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,1
* Division of Functional Histology, Department of Integrated Basic Medical Science and Division of Biochemical Pharmacology, Department of Fundamental Medical Science, School of Medicine, Ehime University, Shitsukawa, Toon City, Ehime, 791-0295, Japan
1 To whom correspondence should be addressed. E-mail: yokim{at}m.ehime-u.ac.jp.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • high-fat • high-sucrose • glucose intolerance • obesity • lean
Insulin resistance is associated with a number of metabolic disorders such as obesity, hyperlipidemia, and hypertension. These factors can increase the risk of coronary heart disease (1,2). Both genetic and environmental factors contribute to the development of metabolic abnormalities. Diet represents one environmental factor that can influence a metabolic disorder. Several experimental studies demonstrated that the macronutrient composition of a diet is an important environmental determinant of the quality of insulin action (3–6).
High-fat (HF)2 and high-sucrose (HS) intakes were shown to contribute to syndromes such as hyperlipidemia, glucose intolerance, hypertension, and atherosclerosis (7–9). Numerous studies showed that a HF and/or HS diet induces insulin resistance in rodents (10–14). The pathogenesis of insulin resistance caused by HF and/or HS is unclear. It was reported that excess circulating free fatty acids (FFA) and glucose may contribute to insulin resistance (15,16).
On the other hand, it was reported that adipocytokines such as leptin, adiponectin, tumor necrosis factor (TNF)-
, plasminogen activator inhibitor (PAI)-1, and IL-6 are secreted from adipose tissue. The alteration of lipid metabolism and the secretion of adipocytokines in adipose tissue may be critical for the development of lifestyle-related diseases such as obesity, hyperlipidemia, diabetes, hypertension, and atherosclerosis.
Thus, it is important to clarify the mechanisms underlying the metabolic disorders that result from the long-term consumption of HF or HS diets. A HF diet causes obesity, and it seems likely that obesity contributes to insulin resistance (17). On the other hand, it is unclear whether insulin resistance due to long-term consumption of a HS diet is associated with obesity. The diabetes- and obesity-prone C57BL/6 mouse fed a HF diet is a good model of human obesity and type II diabetes (18–20).
In this study, we examined the effects of consuming high-fat or high-sucrose diets for a long time (55 wk) on insulin resistance and lipid metabolic alterations in C57BL/6J mice.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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antibody was obtained from Santa Cruz Biotechnology. Human recombinant insulin was purchased from Novo Nordisk. 3-Hydroxy-3-methyl [3-14C] glutaryl-CoA and [1-14C] acetyl-CoA were obtained from Amersham Biosciences UK. [9,10-3H(N)]-triolein and [1-14C]-palmitic acid were from Perkin Elmer Life Sciences. Other chemicals were of reagent grade. Animals and diets. Male C57BL/6J mice (4 wk old) were obtained from Japan SLC and housed in a room with a 12-h light:dark cycle and controlled for temperature and humidity. They were fed a standard laboratory diet (8 g water, 51.3 g crude carbohydrate, 24.6 g crude protein, 5.6 g crude lipid, 3.1 g crude fiber, 6.4 g mineral mixture, and 1 g vitamin mixture/100 g diet; Oriental Yeast) for 1 wk to adapt to the lighting conditions. After this period of adaptation, they were given free access to water and the experimental diets (Table 1) for 55 wk. The diets were a low-fat low-sucrose (LL) diet (3% fat, 5% sucrose, wt/wt), a HF diet (45% fat, wt/wt), and a HS diet (50% sucrose, wt/wt). Body weight and food intake were recorded weekly. Because both the LL and HS diets contained water, intake of these diets was corrected using the dry weight of the diet. The energy intakes of the mice fed the diets were constant throughout the experiment [kJ/(mouse·d): LL, 54.50 ± 0.53; HS, 52.67 ± 0.55; HF, 47.89 ± 0.49].
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Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). The OGTT was carried out at wk 6 and every 5 wk beginning at wk 10. After at least 4 h of food deprivation, glucose (556 µmol/mouse) was administered orally to the mice. The ITT was conducted at wk 5, 15, and 45. After 4 h of food deprivation, insulin (5.6 nmol/kg) was injected i.p. Blood samples were taken from the tail at the indicated times and blood glucose concentrations were measured using GLUCOCARDTM (GT-1640, Arkray). In the OGTT at wk 40, the plasma was separated and insulin was measured using the ELISA kit.
Plasma measurements. At wk 55, blood was obtained by venous puncture from mice anesthetized with NEMBUTAL® (Dainippon Pharmaceutical). Plasma was separated by centrifugation (2000 x g; 15 min) and frozen at –20°C. Triglyceride (TG), total cholesterol (TC), and FFA concentrations in the plasma at wk 55 were determined using the respective test kits; insulin, leptin, adiponectin, and monocyte chemoattractant protein 1 (MCP-1) concentrations in plasma were measured using the respective ELISA kit.
Liver lipid concentrations. TG and TC concentrations in liver were measured by the methods of Fletcher (22) and Zak et al. (23).
Histological examination. Epididymal adipose tissue was fixed in 10% (v/v) buffered formalin, embedded in paraffin, and sectioned. The epididymal adipose tissue segments were stained with hematoxylin and eosin. The plates were photographed, and >100 adipose cells were randomly selected and their cell diameters measured.
Enzyme activities
Lipoprotein lipase (LPL). LPL activity in muscle and epididymal adipose tissue was determined as described by Iverius et al. (24). Tissue was homogenized in 0.178 mol/L Tris buffer, pH 8.2, containing 0.25 mol/L sucrose, 2 g/L deoxycholate, and 50 mg/L heparin. After centrifugation at 12000 x g, the supernatant was used for the assay.
Lipolysis. Epididymal adipose tissue (50 mg) was added to HBSS (pH 7.4) containing 2.5% bovine serum albumin with or without norepinephrine (0.1 µmol/L; Wako Pure Chemical) and insulin (1 nmol/L; Wako Pure Chemical). After incubation at 37°C for 30 min, the FFA released was determined by the method of Han et al. (25) using copper reagent.
Glucose-6-phosphatase (G6Pase). The liver microsomal fraction was separated by the method of Daniele et al. (26) with slight modifications. Briefly, the liver was cut and homogenized immediately on ice in 10 mmol/L HEPES buffer (pH 7.2) containing 0.25 mol/L sucrose and protease inhibitor, using a Teflon glass homogenizer. The homogenate was centrifuged at 9000 x g for 20 min at 4°C; the supernatant was then further centrifuged at 105,000 x g for 60 min at 4°C. The microsomal pellet was suspended in homogenized buffer. The assay quantified the amount of inorganic phosphate (Pi) released from glucose-6-phosphate (G6P) as G6Pase activity. The microsomal fraction was added to 20 mmol/L Tris buffer (pH 7.4) containing 5 or 20 mmol/L G6P, and incubated at 37°C for 10 min. The reaction was stopped by the addition of 8% trichloroacetic acid, and Pi was determined by the methods of Fiske and Subbarow (27).
3-Hydroxymethylglutaryl CoA (HMG-CoA) reductase. The liver microsomal fraction was separated by the method described above. The microsomal pellet was suspended in 0.1 mol/L phosphate buffer (pH 7.4), and added to a reaction mixture containing 0.128 mmol/L HMG-CoA (14C-HMG-CoA, 144 MBq/mmol), 1 mmol/L NADPH, 10 mmol/L dithiothreitol, and 10 mmol/L EDTA in 0.12 mol/L phosphate buffer (pH 7.4). The mevalonic acid released was separated on a silica gel 60 F254 TLC plate (Merck) (28). The plate was exposed to an imaging plate (Fuji film), and examined with an imaging analyzer BAS 1000 (Fuji film).
Fatty acid synthase (FAS). The liver was homogenized on ice in 10 mmol/L HEPES buffer (pH 7.2) containing 0.25 mol/L sucrose and protease inhibitor, and centrifuged at 12,000 x g for 10 min at 4°C. The activity was determined by measuring the incorporation of 14C-acetyl-CoA into fatty acids (29). The reaction was stopped by the addition of chloroform:methanol (2:1, v:v), and mixed using a vortex mixer. After centrifugation (1500 x g; 10 min), the supernatant was removed by aspiration, and the residue was washed twice with water under acidic conditions. The residual radioactivity was quantified with a liquid scintillation counter.
Sucrase. The mucosa of the small intestine was scraped off on ice and homogenized in PBS. After centrifugation at 600 x g for 10 min at 4°C, the supernatant was used for the assay (30). The glucose concentration was determined with a Glucose C-II Test Kit (Wako Pure Chemical).
Immunoblotting.
Muscle was homogenized in a solubilizing buffer [50 mmol/L HEPES buffer (pH 7.4) containing 5 mmol/L EDTA, 150 mmol/L NaCl, 1% TritonX-100 and protease inhibitor] and then centrifuged at 12,000 x g for 15 min at 4°C. The amount of protein in the supernatant was measured using a protein assay reagent (Bio-Rad). After denaturing at 99°C, the protein was resolved by SDS-PAGE. The gel was transferred to polyvinylidene fluoride membrane, and the membrane was blocked with 5% skim milk. The membrane was incubated with anti-PPAR antibody (1:250). Immunoreactivity was visualized with alkaline phosphatase-conjugated goat anti-rabbit IgG (ICN Pharmaceuticals) and the ECF system (Amersham Biosciences).
Statistical analysis. All values are expressed as means ± SEM. Data were analyzed by 1-way, 2-way, or repeated-measures ANOVA. When the F-test was significant, means were compared using Fisher's Protected LSD test with StatView (SAS Institute). Differences were considered significant at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Lipolysis in adipose tissue. Basal lipolysis did not differ among the 3 groups (µmol FFA released/g epididymal adipose tissue) LL: 2.32 ± 0.50, HS: 2.79 ± 0.45, HF: 1.98 ± 0.24. The basal lipolysis per fat pad in mice fed the HF diet was greater than that in mice fed the LL or HS diet. Therefore, at least in mice fed the HF diet, the plasma FFA level may depend on the volume of adipose tissue as a source of FFA. On the other hand, lipolysis in mice fed the LL diet and HS diet was significantly increased by the addition of norepinephrine, but it was not increased by adding norepinephrine to the adipose tissue of mice fed the HF diet. Norepinephrine-induced lipolysis in all 3 groups was not affected by insulin (Fig. 2A).
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PPAR protein and LPL activity in skeletal muscle.
TG concentrations in femoral muscle were reduced in mice fed the HS diet (0.38 ± 0.06 µmol/ g protein), compared with those fed the LL diet (0.55 ± 0.05 µmol/mg protein) or HF diet (0.56 ± 0.06 µmol/mg protein; P < 0.05). Muscle LPL activity was lower in mice fed the HF (0.25 ± 0.02 µmol FFA released /mg protein) and HS diets (0.28 ± 0.03 µmol FFA released /mg protein) compared with that of mice fed the LL diet (0.42 ± 0.04 µmol FFA released /mg protein; P < 0.05).
The amount of PPAR protein in muscle was greater in mice fed the LL diet than in those fed the HS diet or HF diet (data not shown).
OGTT and ITT. In the OGTT, the concentration of blood glucose of mice fed the LL and HS diets increased to a maximum at 10 min after the oral administration of glucose, and then declined to the basal value (Fig. 3A). At wk 10, the plasma glucose concentration at 10 min was higher in mice fed the HS diet than in those fed the HF or LL diets. On the other hand, the glucose levels of mice fed the HF diet were significantly higher at 20, 30, and 60 min after the oral administration of glucose than those of mice fed the LL or HS diet, and the glucose levels at 10 to 60 min in mice fed the HF diet were maintained. The glucose concentrations at 10, 20, 30, and 60 min after the oral administration of glucose did not differ in this group. Thus, glucose clearance in mice fed the HF diet at wk 10 was impaired compared with that in mice fed the LL and HS diets (Fig. 3A). At wk 30 and 50, the concentration of glucose in the blood increased to a maximum at 10 min in all groups. The glucose levels of HS diet-fed mice at 10 min after administration were higher than those of mice fed the LL and HF diets. On the other hand, the blood glucose levels at 20, 30, or 60 min in the HF diet-fed mice were less (P < 0.05) than the maximal glucose levels at 10 min, at wk 30 and/or 50. Thus, at wk 30 and 55, the clearance of glucose from the blood after oral administration was apparently improved in the mice fed the HF diet (Fig. 3A). The different types of impaired glucose tolerance were caused by feeding the HS diet and the HF diet for a long time.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, and PAI-1. PPAR
induces adipocytes to differentiate, and leptin and adiponectin are involved in the metabolism of glucose and lipids. In the present study, we found that long-term feeding of a HF diet to mice caused obesity, with increases in fat volume, fat size (Fig.1 and Table 2), and PPAR protein levels (data not shown). Insulin did not affect epididymal adipose tissue lipolytic activity (Fig. 2A). Other features of obese mice included elevated TG and PPAR concentrations in muscle, reduced muscle LPL activity, increased hepatic TG concentrations, increased plasma FFA, insulin, and leptin concentrations, and glucose intolerance after an ITT. Although circulating FFA upregulate the secretion of insulin from the pancreas (31), the increase in FFA induces peripheral insulin resistance (15,32). It was reported that the accumulation of TG and the reduction of PPAR expressions in muscle may cause insulin resistance (33). In the present study, the muscle TG concentrations in the HF and LL diet-fed mice were greater than those of the HS diet-fed mice. Furthermore, muscle PPAR expression in the HF and HS diet-fed mice was lower than that in the LL diet-fed mice. These findings suggest that the insulin resistance caused by feeding the HF diet for a long time may be due to the decrease in PPAR expression and the accumulation of TG in the muscle. Although the HS diet-fed mice had potent insulin sensitivity in the ITT, HS diet-fed mice demonstrated glucose intolerance in the OGTT. The glucose intolerance after feeding the HS diet cannot be explained by the reduction in muscle PPAR expression. Further studies are warranted to clarify the relation between PPAR expression and lipid metabolism in the muscle of HS diet-fed mice. Yamuuchi et al. (34) reported that adiponectin stimulated glucose utilization and FFA oxidation by activation of the 5'-AMP-activated protein kinase. However, the concentration of adiponectin did not differ among the groups (Table 3). Arita et al. (35) reported that levels of adiponectin were reduced in obese individuals and that the reduction was inversely correlated with an increase in visceral fat volume; on the other hand, it was reported that there was no relation between the plasma adiponectin level and obesity (36,37). In the present study, the adiponectin level, glucose intolerance, and visceral adipose tissue weight were not interrelated. The visceral fat weight of female C57BL/6J mice fed a HF diet for 70 wk was much greater than that of male mice; conversely, adiponectin levels were lower in the female mice than in the male mice (unpublished data). Insulin is a lipogenic hormone, acting to increase the expressions and activities of acetyl CoA carboxylase, FAS, malic enzyme, and HMG-CoA reductase (38). Recently, Najjar et al. (39) reported that acute insulin did not significantly reduce hepatic FAS activity in refed obese hyperinsulinemic (ob/ob) mice compared with normoinsulinemic mice, and suggested that this is consistent with the blunted ability of insulin to activate insulin receptors in chronic hyperinsulinemia. We found that hepatic FAS activity in mice fed the LL and HS diets was elevated compared with those fed the HF diet (Fig. 2B), but the FAS activity of HF diet-fed mice with hyperinsulinemia was not affected compared with the mice fed a laboratory diet (data not shown). Moreover, the HMG-CoA reductase in the HF diet-fed mice was lower than that in the LL and HS diet-fed mice (Fig. 2C) or laboratory diet-fed mice (data not shown). These findings also show that the HF diet causes insulin resistance of liver lipid metabolism. Therefore, it seems likely that the elevated plasma FFA levels in mice fed the HF diet may be associated with fat volume and basal lipolysis in white adipose tissue and the accumulation of TG in muscle and liver; consequently, the mice may develop insulin resistance and hyperinsulinemia (Table 3, 4, Fig. 2A). In addition, because hyperleptinemia was reported to suppress second-phase insulin secretion (40), we suggest that glucose intolerance in mice fed the HF diet in OGTT may be caused by the regulation of insulin secretion from the pancreas through higher levels of circulating FFA and leptin. Although atherosclerosis was not induced, a slight accumulation of lipids in the main artery occurred in mice fed the HF diet (data not shown). It was shown recently that MCP-1 is responsible for the macrophage accumulation in atherogenesis (41–43). Obesity is associated with the accumulation of macrophages and the overexpression of MCP-1 in adipose tissue (44,45). Plasma MCP-1 levels in HF diet-fed mice tend to be greater than those in LL or HS diet-fed mice (P < 0.08, Table 3). On the basis of these results in HF diet-fed mice, we suggest that the incidence of atherosclerosis may arise together with obesity by feeding a HF diet. It is of great interest that glucose intolerance differed between mice fed the HS and HF diets for a long period time (Fig. 3). In the OGTT, the Cmax of blood glucose (at 10 min) was higher in the mice fed the HS diet than in those fed the LL or HF diets. Thus, the blood glucose clearance in the HS diet-fed mice was impaired 10 min after OGTT (Fig. 3A), but the blood glucose concentration in the HS diet-fed mice was rapidly lowered by the ITT (Fig. 3B). The small intestinal sucrase activity was increased by feeding the HS diet for a long time. Furthermore, hepatic G6Pase activity was increased by feeding the HS diet for 25 wk, but its activity in mice fed that diet for 55 wk was not affected. Therefore, these findings suggest that the glucose intolerance in HS diet-fed mice is not associated with the hepatic gluconeogenesis, but rather may be due to a reduction in early insulin secretion from pancreatic islets and an increase in sucrase activity in the small intestine. Further studies are warranted to clarify the mechanisms (e.g., glucose-stimulated insulin release, glucose transporter expression in islets, and pancreatic injury).
Thus, we found that the excess consumption of fat and sucrose diets induced 2 different types of glucose intolerance not only in obese but also in lean mice. It is important to consider the effects of macronutrients lean as well as obese mice to clarify the pathogenesis of metabolic disorders. Further study is warranted to clarify the mechanisms of insulin resistance in both obese and lean animals fed the HF or HS diets for a long time.
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FOOTNOTES |
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Manuscript received 6 September 2005. Initial review completed 10 October 2005. Revision accepted 19 December 2005.
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