Modification of glucocorticoid effects on body weight gain, plasma lipids by changes in diet composition

Nutrition Research 23 (2003) 1105–1115 www.elsevier.com/locate/nutres

Modification of glucocorticoid effects on body weight gain, plasma lipids by changes in diet composition Carmel Bouclaousa, Naji Torbaya, Camille Nassarb, Nahla Hwalla (Baba)* a

Department of Nutrition and Food Science, American University of Beirut. P.O. Box: 11-0236, Riad El Solh, Beirut 1107 2020, Lebanon b Department of Physiology, American University of Beirut, Beirut, Lebanon

Abstract The effects of macronutrient composition of the diet and glucocorticoid administration on weight gain, intestinal absorption and plasma lipids were investigated. Thirty seven male Wistar rats were divided into 4 groups, implanted with pellets continuously delivering either prednisolone (0.25mg/ day) or placebo and fed two isocaloric diets providing either high fat (HF: 50% of energy) or high carbohydrate (HC: 70% of energy). The four groups [group I (HC, placebo), group II (HC, prednisolone), group III (HF, placebo), group IV (HF, prednisolone)] were pair fed and given the mean amount of food eaten by the group with the least amount of energy intake on the previous day. After 4 weeks, the animals were sacrificed and serum glucose, total cholesterol (TC), HDL-cholesterol (HDL) and triglycerides (TG) were measured. All groups showed a decrease in relative intestinal absorption with time. Prednisolone-treated groups revealed significantly lower intestinal absorption. However, prednisolone-treated high-carbohydrate (HC) fed rats showed significantly higher weight gain, concomitant with a significant increase in feed efficiency. The HC diet induced a statistically significant increase in TG concentration. The results show that prednisolone treatment induces more weight gain on a HC as compared to a high fat (HF) diet possibly through a rise in feed efficiency. © 2003 Elsevier Inc. All rights reserved. Keywords: Glucocorticoids; Pair feeding; Weight gain; Intestinal absorption

1. Introduction Obesity is a substantial contributor to premature death, given its high prevalence and deleterious effect on longevity [1]. While many factors contribute to the problem of obesity

* Corresponding author. Tel.: 96-11-374444 (Ext, 4540); fax: 96-11-744460. E-mail address: [email protected] (N. Hwalla [Baba]). 0271-5317/03/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0271-5317(03)00104-0

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such as changes in diet, physical activity, behavior, and smoking rates [2], prescription medications are also associated with substantial weight gain [3]. Steroid hormones are probably the greatest contributors to medication-associated weight gain. Therapeutic use of glucocorticoids (GCs) is associated with increased weight, a side effect that can be used beneficially in terminally ill patients [4] but is undesirable and detrimental in other conditions such as asthma and rheumatoid arthritis. Moreover, in obese individuals, further weight gain may exacerbate obesity-associated medical conditionsnotably glucose intolerance, hypertension, dyslipidemias, other cardiovascular diseases, and osteoarthritis [3]. Glucocorticoids play a role in the physiologic control of adiposity by regulating energy metabolism and/or food intake [5]. In animals, the role of GCs in regulating the level of adiposity is very convincing since the chronic administration of the antiglucorticoid RU 486 prevents genetic as well as diet-induced forms of obesity [6,7]. In fact, glucocorticoids favor the development of a moderate form of obesity with a characteristic abdominal fat accumulation [8 –11] that could be attributed to differences in glucocorticoid-receptor protein [12] or mRNA density [13,14]. Recently, a direct association has been established between GC administration and increased food intake [5]. Indeed, GCs induce obesity mostly by promoting energy intake, an effect which may be related to the ability of GCs to directly or indirectly affect the central regulation of appetite [5]. The aim of the present study is to investigate how pharmacological doses of GCs may influence intestinal caloric absorption in male Wistar rats. We hypothesized that with controlled food intake, weight gain in response to glucocorticoid administration might be dependent on diet composition, despite a change in intestinal absorption.

2. Methods 2.1. Experimental design Thirty seven male Wistar rats (Charles River Laboratories, USA), were housed in individual wire-mesh cages in a room maintained at 22 ⫾2°C, with a 12-hour light cycle (07:00-19:00 h). Rats had free access to a nonpurified diet (rat chow no. RMH 420, Charles River) and tap water. After a 4-day acclimatization period, rats were randomly divided into four groups (group I (n⫽9), group II (n⫽10), group III (n⫽9), group IV (n⫽9)) with an average rat weight of 194.2 ⫾ 6.94g. The animals were divided into two dietary cohorts. One cohort (groups I and II) had free access to a purified high-carbohydrate diet (HC) (70% CHO20% protein- 10% fat) and the other (groups III and IV) was fed a purified high-fat diet (HF) (30% CHO - 20% protein - 50% fat). The composition of the two experimental diets is shown in Table 1. Diets were matched in terms of protein, fiber, vitamins and minerals and differed from each other by their carbohydrate-fat ratio. Diets were freshly made every 3-4 days and stored at 4oC. Rats were allowed to adapt to their diets for a week preceding the experiment. Body weights were taken weekly. Food intake and spillage were recorded every other day. Every three days, feces were collected and stored for later determination of caloric content.

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Table 1 Composition of Experimental Diets Ingredients (g/100g)

HC (High-carbohydrate diet) (70% CHO; 20% protein; 10% fat)

HF (High-fat diet) (30% CHO; 20% protein; 50% fat)

Sucrose (g) Corn Starch (g) Corn oil (g) Casein (g) Alphacel1 (g) Salt mixture2 (g) Vitamin Mix3 (g) Gross Energy, Kcal/g

21.62 43.60 4.14 18.64 8.00 4.00 0.47 4.24

12.20 24.40 26.90 24.40 8.00 4.00 0.47 5.60

1

Commercial name for cellulose. Salt mixture USPXIV from ICN Nutritional Biochemicals contains (g/100g mixture): calcium carbonate 6.86; calcium citrate 30.83; calcium biphosphate 11.28; magnesium carbonate 3.52; magnesium sulfate 3.83; potassium chloride 12.47; potassium phosphate 21.88; sodium chloride 7.71; copper sulfate 0.0078; ferric citrate 1.53; manganese sulfate 0.02; potassium aluminum sulfate 0.009; potassium iodide 0.04; sodium fluoride 0.051. 3 Vitamin Diet Fortification Mixture from ICN Nutritional Biochemicals contains (g/Kg mixture); vitamin A acetate 1.8; vitamin D concentrate 0.125; ␣-tocopherol 22.0; ascorbic acid 45.0; inositol 5.0; choline chloride 75.0; menadione 2.25; P-amino benzoic acid 5.0; niacin 4.25; riboflavin 1.0; pyridoxine hydrochloride 1.0; thiamin hydrochloride 1.0; calcium pantothenate 3.0; biotin 0.20; folic acid 0.09; vitamin B12 0.00135. Source: ICN Nutritional Biochemicals. 2

Following a week of adaptation to the experimental diets, hormone administration was initiated by subcutaneously implanting the rats, under short ether anesthesia, with pellets continuously delivering either prednisolone (15mg/pellet) or vehicle (15mg/pellet) over a 5-week release period (Innovative Research of America, Toledo, Ohio USA). Thus, each of the two dietary cohorts had two hormonal treatments: groups I and III received placebo pellets, groups II and IV had prednisolone pellets. Rats were allowed to recover for a period of 8 days with free access to their experimental diet and tap water. Food consumption was still measured and body weights were recorded weekly. From the 9th day onward, a pair feeding regimen was initiated to avoid differences in energy intake. Each day, three groups of rats were given the mean amount of food eaten by the group with the least calorie intake on the previous day. Any spillage in diet was collected and accounted for to ensure that the animals were receiving isocaloric diets. At the end of the four-week pair feeding period, rats were fasted overnight and sacrificed by decapitation, after an overnight fast. Blood was collected in dry test tubes, and centrifuged (2000 rpm, 4°C, 15min). The separated serum was stored at –70°C for later determination of glucose and lipids. The procedure was approved by the University Research Board and guided by the Helsinki Declaration for the care of animals. 2.2. Fecal calorimetry Weekly feces collections for each rat were dried in the oven overnight at 80°C, weighed and ground into powder form. Samples of approximately one gram were compacted using a

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pellet press. A bomb calorimeter was used to determine the caloric content of the pellets (1266 Parr Instrument Company, Illinois, USA). The weekly caloric excretion per rat was calculated as: Caloric density of the pellet (cal/g) ⫻ weekly dry feces weight (g). Relative intestinal absorption (%) ⫽ (Intake ⫺ excretion)/(Intake) ⫻ 100 [15] 2.3. Serum analysis Serum samples were analyzed for glucose using the UV test based on the hexokinase/ G6P-DH assay (provided by Boehringer Mannheim, Germany). Total cholesterol (TC) was analyzed by an enzymatic colorimetric test provided as a kit by Boehringer Mannheim, Germany. Triglycerides (TG) were measured by an enzymatic colorimetric method using a reagent kit (Boehringer Mannheim) that allowed correction for free glycerol. Serum HDLcholesterol (HDL-C) was determined by a direct colorimetric test (Randox). 2.4. Pellet insertion Under light anesthesia and sterile conditions, a 1-cm transverse incision was made in the rat dorsal region. A slow release implant containing prednisolone or vehicle (inert matrix) was inserted horizontally and the incision was closed with a single stitch. After that, the wound was disinfected with Betadine and an antibiotic ointment (Baneocin) was applied. Rats were given a single intramuscular injection of 0.2ml penicillin. 2.5. Statistical analysis All experimental data are expressed as means ⫾ SE. Statistical analyses were performed using analysis of variance (ANOVA) and means were compared by Duncan’s Multiple Range Test using MSTAT-C package (MSTAT-C, 1989). Data were considered to be significant at ⬍0.05. 3. Results 3.1. Food intake Rats were pair fed either a HC or an isocaloric HF diet, for the length of the experimental period (4 weeks), and hence there was no significant difference in total caloric intake. This similarity in energy intake allowed for comparison between experimental groups of body weight gain, feed efficiency, serum levels and intestinal absorption (Table 2). 3.2. Body weight gain A decrease in body weight was observed during the first week of prednisolone administration prior to pair feeding(-10⫾1g). Therefore, pair feeding was initiated on control rats at

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Table 2 Nutritional and fasting blood parameters in male Wistar rats after four weeks on HC or an isocaloric-HF diet with or without prednisolone administration at sacrifice.

Energy intake (Kcal) Fecal excretion (calories/week) Weight gain, (g) Feed efficiency (g/Kcal) Glucose, mg/dl TC, mg/dl TG, mg/dl HDL, mg/dl HDL/TC

Group I (HC, placebo) n⫽9

Group II (HC, prednosolone) n ⫽ 10

2891.0 ⫾ 72.74

2678.4 ⫾ 69.01

Group III (HF, placebo) n⫽9

Mean ⫾ SE 2795.3 ⫾ 72.74

Group IV (HF, prednosolone) n⫽9 2826.8 ⫾ 72.74

8.1 ⫾ 0.24

8.8 ⫾ 0.23

8.0 ⫾ 0.24

8.2 ⫾ 0.24

85.3 ⫾ 5.90b 2.9⫻ 10⫺2 ⫾ 0.00b 125.1 ⫾ 3.44 57.1 ⫾ 3.42 87.2 ⫾ 11.52a 28.0 ⫾ 1.65 0.49 ⫾ 0.01

106.0 ⫾ 5.60a 3.9⫻ 10⫺2 ⫾ 0.00a 122.2 ⫾ 3.26 59.7 ⫾ 3.20 95.1 ⫾ 10.93a 29.2 ⫾ 1.57 0.49 ⫾ 0.01

94.8 ⫾ 5.90a,b 3.4⫻ 10⫺2 ⫾ 0.00a,b 131.8 ⫾ 3.44 62.2 ⫾ 3.40 35.6 ⫾ 11.52b 32.0 ⫾ 1.65 0.51 ⫾ 0.01

92.8 ⫾ 5.90a,b 3.3⫻ 10⫺2 ⫾ 0.00b 125.6 ⫾ 3.44 63.3 ⫾ 3.41 33.1 ⫾ 11.52b 32.2 ⫾ 1.65 0.51 ⫾ 0.01

a,b,c

Values in the same row with different superscripts are different at p⬍0.05. * using covariance analysis.

the start of the experimental period. As shown in Figure 1, total weight gain after 4 weeks of pair feeding was statistically significant between groups I (HC, placebo) and II (HC, prednisolone), group II being higher than group I (p⬍0.05). However, no significant difference was observed between groups III (HF, placebo) and IV (HF, prednisolone) although there seems to be a trend towards divergence after 4 weeks. When comparing placebo groups on a HF or a HC diet, HF fed rats (group III) had higher total weight gain than HC fed rats (group I). The total weight gain in group II (HC, prednisolone) was higher than in group IV (HF, prednisolone), but did not reach statistical significance. 3.3. Feed efficiency In order to determine the effect of dietary and hormonal treatments on weight gain, feed efficiency was calculated as body weight gain per kilocalorie intake (Table 2). A significantly higher feed efficiency (p⬍0.05) was found in group II (HC, prednisolone) as compared to group I (HC, placebo). A difference was not observed between groups III (HF, placebo) and IV (HF, prednisolone). Feed efficiency was also significantly higher (p⬍0.01) in group II (HC, prednisolone) than group IV (HF, prednisolone). 3.4. Serum levels At sacrifice, results of fasting blood analysis showed a significant rise of plasma TG values after a HC diet as compared to a HF diet in both placebo and prednisolone treated groups (Table 2). However, within the diet groups, there were no significant differences between

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Fig. 1.

placebo and prednisolone treated groups. No statistical difference was shown between experimental groups for glucose, serum TC, HDL-C and the HDL-C/TC ratio (Table 2). 3.5. Intestinal absorption 3.5.1. Effect of treatment When comparisons are made, the effect of prednisolone on caloric absorption is evident in both diet groups. In other words, prenisolone lowered absorption in both the HC and the HF groups (Table 3).

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Table 3 Differences in relative intestinal caloric absorption between male Wistar rats fed either a HC or an isocaloricHF diet with or without prednisolone administration.

week 1 week 4 a,b x,y

Group I (HC, placebo) n⫽8

Group II (HC, prednisolone) n ⫽ 10

91.1 ⫾ 0.26a 88.4 ⫾ 0.26b,x

91.2 ⫾ 0.58a 85.8 ⫾ 0.58b,y

Group III (HF, placebo) n ⫽9

Mean % ⫾ SE 91.3 ⫾ 0.19a 88.6 ⫾ 0.19b,x

Group IV (HF, prednisolone) n ⫽9 91.3 ⫾ 0.49a 86.1 ⫾ 0.49b,y

Values in the same column with different superscripts are different at p⬍0.05. Values in the same row with different subscript are different at p⬍0.05.

3.5.2. Effect of time In all four groups, the effect of time was found to be highly significant (p⬍0.01). Relative intestinal energy absorption was found to be significantly lower after the fourth week of pair feeding as compared to week 1 in all groups, with a tendency for a higher decrease in prednisolone treated groups (II, IV) (Table 3).

4. Discussion In this experiment, a decrease in body weight was noted during the first week of prednisolone administration. This is in accordance with previous studies, where treatment of male Wistar rats with dexamethasone for 5 days [16] or corticosterone for 12 days [11] showed significant weight loss. Following the initial weight loss in prednisolone treated rats, a steady weekly weight gain was observed in all groups. At the end of the study, the prednisolone treated group on a HC diet showed a significantly higher body weight gain as compared to the placebo group on a HC and to both groups on HF diet. This is in agreement with previous observations [17–20] where weight gain was observed when animals were subjected to prednisolone treatment. A down regulation of GC receptors or a change in intracellular signaling pathways in different tissues led to weight increase in prednisolone treated animals. Moreover, corticosteroids seem to exert a dual metabolic action on gain in body weight and feeding efficiency, strictly depending on the dose used [21]. Administration of corticosteroid doses similar to those given in our study were shown to have an anabolic activity, which was accompanied by increased appetite in humans and stimulation of food intake in laboratory animals [21]. To our knowledge, this is the first study that attempts to investigate the effect of diet composition in conjunction with prednisolone therapy on weight gain, intestinal absorption and feed efficiency while using pair feeding to control energy intake. In this study, by the end of 4 weeks of pair feeding, administration of pharmacological doses of prednisolone to animals caused a statistically significant reduction in energy absorption by the intestine under both HC and HF diets (Table 3). This drop may be induced by the hormone (p⬍0.01) and the hormone-diet interaction (p⬍0.01). To our knowledge, no

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previous studies have investigated the interactive effect of prednisolone administration and diet composition on intestinal absorption in animals. Previous research on intestinal absorption in animals has focused either on intestinal electrolyte absorption [22–27] or on a specific nutrient absorption [28 –35]. In vitro studies showed that hydrocortisone and desoxycorticosterone treatments increased significantly the intestinal absorption of glucose [32]. In vivo, galactose absorption per centimeter of intestine was reported to increase after prednisolone treatment [30]. In our study, all experimental groups were pair fed, and weight gain was higher in the prednisolone treated group on the HC diet. These differences in total weight gain could not be attributed to variations in food intake. When feed efficiency was calculated, it was found to be significantly higher in the HC-fed prednisolone-treated group as compared to other groups. A significant effect of prednisolone treatment (p⬍0.05) and a significant effect of diet-hormone interaction (p⬍0.01) were obtained. This suggests that under pharmacological doses of GCs, feed efficiency is higher on a HC than on a HF diet. Previous studies on feed efficiency did not attempt to check the effect of diet composition in GC treated rats [21]. In many studies [36 –39,31], food intake was not controlled, and rats or subjects were allowed ad libitum access to food. The adrenocortical system was found to be heavily involved with food intake [36]. Patients treated with GCs have a marked increase in appetite [37]. GCs were found to activate hunger signals in the brain [38 – 40]. Obviously if food intake is increased by GCs, there are more substrates to support fat synthesis [41]. The role of GCs in regulating hepatic lipogenesis has been studied carefully. The first suggestion that GCs might have a role in the control of lipogenesis came from studies of the responses of rats to starvation-refeeding [42]. Animals starved for periods of 36-56 hours and then refed a high glucose diet showed a two to threefold increase in fatty acid synthesis, glucose-6-phosphate dehydrogenase and malic enzyme activities. This increase in enzyme activity is referred to as enzyme overshoot. This overshoot can be reduced in magnitude by adrenalectomy and restored when the missing GC is replaced [42]. Diet influences both the magnitude of the lipogenic response to starvation-refeeding and the effect of adrenalectomy and GC replacement [43]. A 65% protein diet elicits less of an overshoot than does a 65% glucose diet, and a 40% fat diet elicits a very small overshoot. In the present study, a significant rise of plasma TG values was observed after a HC diet as compared to a HF diet in both placebo and prednisolone treated groups. These differences were caused by dietary macronutrient composition (p⬍0.01) although the animals were pair fed. It has been documented in earlier studies that a HC diet causes a significant rise in endogenous VLDL containing TG and a reduction in triglyceride clearance and possibly fat oxidation, reflected in the fasting state [44 – 47]. Thus, carbohydrate induced hypertriglyceridemia is a consequence of endogenous synthesis and clearance. The mechanisms underlying such carbohydrate-induced elevations in TG are still under investigation. While, Parks et al. [48] attributed it to a reduction in VLDL-TG clearance and whole-body fat oxidation, Mittendorfer and Sidossis [47] reported an increased endogenous secretion of VLDL-TG. Moreover, the long-term administration of GCs has been associated with selective or combined elevation in serum levels of TG in animal models [49 –51]. However, in previous studies, the effect of diet composition on glucocorticoid-induced changes in lipid profile was not sought. In the present study, it was noted that the diet composition solely had an effect

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on triglyceridemia. It is, however, important to note that differences in the type of glucocorticoid used in the previous studies, may explain discrepancies in plasma parameters. Given at equipotent doses, different corticosteroids, triamcinolone and dexamethasone have been shown to increase TGs respectively, while hydrocortisone did not change TG levels [52]. In such studies, initial plasma values were available for comparison with final plasma levels. Plasma glucose, TC, HDL-C, and HDL-C/TC ratio were not significantly affected by treatment conditions. In conclusion, the findings of this study show that diet composition is an important determinant of weight gain in pair-fed animals receiving prednisolone. Our data support the existence of higher feed efficiency in prednisolone-treated HC fed rats; thus, leading to weight gain. This result provides evidence for a possible influence of diet composition in humans on prednisolone therapy. Diet composition seems to be an important factor for weight gain in long-term GC therapy. It is recommended that further investigations be conducted to find the optimal diet composition for patients on GCs in order to prevent weight gain. It is evident from the results of the present study that chronic administration of GCs in association with a high fat diet did not result in the weight gain, hypertriglyceridemia, and increased feed efficiency that were observed when the diet was high in carbohydrates. Thus, when GCs need to be administered, the present study suggests that a high fat diet is preferable to a HC diet. Other perturbations in diet composition need further investigation. A diet rich in protein and limited in fats and carbohydrates or a modified diet containing mono- and ␻-3 polyunsaturated fatty acids are speculated to be more effective in preventing weight gain. With long-term GC therapy, diet composition may provide a therapeutic potential in the prevention of weight gain and dyslipidemia.

Acknowledgments This work was conducted partly by Ms. Carmel Bouclaous in partial fulfillment of her MSc Degree. Ms. Bouclaous conducted the experiment and wrote the manuscript under the supervision of Dr. Nahla Hwalla, Director of thesis. Drs. Hwalla and Torbay were responsible for design of the study. Dr. Nassar participated in reviewing the manuscript and as a member of the thesis supervisory committee. All authors have approved the manuscript. This work was supported by a grant from the University Research Board, American University of Beirut.

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