Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile

Abstract

OBJECTIVE: We recently reported that an 8-week high-fat diet-induced hepatic steatosis was completely prevented if an exercise training programme was introduced and pursued concurrently with the diet. The purpose of the present study was to determine the extent to which introducing exercise training at mid-point in the course of a 16-week high-fat diet regimen contributes to the reversal of liver lipid infiltration and the reduction of blood lipid profile deterioration and body fat accumulation.

DESIGN AND SUBJECTS: Two groups of rats were fed a high-fat diet (42% kcal) for 16 weeks, one remaining sedentary during this entire period (HF-Sed) and the other being exercise trained for the last 8 weeks (HF-Tr). A third group was fed a standard diet and remained sedentary for all 16 weeks (SD-Sed). Training (5 days/week for 8 weeks) began 8 weeks after introducing the high-fat diet and consisted of treadmill running that was progressively increased to reach 60 min at 26 m/min, 10% grade, for the last 4 weeks.

MEASUREMENTS: Various parameters including liver lipid infiltration, fat depots and blood lipids.

RESULTS: Unexpectedly, liver lipid infiltration was not significantly higher in HF-Sed than in SD-Sed rats (means±s.e.: 14.9±1.7 vs 12.3±0.4 mg/g; P>0.05). High-fat compared to age-matched standard fed rats also showed an absence of difference (P>0.05) in the weight of total visceral fat pads (13%), plasma nonesterified fatty acids (NEFA), and leptin concentrations, but depicted significantly (P<0.01) higher values for subcutaneous fat pad weight and plasma triacyglycerol. Exercise training largely decreased visceral and subcutaneous fat accumulation by 30 and 26%, respectively (P<0.01) as well as NEFA, triacylglycerol, and leptin concentrations (P<0.01).

CONCLUSION: Liver lipid infiltration does not seem to progress linearly over 16 weeks of high-fat feeding in light of what has previously been observed after 8 weeks of high-fat feeding. Introducing a training programme in the course of a 16-week high-fat diet protocol reduced adiposity, plasma NEFA, and leptin concentrations below the levels observed in standard fed rats. These data indicate that, exercise training, whether conducted concurrently or introduced during the course of a high-fat diet, is an asset to reduce the deleterious effects of a high-fat diet.

Introduction

It is well established that the ingestion of a high-fat diet induces deleterious metabolic effects including fat accretion in adipocytes, hyperlipidaemia, and insulin resistance in both rodents and human beings.1, 2, 3 Recent data also indicate that such high-fat diets result in liver lipid infiltration, which is now recognised as an integral part of the metabolic syndrome. More specifically, hepatic steatosis, which is characterised by an excessive accumulation of triacylglycerol within hepatocytes, has been associated with the development of insulin resistance and insulin signalling defects.4, 5, 6, 7, 8 As a consequence, information relative to the development and the reversal of hepatic steatosis has a clinical importance that might have been overlooked in the past studies. Specific concerns such as how physical training interacts with the development and reversal of hepatic steatosis become important to counteract deleterious metabolic effects resulting from high-fat diet-induced obesity.

Exercise training and a low-fat diet have long been prescribed as part of the treatment in the management of obesity and type II diabetes. Previous studies have shown that when imposed at the same time of a switch to a high-fat diet, exercise training attenuates excessive fat gain, blood lipid profile deterioration, and the development of an insulin-resistant state that would otherwise occur with sedentarity and high-fat feeding.9, 10, 11 Precise information on the role of exercise training as a preventive and/or a reversal agent of liver lipid infiltration is, however, relatively limited. Our group has recently reported data showing that exercise training pursued at the same time as an 8-week high-fat diet completely prevented the high-fat diet-induced macrovesicular hepatic steatosis.12 These data confirmed what has been reported in earlier studies using different approaches.13, 14 However, there are other studies reporting an absence of effects of exercise training on hepatic steatosis.15, 16 One of the reasons put forward to explain this discrepancy was that exercise training began after fatty liver had been induced. It was suggested that to be most effective, exercise must be concurrent with the induction of fatty liver.12 It is not known if exercise training introduced during the course of a high-fat diet may be beneficial to counteract some of the effects of the high-fat diet while maintaining the high-fat diet regimen. Such information may be important to incite people to undertake a programme of physical exercise, even if they do not intend to change their dietary habits. Moreover, it is not known how hepatic steatosis progresses if the high-fat feeding in rats is pursued beyond a short-term period (>8 weeks). The present study was designed to determine the extent to which exercise training, introduced in the course of a relatively long-term high-fat diet regimen (16 weeks), may contribute to the reversal of hepatic steatosis and its associated blood lipid profile deterioration and adipose tissue fat accumulation. To do this, exercise training was imposed during the last 8 weeks of a 16-week high-fat diet regimen in rats.

Methods

Animal care

Female Sprague–Dawley rats (n=27, Charles River, St Constant, PQ, Canada), 6 weeks old, weighing 180–200 g were housed by pairs and had free access to food and tap water. Their environment was controlled in terms of light (12:12-h light–dark cycle starting at 0600 hours), humidity and temperature (20–23°C). All experiments were conducted in accordance with the regulations of the Canadian Council on Animal Care.

Diet and exercise protocol

A few days after their arrival, all animals were randomly assigned to either a high-fat or a standard diet protocol for 16 weeks. The HF diet consisted of 42% lipid (80% lard, 20% corn oil), 36% carbohydrate, and 22% protein (kcal) and was provided in small pellets from ICN Pharmaceuticals (NY, USA). The standard diet (12.5% lipid, 63.2% carbohydrate, and 24.3% protein; kcal) consisted of usual pellet rat chow (Agribrands Purina Canada, Woodstock, Ontario, Canada). Details of the diets have been reported elsewhere.12 Animals submitted to the high-fat diet were divided into two groups. One group of rats remained sedentary for the whole 16-week period (HF-Sed, n=9), while the second group of rats remained sedentary for the first 8 weeks and were exercise trained for the remaining 8-week period (HF-Tr, n=9). The third group consisted of rats fed a standard diet while remaining sedentary for the whole 16-week period (SD-Sed, n=9). Exercise training consisted of continuous running on a motor-driven rodent treadmill (Quinton Instruments, Seattle, WA, USA) 5 times a week for 8 weeks. Rats ran progressively from 15 min/day at 15 m/min, 0% slope, up to 60 min/day at 26 m/min, 10% slope for the last 4 weeks. All rats were weighed two times per week and food intake was monitored three times per week.

Blood and tissue sampling

At the end of the dietary and exercise protocol, all animals were killed between 0900 and 1200 hours. All trained animals were restrained from training 48 h before the killing. Food was removed from the animals' cage at least 2 h before killing. After complete anaesthesia (sodium pentobarbital, 50 mg/kg, i.p.), the abdominal cavity was rapidly opened following the median line of the abdomen. Blood was drawn rapidly (<45 s) and simultaneously from the abdominal vena cava (4 ml) and the hepatic portal vein (1.5 ml) into syringes pretreated with EDTA (15%). Blood was centrifuged (3000 r.p.m. for 8 min, 4°C) and the plasma kept for further analysis. Several organs, muscles and fat deposits were excised and weighed in the following order: liver, mesenteric fat, triceps surae muscles (plantaris, soleus, medial and lateral gastrocnemius), urogenital fat, retroperitoneal fat, and subcutaneous fat. All tissue samples were frozen in liquid nitrogen immediately after being weighed. The liver median lobe was freeze-clamped and used for triacylglycerol determinations. Mesenteric fat pad included the adipose tissue surrounding the gastrointestinal tract from the gastro-oesophageal sphincter to the end of the rectum. Special care was taken in distinguishing and excluding pancreatic cells. Urogenital fat pad included adipose tissue surrounding the kidneys, ureters, and bladder as well as ovaries, oviducts, and uterus. Retroperitoneal fat pad was taken as that distinct deposit behind each kidney along the lumbar muscles. For subcutaneous deposit measurement, a rectangular piece of skin was taken on the right side of each animal, from the median line of the abdomen to the spine and the right hip to the first rib as described by Krotkiewski and Bjorntorp.17 All plasma and tissue samples were stored at −78°C until analyses.

Analytical procedures

Plasma glucose concentration was determined with the use of a glucose analyser (Yellow Springs Instruments 2300, Yellow Springs, OH, USA). Insulin concentration was measured with a commercially available radioimmunoassay kit (Medicorp, Montréal, P.Q. and ICN Pharmaceuticals, New York, NY, USA). Leptin concentration was measured with a commercially available radioimmunoassay kit (Linco Research Inc., St Charles, MO, USA). Plasma nonesterified fatty acids (NEFA) levels were measured with a commercially available kit from Roche Diagnostics (Mannheim, Germany). Triacyglycerol (TAG), and beta-hydroxybutyrate were measured with kits from Sigma Diagnostics (St Louis, MO, USA).

Liver TAG concentration was estimated from glycerol released after ethanolic KOH hydrolysis using a commercial kit (Sigma Diagnostics, St Louis, MO, USA). Although this method does not discriminate between glycerol from phospholipids or TAG, Frayn and Maycock18 have shown that omitting removal of phospholipids leads to only a±2% error in the determination of tissue TAG.

Statistical analysis

Values are expressed as means ±s.e. Statistical analyses were performed by a one-way ANOVA for nonrepeated measures. Fisher's post hoc test was used in the event of a significant (P<0.05) F-ratio. Relationship between leptin concentration and total fat pad weight was evaluated by linear regression analysis.

Results

There was no difference (P>0.05) in final body weight or mean daily energy intake among the three groups (Table 1). Exercise training in HF-fed rats resulted in a significantly (P<0.05) higher sum of relative weights of the triceps surae muscles compared to the other two sedentary groups (Table 1). There was no significant difference (P>0.05) in liver triacylglycerol concentration among the three groups, despite a 22% higher level observed in HF-Sed compared to SD-Sed rats (Figure 1a). Plasma NEFA concentration was not significantly (P>0.05) affected by the HF diet (Figure 1b). Exercise training, however, resulted in significantly (P<0.01) lower levels of NEFA compared to SD-Sed. The high-fat diet resulted in 2-fold increase (P<0.05) in plasma triacylglycerol concentration (Figure 1c). Exercise training in HF-fed rats resulted in significantly (P<0.01) lower levels in plasma concentrations of triacylglycerol, compared to HF-Sed rats. No difference (P>0.05) was found in β-hydroxybutyrate concentration among the three groups (Figure 1d).

Table 1 Final body weight, daily energy intake and the sum of right calf muscle relative weights in rats fed a high-fat diet and remaining sedentary for 16 weeks (HF-Sed), fed a high-fat diet for 16 weeks and exercise trained for the last 8 weeks of their diet protocol (HF-Tr), and rats fed a standard diet while remaining sedentary for the duration of 16 weeks (SD-Sed)
Figure 1
figure1

Liver Triacylglycerol (a), plasma nonesterified fatty acids (NEFA) (b), triacylglycerol (c), and β-hydroxybutyrate (d) concentrations in standard- (SD) and high-fat (HF)-fed rats in the sedentary state (Sed) and in HF-trained (Tr) rats. Values are means ±s.e., n=9 rats/group. aSignificantly different from SD-fed rats P<0.05, aaP<0.01. bbSignificantly different from HF-Sed rats P<0.01.

The HF diet in rats in the Sed state resulted in a larger (P<0.001) deposit of subcutaneous and retroperitoneal fat than rats fed the SD diet (Figure 2a). However, mesenteric and urogenital fat pad weight was not significantly different (P>0.05) between HF-Sed and SD-Sed rats. The combined weight of the visceral fat pads was 13% higher in the HF-Sed rats compared to SD-Sed rats, but this difference did not reach statistical significance (P>0.05; Figure 2b). When the four fat pads were compiled together, a 17% higher fat relative weight was found between HF-Sed and SD-Sed groups (P<0.07). Exercise training while on the high-fat diet resulted in a lower level (P<0.05) of fat accumulation in every fat pad (Figure 2a).

Figure 2
figure2

Mesenteric (MES), subcutaneous (SC), retroperitoneal (RP), and urogenital (UG) fat weight (WT) relative to 100 g body weight (BW) and the sum of the relative weights of the three visceral fat pads (MES, RP, and UG) and the four fat pads (including SC) in standard- (SD) and high fat (HF)-fed rats in the sedentary state (Sed) and in HF-trained (Tr) rats. Values are means ±s.e., n=9 rats/group. aSignificantly different from SD-fed rats P<0.05, aaP<0.01, aaaP<0.001. bSignificantly different from HF-Sed rats P<0.05, bbP<0.01, bbbP<0.001.

Plasma glucose concentration was not significantly (P>0.05) different among the three groups (Figure 3a). Insulin concentration was lower in the two HF-fed groups compared to the SD-fed group (P<0.001) (Figure 3b). Portal insulin was not significantly (P>0.05) different between the three groups (Figure 3c). Exercise training did not have any effect on peripheral and portal insulin concentrations (P>0.05). Leptin concentration was not significantly different between HF-Sed and SD-Sed groups (P>0.05) despite a 19% higher value in HF-Sed rats (Figure 3d). Exercise training, however, resulted in a significant (P<0.001) lower plasma leptin concentration level compared to the two sedentary groups. The same differences between groups were reproduced when the leptin response was expressed per g of fat measured as the sum of the four fat pads (Figure 3e). Leptin concentration for all groups was highly correlated with total fat pads weight (R2=0.81; P<0.001).

Figure 3
figure3

Plasma glucose (a), peripheral insulin (b), portal insulin (c) and leptin concentrations expressed in absolute (d), and relative to the sum of the fat pad weights (e) in standard- (SD) and in high-fat (HF)-fed rats in the sedentary state (Sed) and in HF-trained (Tr) rats. Values are means ±s.e., n=9 rats/group. aSignificantly different from SD-fed rats P<0.05, aaP<0.01, aaaP<0.001. bSignificantly different from HF-Sed rats P<0.05, bbP<0.01, bbbP<0.001.

Discussion

In a recent study, we reported that exercise training pursued at the same time as a high-fat diet regimen of 8 weeks in rats completely prevented the development of hepatic steatosis.12 The present experiment, in continuity with this first study, was designed to evaluate the effects of the same 8-week training programme but conducted during the last 8 weeks of a 16-week high-fat diet regimen. Comparisons of the main results of these two studies are presented in Table 2. Surprisingly, the first observation made from these comparisons is that, compared to respective SD fed rats, liver lipid infiltration was more than 3 times higher after eight weeks of high-fat diet than after 16 weeks of the same high-fat diet. A possible explanation for this observation is that liver lipid infiltration occurs rapidly when rats undertake a high-fat diet regimen and decreases to a certain extent as part of the adaptations to the high-fat diet. It is possible that, the role of the liver during a relatively short period (8 weeks) of high-fat feeding is to take up lipids from the circulation, and thereafter progressively release them back into circulation as the animal adapts to the high-fat feeding. This would be consistent with the suggestion that the liver acts as a systemic lipid buffer during periods of high lipid influx.12, 19 This, however, does not mean that liver lipid infiltration may not increase again if the high-fat diet is pursued for a longer period of time. High-fat feeding for 10 months in male Wistar rats resulted in a large increase in liver triacyglycerol concentrations.20

Table 2 Relative changes in lipid variables computed from data in the present study and in a previous study12 conducted under the same experimental conditions but for a shorter duration.

One of the interests of the present study was to test the effects of an 8-week training programme during the course of a 16-week high-fat diet regimen on liver lipid infiltration. Since the development of liver lipid infiltration, independent of age, was much smaller after 16 weeks than after 8 weeks, the answer to this question is not readily obtained. At first glance, it seems that exercise training in the present study did not have any effect on hepatic steatosis. This would be consistent with results from other studies showing an absence of effect of exercise training on hepatic lipid content when it was conducted after hepatic steatosis had been induced.15, 21 One reason for this might be that once liver lipid infiltration is induced, a process that occurs relatively rapidly, the liver will by itself release lipids back into circulation, reducing the potential beneficial contribution of exercise training. Notwithstanding this interpretation, it can be observed in Table 2 that liver lipid infiltration was somewhat attenuated in HF-Tr rats, compared to SD fed rats, when training was initiated during the course of the HF diet (16-week protocol).

One reason to assume that rats in the present study adapted to the 16-week high-fat regimen is the surprisingly low increase in weight of visceral fat pads (Figure 2b). Although fat-pad weight was significantly increased in retroperitoneal and subcutaneous areas, there was no significant increase in mesenteric and urogenital fat-pad weights. The difference in increase in total visceral fat-pad weight, taking age into account, between HF and SD fed rats, was much lower after 16 weeks than what has been observed after 8 weeks of the same high-fat diet (Table 2). This strongly suggests that rats adapted to the high-fat diet, most likely by oxidizing more lipids.22 On the other hand, the weight of the subcutaneous fat deposit increased more after 16 weeks than after the 8-week high-fat diet (55 vs 33%; Table 2). Although reasons for this are not clear, it does suggest that the different deposits of fat do not follow a similar response to obesity. Even though the increase in visceral fat-pad weight was lower in the present 16-week regimen than in the previous 8-week high-fat diet (Table 2), the introduction of exercise training in the course of the present 16-week high-fat diet had a marked effect on reducing the weight of all fat deposits such that overall fat accumulation was even 30% smaller than in standard diet fed counterparts (sedentary; Figure 2b). This, at the least, indicates that exercise training has a profound reducing effect on body fat accumulation whether exercise is carried out at the same time or introduced during the course of a high-fat diet regimen. It also indicates that liver lipid infiltration and/or reversal follows a pattern somewhat different from body fat accumulation and/or reduction. Tiikkainen et al23 recently reported data in obese women suggesting that liver fat content does not simply reflect the size of endogenous fat stores. On the other hand, the large reduction in body fat accumulation with exercise training during the course of the present high-fat feeding gives some support to the interpretation that exercise training might also have hindered the development of hepatic steatosis.

An interesting observation of the present study is that the 16-week high-fat feeding, as compared to SD feeding, resulted in a large increase in plasma triacyglycerol concentrations and an absence of change in plasma NEFA levels (Figure 1b,c). This response is the opposite to what has been found after 8 weeks of the same high-fat diet as the plasma NEFA were elevated and not the triacyglycerols (Table 2). Similar findings were found by Barnard et al24 who reported an early increase in plasma glycerol and a large increase in plasma TAG after 2 and 6 months, respectively, of high-fat feeding. As previously suggested,12 the increase in plasma NEFA after the 8-week high-fat diet protocol probably resulted in a higher uptake of lipid by the liver since NEFA uptake is mostly done in a concentration-dependent manner.25 The large increase in plasma NEFA concentrations in this shorter-term condition is possibly due to an increased rate of lipolysis and may explain the large increase in liver lipid infiltration. A different response is, however, seen after 16 weeks of the same high-fat diet. With time (16 weeks), exposure of the liver to lipids may have resulted in an increase in VLDL secretion causing in turn a large increase in plasma TAG level.26 This might explain why, as compared to rats on the SD diet, liver lipid infiltration was much smaller after 16 weeks than after 8 weeks of the same high-fat diet. The lower levels of change in plasma NEFA after 16 weeks compared to after 8 weeks of the same high-fat diet might be explained by adaptations to the high-fat diet such as a greater capacity to oxidize fat and possibly a better capacity to sequester the lipids inside the adipocytes. On the other hand, plasma β-hydroxybutyrate levels, which may be taken as an index of liver lipid oxidation, were not changed by the present diet conditions. Altogether the increase in plasma TAG, most likely reflecting an increase in liver VLDL secretion, and the absence of a significant change in plasma NEFA may both be put forth to explain the finding that liver lipid infiltration is less accentuated after 16 weeks than after 8 weeks of the same high-fat diet. Exercise training in the present 16-week high-fat fed rats reduced circulating TAG as well as plasma NEFA. The decreased plasma TAG in exercising high-fat fed rats may reflect a decreased need for VLDL–TAG secretion due to the diminished delivery of NEFA to the liver. It could also reflect an increased utilisation of circulating VLDL–TAG as energy substrate during exercise on a high-fat diet.27

On the whole, the plasma NEFA and TAG data indicate that a high-fat diet regimen of 16 weeks leads to perturbations in lipid metabolism that are less accentuated than after only 8 weeks of high-fat feeding. Nevertheless, exercise training was instrumental in reducing the detrimental effects of high-fat feeding on lipid metabolism whether it is conducted at the same time or introduced during the course of a high-fat diet. In contrast to lipid metabolism, our data do not show any alterations in glucose metabolism either by high-fat feeding or the training status. Although peripheral insulin was found to be lower in the high-fat fed groups, plasma glucose and portal insulin levels were similar in all three groups. These data do not provide any indication of the development of an insulin-resistant state in the present 16-week high-fat fed rats. It is possible that insulin resistance may be more present after 8 weeks of high-fat feeding, as in our previous study,12 than after 16 weeks when rats depicted a higher level of adaptation to high-fat feeding.

Body weight measured at mid-point (8 weeks) in rats of the present study, which evolved into an absence of difference in final body weight between the groups, also support the interpretation of an adaptation to prolonged high-fat feeding. Exercise training introduced in the middle of a 16-week high-fat diet protocol did not affect body weight nor daily food intake but had a noticeable effect on body composition, largely reducing body fat content and increasing muscle weight, assuming that the latter reflects increased muscle protein mass (Table 1). Exercise training also largely diminished plasma leptin concentration. Interestingly, reduced adiposity could not account for all of the lowering effect of training on plasma leptin since when expressed per gram of fat, exercise-trained animals still had lower leptin values than the two other groups. Similar effects of training have been reported in humans28 and male rats.21 It has been proposed by Reseland et al28 that regular exercise could allow a resetting of the leptin concentration so that a lower concentration can be maintained at a certain body fat content.

In summary, our results from rats submitted to a 16-week high-fat diet have led to a number of new information in the light of what has been previously reported12 following 8 weeks of the same high-fat diet: (1) liver lipid infiltration that was largely increased after 8 weeks of high-fat diet was not different between the 16-week high-fat fed rats and the age-matched rats fed the standard diet; (2) visceral, but not subcutaneous, fat accumulation was comparatively less after 16 weeks than after 8 weeks of high-fat feeding; (3) contrary to the observations made after 8 weeks, 16 weeks of high-fat feeding was associated with an increase in plasma triacylglycerol and no change in NEFA; and (4) exercise training whether conducted concurrently to an 8-week high-fat diet or introduced during the course of a 16-week high-fat diet largely reduced fat accumulation and attenuated the deterioration of blood lipid profile. It is suggested that the liver acts as a lipid buffer in the early phase of a high-fat diet and progressively releases lipids into the circulation as the animal adapts to the high-fat diet. On the other hand, exercise training, whether conducted concurrently or introduced during the course of a high-fat diet, is an asset to reduce the deleterious effects of a high-fat diet. More research will be needed to better characterise the time course of the response of the triad liver–adipocyte–plasma to high-fat diet-induced obesity.

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Acknowledgements

This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC).

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Correspondence to J-M Lavoie.

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Gauthier, M., Couturier, K., Charbonneau, A. et al. Effects of introducing physical training in the course of a 16-week high-fat diet regimen on hepatic steatosis, adipose tissue fat accumulation, and plasma lipid profile. Int J Obes 28, 1064–1071 (2004). https://doi.org/10.1038/sj.ijo.0802628

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Keywords

  • high-fat diet
  • exercise training
  • adiposity
  • lipid profiles
  • hepatic steatosis

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