK and LABEL and with DAB solution (BioGenex, San Ramon, CA). The slides were then washed, stained in hematoxylin, dehydrated in absolute ethanol, and cleared in xylene. The slides were photographed, and the area labeled with antibody was determined using MetaMorph 5.05r. The results were expressed as a ratio of the area that was antibody-positive versus the total area. Statistical analyses were based on a minimum of four villi per animal and four animals per group.
Statistical Analyses
The results obtained were expressed as means ± SE. The statistical significance of the differences between the four groups was determined by ANOVA for values of P
0.05. The significant differences between sucklings versus weanlings were determined using a Student's t-test. Statistical significance was accepted for values of P
0.05.
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RESULTS
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Body and Intestinal Weights and Villous Morphology
Injecting GLP-2, Dex, or GLP-2 plus Dex into the suckling animals for 10 days had no effect on the animal's body weight (data not shown). In contrast, the mean body weight of the weanlings injected 6 wk previously with Dex was
25% lower than in the control animals (162 vs. 213 g). When GLP-2 was given with Dex, the decrease in body weight in the weanlings given Dex was not observed.
Giving GLP-2, Dex, or GLP-2 plus Dex to the suckling rats had no influence on the jejunal or ileal weights, weight of the mucosa, or percentage of the intestinal wall comprised of mucosa (data not shown). In contrast, in weanlings, the total ileal weight was increased from 7.6 ± 0.8 mg/cm in controls to 10.1 ± 0.8 mg/cm (P < 0.05) in those given GLP-2 (data not shown). Neither Dex nor GLP-2 plus Dex influenced the intestinal characteristics in weanlings.
GLP-2 increased the crypt depth in the jejunum of sucklings, whereas Dex as well as GLP-2 plus Dex increased the jejunal villous height, width at the villous base, and crypt depth (Table 1). In the ileum of sucklings, GLP-2 decreased the width of five villi, Dex alone had no effect, whereas GLP-2 plus Dex increased all the morphological parameters of the intestine (Table 2).
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Table 1. The effect of treatment of suckling rats with GLP-2, Dex, and GLP-2 + Dex on jejunal morphology of the suckling offspring
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Table 2. The effect of treatment of suckling rats with GLP-2, DEX, and GLP-2 + DEX on ileal morphology of the suckling offspring
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In the jejunum of weanlings, GLP-2, Dex, and GLP-2 plus Dex increased the width of five cells, indicating an increase in enterocyte size; GLP-2 plus Dex also increased the villous height (Table 3). In the ileum of weanlings, GLP-2 by itself had no effect, Dex increased the villous height and cell size, whereas GLP-2 plus Dex decreased the villous width, crypt depth, width of five villi, and enterocyte size (Table 4).
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Table 3. The effect of treatment of suckling rats with GLP-2, Dex, and GLP-2 + Dex on jejunal morphology of the weanling offspring
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Table 4. The effect of treatment of suckling rats with GLP-2, Dex, and GLP-2 + Dex on ileal morphology of the weanling offspring
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Lipid Uptake
Because of the influence of GLP-2 and Dex on the morphology and characteristics of the intestine (Tables 14), lipid uptake was expressed on the basis of the weight of the mucosa (Jm; nmol·100 mg mucosal tissue1·min1).
In sucklings, GLP-2 had no effect on the jejunal or ileal uptake of lipids (Table 5). Dex increased the uptake of 18:3 in the jejunum. GLP-2 plus Dex had no effect on jejunal or ileal uptake.
In weanlings 4 wk after the previous injection of GLP-2, there was no difference in the jejunal or ileal uptake of lipids (Table 6). In contrast, Dex increased the ileal uptake of 18:0, and GLP-2 plus Dex increased the ileal uptake of 12:0, 18:0, 18:1, 18:2, and 18:3.
The ileal uptake of 12:0 and cholesterol was lower in weanlings than in sucklings (Table 7). Giving GLP-2, Dex, or GLP-2 plus Dex directly to the suckling rats did not affect this age-dependent decline in lipid uptake.
Immunohistochemistry
GLP-2 plus Dex did not change the abundance of I-FABP or L-FABP in the ileum of the weanlings (data not shown).
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DISCUSSION
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GLP-2 in a dose of 5 µg/day (
0.16 µg·g body wt1·day1, slightly greater than our dose of 0.1 µg·g body wt1·day1) given for 10 days enhances the intestinal uptake of [14C]triolein in adult mice (4) and improves fat absorption measured by balance studies in humans (dose
0.01 µg·g body wt1·day1) (24). Also, the intestinal absorption of other nutrients, such as leucine (4) and sugars (810), is enhanced in adult rats after the administration of GLP-2. In contrast, when GLP-2 treatment was given subcutaneously for 10 days to the suckling rats, there was no effect on lipid uptake (Tables 5 and 6). GLP-2 had no effect on body weight in the suckling or weanling rats (data not shown), although in previous studies, GLP-2 enhanced the body weight of adults (24, 36). Also, GLP-2 has a trophic action on the adult intestine (12, 13). In sucklings, the total weight of the ileum was increased as well as the crypt depth (Table 2). Furthermore, when GLP-2 is given with Dex, there was a marked enhancement in the ileal morphology in the suckling rats. This suggests that GLP-2 given to suckling rats has a modest trophic effect, which may be facilitated by the coadministration of Dex.
The finding of only a modest effect of GLP-2 on intestinal morphology when given alone was surprising, because receptors for GLP-2 (GLP-2R) are present in the intestine of young rats, and, in fact, their level is higher at this time than in adults (7, 26). Of interest, Petersen and co-workers (33) showed a lack of any trophic effect for GLP-2 in the intestine of pigs when given before birth. Our data suggest that the GLP-2Rs in the young animals are capable of responding to this dose of GLP-2 with only very modest changes in the characteristics of the intestine but with no alteration in lipid uptake. Therefore, whereas GLP-2Rs are present in the developing intestine, the receptors may be less responsive to GLP-2 than those receptors found in the mature intestine. Clearly on the basis of our data, it is unlikely that GLP-2 would be useful to accelerate intestinal morphological development or to enhance lipid absorption in young animals.
Glucocorticosteroids such as Dex are capable of accelerating the ontogeny of the intestine, including enhancing the absorption of nutrients such as sugars and amino acids (5, 20, 21). Glucocorticosteroids also enhance the intestinal uptake of lipids in adult rats (39, 40). Dex increased the uptake of 18:3 (Table 5), and in the jejunum, this was associated with an increase in villous height, villous width, and crypt depth (Table 1). Thus Dex is capable of stimulating morphological changes, however, intestinal lipid uptake was largely unchanged.
A major finding in this study was the stimulating effect of GLP-2 plus Dex on lipid uptake into the ileum, not at the time of injection, but rather 4 wk later in weanlings (Table 6). This was not obviously due to any change in body weight (data not shown), intestinal characteristics (data not shown), villous morphology (Table 4), or the abundance of the enterocyte lipid binding proteins I- or L-FABP (data not shown). Other workers have also observed that changes in I-FABP abundance do not necessarily reflect alterations in lipid uptake (1, 43).
The late effect of early nutrition has been described previously, and the concept of "critical period programming" is documented (25, 30). For example, changes in the dietary content of carbohydrates, lipids, or proteins during the suckling or weanling period influence the morphology and/or the nutrient uptake in the intestine (25, 41, 42). Moreover, the maternal diet consumed during pregnancy and nursing influences the intestinal morphological development and the absorption of nutrients in the offspring (22, 31).
Thus, whereas GLP-2 does not appear to be stimulating to the suckling intestine, it does have an effect on the morphology and function of the postweaning intestine when combined with Dex. These studies did not establish the mechanism(s) of this late effect of GLP-2 plus Dex. The persistent enhanced uptake of lipids (Table 6) and trophic changes in the crypt-villous morphology (Tables 3 and 4) seen in the weanlings exposed 1 mo previously to GLP-2 plus Dex raises the possibility that these alterations may continue into later life and could, thereby, potentially contribute to unwanted abnormalities in lipid absorption. It would be important for future studies to clarify this issue and especially to determine whether there is continued hyperabsorption of lipids and whether this has any adverse influence on the animal's body weight later on or on the development of hyperlipidemia.
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FOOTNOTES
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Address for reprint requests and other correspondence: A. B. R. Thomson, Univ. of Alberta, 205 College Plaza, 8215 112 St., Edmonton AB T6G 2C8 (E-mail: alan.thomson{at}ualberta.ca)
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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