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Nutrient-Gene Interactions

Dietary -Linolenic Acid–Rich Diacylglycerols Reduce Body Weight Gain Accompanying the Stimulation of Intestinal ß-Oxidation and Related Gene Expressions in C57BL/KsJ-db/db Mice

Biological Science Laboratories, Kao Corporation, Ichikai, Haga, Tochigi 321-3497, Japan

¹To whom correspondence should be addressed. E-mail: tokimitsu.ichirou{at}kao.co.jp.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Dietary fat contributes to the development of obesity. We examined the effect of dietary diacylglycerol (DG), which is a minor component of edible oils, on the development of obesity and expression of genes involved in energy homeostasis in C57BL/KsJ-db/db mice. Mice were fed diets containing either 14 g/100 g (%) triacylglycerol (TG), 10% TG + 4% -linolenic acid-rich TG (ALATG), or 10% TG + 4% -linolenic acid-rich diacylglycerol (ALADG) for 1 mo. Mice fed ALADG, but not ALATG had less body weight gain and higher rectal temperature than the TG-fed controls. These effects were accompanied by up-regulation of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase, fatty acid binding protein, and uncoupling protein (UCP)-2 mRNA and ß-oxidation activity in the small intestine. In contrast, the treatments did not affect ß-oxidation and related gene expressions in the liver or UCP-3 mRNA level in skeletal muscle. These results indicate that stimulation of lipid metabolism in the small intestine might be closely related to the antiobesity and thermogenic effects of dietary DG. In addition, structural differences between DG and TG, not variations in the composition of fatty acids, are responsible for the different effects of the lipids.

KEY WORDS: • diacylglycerol • -linolenic acid • small intestine • obesity • mice

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Obesity is a worldwide health problem that results from a disequilibrium between energy intake and expenditure, and is a strong risk factor for noninsulin-dependent diabetes mellitus associated with insulin resistance (1 ,2 ). Because high fat intake has been shown to contribute to the development of both obesity and diabetes in humans and rodents, numerous studies on the bioavailability of various lipids have been conducted for possible use in the management of obesity (3 –6 ). Fish and perilla oils rich in (n-3) polyunsaturated fatty acids (PUFA)² are considered to be favorable dietary components for alleviation of obesity. Dietary (n-3) PUFA have been reported to reduce the activities of enzymes involved in fatty acid and triacylglycerol (TG) synthesis, and to stimulate fatty acid oxidation and thermogenesis in the liver, skeletal muscle and adipose tissue (7 –9 ). Thus, certain dietary oils, possibly because of their constituent fatty acids, beneficially affect lipid metabolism in various organs and thereby, obesity and diabetes.

Diacylglycerols (DG) are a minor component of various edible oils and are composed mainly of 1,3-species. Previous studies have shown that structural differences in DG and TG, but not differences in the composition of fatty acids, alter the effects of dietary lipids (10 –13 ). We showed recently that dietary DG suppressed high fat and high sucrose diet–induced body fat accumulation in C57BL/6J mice more than did dietary TG of similar fatty acid composition (13 ). Hara et al. (11 ,12 ) reported that after a single dose of DG emulsion, the increase in postprandial serum TG, especially of chylomicron TG, was less than that in rats administered a TG emulsion, suggesting that intestinal events play an important role in the effects and the fate of acylglycerols. Furthermore, because the small intestine is the first and most susceptible organ to dietary fat, it is likely that the structures of acylglycerols directly influence intestinal function. However, little is known about the dietary effect of oils, including DG, on lipid metabolism in the small intestine or on the development of obesity.

To investigate the antiobesity effect of dietary DG, we examined the effects of dietary supplementation of DG containing mainly -linolenic acid (ALA) as the constituting fatty acid (ALADG) in genetically obese C57BL/KsJ-db/db mice, which develop severe obesity because of their leptin signaling deficiency (14 ). They exhibit increased food intake, increased body weight and decreased energy expenditure (15 ,16 ). Furthermore, to identify the mechanisms of action at the molecular level, we examined the mRNA expression of genes involved in lipid metabolism and thermogenesis in various organs.

	MATERIALS AND METHODS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Test oils.

The TG oil was prepared by mixing soybean and rapeseed oil. The -linolenic acid-rich DG oil (ALADG) was prepared by esterifying glycerol with fatty acids from linseed oil (ALATG) as described previously (17 ). The fatty acid composition of ALADG was similar to that of ALATG (Table 1 ). The ALADG preparation contained 82% DG and 17% TG. The ALADG was comprised of 1,3-DG and 1,2-DG at a ratio of 7:3.

Female C57BL/KsJ-db/db mice (n = 24) obtained from Japan Clea (Tokyo, Japan) at 5 wk of age were maintained at 22 ± 1°C under a 12-h light:dark cycle (lights on from 0700 to 1900h). Mice were divided into three groups (n = 8, 4 mice/cage), and were allowed free access to water and one of the three synthetic diets (Table 2 ) using Roden caffe (Oriental Yeast, Tokyo, Japan) to minimize dispersion of diets. Mice were fed these diets for 1 mo. During the experiments, the mice were cared for in accordance with the principles for the use of animals for research and education, following the Statement of Principles adopted by the FASEB Board.

Body weight was measured weekly throughout the study. Food intake was measured on a per-cage basis throughout the study.

Body temperature measurements.

The rectal temperature of each mouse was measured with a digital thermometer equipped with a rectal probe 1 mm in diameter (Technol Seven, Yokohama, Japan). The probe was inserted 20 mm into the rectum, and the temperature was recorded after stabilization for 10 s.

Blood analysis.

On the final day of experiment, blood was collected via the postcaval vein from anesthetized mice that had not been deprived of food. Plasma TG, total cholesterol and glucose concentrations were determined using the enzyme assay kits (L-type Wako TG-H, L-type Wako CHO-H, and L-type Wako Glu2, respectively; Wako, Osaka, Japan). Plasma insulin and leptin levels were measured using a mouse insulin enzyme immunoassay (EIA) kit and leptin EIA kit (Morinaga, Yokohama, Japan) according to the manufacturer’s instructions.

ß-Oxidation.

ß-Oxidation was measured as previously reported (18 ), with minor modifications. Frozen mouse liver and intestinal mucosa were thawed and homogenized on ice with 5 volumes of 250 mmol/L sucrose containing 1 mmol/L EDTA and 10 mmol/L HEPES (pH7.2), and centrifuged at 600 x g for 5 min. The resultant supernatant was used for assay. The reaction mixture contained Dulbecco’s PBS (pH 7.2), 1 mmol/L ADP, 2 mmol/L ATP, 1 mmol/L MgCl₂, 0.25 mmol/L CoA, 1 mmol/L L-carnitine, 0.5 mmol/L L-malic acid, 1 mmol/L NAD⁺, 1 mmol/L FAD, 1 mmol/L dithiothreitol, (3.7 kBq) [¹⁴C]-palmitic acid and the extract containing 100 µg protein in a final volume of 200 µL. The reaction was started by adding the substrate and incubating the preparation at 37°C for 25 min. The reaction was terminated by adding 200 µL of 0.6 mol/L perchloric acid, followed by centrifugation (2000 x g, 10 min). The supernatant was extracted three times with 800 µL of n-hexane to remove residual radiolabeled palmitate. Radioactivity of the water phase was measured. Protein concentrations were determined using a DC protein assay kit (Bio Rad, Hercules, CA).

RNA extraction and Northern blot analysis.

The small intestine, liver, and skeletal muscle (gastrocnemius and soleus) were dissected from each mouse and frozen in liquid nitrogen for subsequent RNA isolation. Total RNA was isolated using Isogen (Wako) according to the manufacturer’s instructions. Purified RNA (20 µg) was electrophoresed on 1% agarose/formamide gels, and blotted onto Hybond-N+ membranes (Amersham Pharmacia Biotech, Buckinghamshire, UK). Blotted membranes were hybridized with a ³²P-labeled cDNA probe at 42°C overnight. Membranes were washed in 2X SSC/0.1% SDS at room temperature, and again in 0.1X SSC/0.1% SDS at 50°C, then autoradiographed and analyzed with a BAS2000 bioimage analyzer (Fuji Photo Film, Tokyo, Japan). The membranes were also hybridized with a ³²P-labeled ubiquitin probe (Sigma Chemical, St. Louis, MO), and the mRNA levels were calculated relative to the ubiquitin mRNA levels. Normalized values are expressed as percentages, with the value in mice fed the TG diet set at 100%.

Each cDNA probe was prepared by reverse transcription and polymerase chain reaction (RT-PCR) by use of first-strand cDNA from mouse or rat tissue total RNA. The PCR-generated cDNA probes were as follows: acyl-CoA oxidase (ACO) (Genbank AF006688, nt 218–880), MCAD (J02791, nt 671-1199), UCP-2 (AB012159, nt 296-1225), liver fatty acid binding protein (L-FABP; J00732, nt 1–440). Peroxisome proliferator-activated receptor (PPAR) and ubiquitin cDNA probes were purchased from Sigma Chemical. cDNA probes were radiolabeled with [-³²P]dCTP using Ready-To-Go DNA labeling beads (Amersham Pharmacia Biotech).

Statistical analysis.

All values are presented as means ± SD. ANOVA and Fisher’s protected least significant difference test (StatView; SAS Institute, Cary, NC) were used to analyze the differences and data were considered significant at P < 0.05.

	RESULTS

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Energy intake, body weight gain, body temperature and blood chemistry.

There were no differences in the energy intake among the three groups (Table 3 ). Compared with mice fed the TG diet, supplementation with ALADG, but not with ALATG, reduced body weight gain, indicating that dietary ALADG more effectively suppress body weight increase than ALATG, despite their similar fatty acid compositions. Rectal temperatures did not differ between the TG and ALATG diet groups, but were elevated in those fed ALADG (Table 3) . Plasma lipids, glucose and insulin did not differ among the three groups, whereas plasma leptin concentration in ALADG-fed mice was lower than in the other two groups (Table 4 ).

ALADG increased small intestine ß-oxidation activity by 171 and 58% compared with the TG and ALATG diet groups, respectively, indicating that it stimulates lipid catabolism in this tissue (Fig. 1 ). Activity in the ALATG-fed group was greater than in controls. Hepatic ß-oxidation did not differ among the groups (Fig. 1) .

View larger version (19K): [in this window] [in a new window]   FIGURE 1 ß-Oxidation activity in the small intestine and liver of mice fed triacylglycerol (TG), -linolenic acid-rich diacylglycerol (ALADG) or -linolenic acid-rich triacylglycerol (ALATG) for 1 mo. Values are means ± SD, n = 8; those without a common letter differ, P < 0.05.

In mice fed the ALADG diet, the ACO mRNA level in the small intestine was higher than that in mice fed the TG or the ALATG diets (Fig. 2 ). When normalized to the level of ubiquitin mRNA, the ACO mRNA levels in ALADG-fed mice were 73.9 and 41.5% higher than those in the TG and ALATG diet groups, respectively. Medium-chain acyl-CoA dehydrogenase (MCAD) mRNA levels in ALADG-fed mice were 33.5 and 71.7% greater than those of the TG- and ALATG diet-fed mice, respectively. These results indicate that dietary ALADG up-regulate gene expression of ß-oxidation enzymes in the small intestine. The L-FABP mRNA level in the small intestine was higher in mice fed ALADG than in mice fed ALATG, but it did not differ from the level in TG-fed mice.

View larger version (57K): [in this window] [in a new window]   FIGURE 2 Gene expression in the small intestine of mice fed triacylglycerol (TG), -linolenic acid-rich diacylglycerol (ALADG), or -linolenic acid-rich triacylglycerol (ALATG) for 1 mo (A). The amounts of mRNA were expressed as percentages of the corresponding amounts in the TG group (B). Values are means ± SD, n = 8; those without a common letter differ, P < 0.05. Abbreviations: ACO, acyl-CoA oxidase; MCAD, medium-chain acyl-CoA dehydrogenase; L-FABP, liver-fatty acid binding protein; UCP-2, uncoupling protein 2; PPAR, peroxisome proliferator-activated receptor .

PPAR controls the gene expression of various molecules in the liver and small intestine, including fatty acid metabolizing enzymes and UCP (22 –24 ). However, its mRNA level did not differ among the groups, indicating that up-regulation of intestinal gene expression is not due to changes in PPAR mRNA per se. Levels of apolipoprotein E mRNA also did not differ among the groups (data not shown).

Gene expression in the liver and skeletal muscle.

The three groups did not differ in the mRNA levels of ACO, MCAD, L-FABP or PPAR in the liver (data not shown). UCP-3, which is expressed predominantly in skeletal muscle, contributes to whole-body energy expenditure and obesity (25 ). However, the skeletal muscle UCP-3 mRNA level was not influenced by the diet treatments (data not shown).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Many studies have examined the possibility of modifying obesity by dietary intervention (4 –6 ). The fatty acid composition of dietary oils markedly affects the physiologic actions of these oils. Dietary (n-3) PUFA have been reported to reduce body fat deposition by inducing the expression of genes involved in lipid metabolism and thermogenesis, thereby increasing total body heat generation (5 –7 ,26 –28 ). Thus, certain dietary oils, likely because of their constituent fatty acids, show beneficial effects on lipid metabolism and therefore on obesity. In contrast to previous reports, the present study showed that the structure of acylglycerols, not the fatty acid composition, affects intestinal gene expression, heat generation and body weight.

Most of the previous studies focused on biological alterations in the liver, adipose tissues and skeletal muscle. In fact, these organs do play a crucial role in energy homeostasis. However, despite its importance to lipid absorption and metabolism, little attention has been given to dietary effects and the role of the small intestine in relation to obesity. Among the organs examined here, the most marked DG diet–induced changes were in intestinal ß-oxidation and related gene expressions (Fig. 1 ,2) . The ALADG diet up-regulated the mRNA expression associated with fatty acid transport (L-FABP) and mitochondrial and peroxisomal ß-oxidation (MCAD and ACO) in the small intestine, whereas the ALATG diet did not, suggesting that the DG structure potently stimulates intestinal lipid metabolism. Compared with the TG group, intestinal ß-oxidation was stimulated by ALADG supplementation and, to a lesser extent, by ALATG (Fig. 1) . Stimulation of ß-oxidation by ALATG might be due to the effect of its constituent -linolenic acid, a stimulator of ß-oxidation (8 ,9 ). In contrast to the ß-oxidation activity, the mRNA levels examined were not affected by ALATG (Fig. 2) .

It is noteworthy that the level of UCP-2 mRNA was increased in the small intestine of mice fed ALADG. UCP are mitochondrial proton transporters that uncouple oxidative phosphorylation by dissipating the proton gradient across the membrane, and this activity has been proposed to influence thermogenesis and the development of obesity (19 –21 ,29 ). Although the ultimate physiologic function of UCP-2 has not been fully elucidated, it is likely that increased expression of intestinal UCP-2 and accompanying ß-oxidation would increase thermogenesis and contribute to the suppression of body fat accumulation. These results, together with the large size of the small intestine, suggest an important contribution of this organ to whole-body energy metabolism and the antiobesity effect of dietary DG. Furthermore, in light of these findings, up-regulation of intestinal lipid metabolism may be at least partially responsible for the decrease in the postprandial serum TG level due to DG in previous studies (11 ,12 ). Given that impaired postprandial TG clearance has been shown to be associated with visceral obesity (30 ,31 ), stimulation of intestinal lipid metabolism may explain the antiobesity effect of dietary DG.

Although the precise molecular mechanism by which dietary DG stimulate intestinal gene expression remains to be elucidated, a characteristic metabolic pathway of DG may be involved in the process. The majority of ingested TG is hydrolyzed to 2-monoacylglycerol (MG) and fatty acids, then absorbed into intestinal mucosal cells and resynthesized into TG, which are assembled into chylomicrons and secreted into lymph (32 –34 ). In contrast, although the precise metabolic pathway of 1,3-DG has not been clarified, it likely is hydrolyzed to form 1(or 3)-MG and fatty acid, which is probably further hydrolyzed into glycerol or absorbed by the mucosa. Thus, the metabolic pathway and mucosal lipid profile of 1,3-DG are probably different from those of TG. In fact, our preliminary studies have shown that 1,3-DG was digested mainly to 1 (3)-MG and fatty acid in the intestinal lumen, and that the content of 1 (3)-MG and fatty acids in the intestinal mucosa was increased in rats (data not shown). Increases in fatty acids have been reported to up-regulate gene expression through PPAR activation, suggesting that intestinal energy metabolism is influenced by dietary acylglycerols both directly and indirectly.

In summary, we showed that dietary DG are beneficial for the suppression of body weight gain, and that their effects are accompanied by up-regulation of genes involved in lipid metabolism and thermogenesis in the small intestine in C57BL/KsJ-db/db mice. We have also confirmed that the structural difference between DG and TG is responsible for the different effects of the lipids. Understanding the characteristics of dietary DG and their molecular mechanisms, especially in the small intestine, may lead to new insights useful in the management of obesity.

	FOOTNOTES

 
² Abbreviations used: ACO, acyl-CoA oxidase; ALA, -linolenic acid; ALADG, -linolenic acid–rich diacylglycerol; ALATG, -linolenic acid-rich triacylglycerol; DG, diacylglycerols; EIA, enzyme immunoassay; L-FABP, liver-fatty acid binding protein; MCAD, medium-chain acyl-CoA dehydrogenase; MG, monoacylglycerol; PPAR, peroxisome proliferator-activated receptor; PUFA, polyunsaturated fatty acids; TG, triacylglycerols; UCP, uncoupling protein.

Manuscript received 28 February 2002. Initial review completed 2 April 2002. Revision accepted 24 June 2002.

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