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Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet
Psychoneuroendocrinology (2008) 33, 1269—1278
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n
Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet ´atrice Guardiola-Lemaitre b, Natalia Sinitskaya a, Carole Schuster-Klein b, Be ´vet a, Etienne Challet a,* Sylviane Gourmelen a, Paul Pe a
´partement de Neurobiologie des Rythmes, Institut de Neurosciences Cellulaires et Inte ´gratives, CNRS, Universite ´ Louis Pasteur, 5 De rue Blaise Pascal, 67084 Strasbourg, France b ´iades, 92415 Courbevoie cedex, France Institut de Recherches Internationales Servier (IRIS-Servier), 6 Place des Ple Received 27 February 2008; received in revised form 13 June 2008; accepted 3 July 2008
KEYWORDS Obesity; Leptin; Adiponectin; Carbohydrate craving; Winter depression
Summary Background: Photoperiod, i.e., the relative day-length per 24 h, may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption. Methods: To test this hypothesis, hormonal changes, fat accretion and sucrose intake were measured in rats exposed to short- or long-day for 4 weeks and fed with a standard highcarbohydrate low-fat pelleted diet (high-carbohydrate diet (HCD)) or a high-fat, mediumcarbohydrate pelleted diet (HFD), with or without free access to 10% sucrose solution in addition to water available ad libitum. Results: Plasma leptin and adiposity index, defined as epididymal white fat expressed as percentage of body mass, were markedly increased only in HFD-fed animals drinking sucrose under short, but not long, photoperiods. Voluntary ingestion of sucrose under short days was greater in HFD rats compared with HCD animals over the experiment, while a trend for the opposite effect was visible under long days. Total energy intake was not changed overall, as rats proportionally decreased chow intake when they drank sucrose. A noteworthy exception was the HFD group with sucrose access under short days that significantly increased their total calorie intake. Fasting blood glucose was generally unaltered, except for an increase in HFD-fed animals drinking sucrose under long days compared to control animals, suggesting a decrease in glucose tolerance. Insulin resistance was not yet affected by nutritional or photoperiodic conditions after 4 experimental weeks. Conclusions: Even if photoperiod cannot be considered as an obesogenic environmental factor per se, the metabolic effects resulting from the combination of high-fat feeding and voluntary intake of sucrose were dependent on day-length. Exposure to short days triggers a larger increase of sucrose ingestion and hyperleptinemia in rats fed with HFD compared to the control diet. Considering that the cardinal symptoms of winter depression include carbohydrate craving and increased adiposity, the present data provide an experimental basis for developing new animal models of seasonal affective disorder. # 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +33 3 88456693; fax: +33 3 88456654. E-mail address: [email protected] (E. Challet). 0306-4530/$ — see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2008.07.003
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1. Introduction In humans, dietary fat and sugar-rich beverages are major risks of developing visceral obesity, type 2 diabetes, and cardiovascular disease, these symptoms together defining the so-called metabolic syndrome (e.g., Astrup, 2005). Of note, epidemiologic analyses suggest that the human metabolic syndrome could be linked in part to seasonality (Rintama ¨ki et al., 2008). Moreover, a few previous reports have mentioned possible seasonal fluctuations of energy intake in humans (e.g., de Castro, 1991; Ma et al., 2006; Watson and McDonald, 2007). Thus, photoperiod (i.e., the relative daylength per 24 h depending on seasons) may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption. The seasonal affective disorder (SAD, also known as socalled winter depression) typically occurs under short photoperiods and is often associated with carbohydrate craving (Wurtman and Wurtman, 1995; Kra ¨uchi et al., 1997; Yanovski, 2003). There are indications that SAD is associated with altered glucose metabolism (Allen et al., 1992; Kra ¨uchi et al., 1999). Besides carbohydrate craving, another cardinal symptom of SAD is gain in body mass and fat (Wehr et al., 1991). Classical animal models of major depression are associated with reduced sucrose intake (Willner, 1984; Monleon et al., 1995). By contrast, an appropriate animal model of SAD would aim at combining increases in sucrose intake and adiposity, possibly depending on photoperiod. Photoperiod may by itself directly or indirectly affect energy metabolism. Natural fluctuations of food intake and/or body mass and adiposity are well known to occur according to the seasons in photoperiodic species (Bartness and Wade, 1985; Adam and Mercer, 2004). In those animals, physiology is specifically and reversibly regulated on a seasonal basis. In particular, metabolism of white adipose tissue is influenced by day-length in photoperiodic species (Faulconnier et al., 2001; Bowers et al., 2005). The photoperiodic information is transduced into neuroendocrine changes via the nocturnal secretion of melatonin by the pineal gland (Malpaux et al., 2001; Pe ´vet, 2003). Interestingly, in photoperiodic rodents such as Syrian hamsters, the metabolic effects of HFD are exaggerated when animals are housed in short days (Wade, 1983). In rats under 12:12 photoperiod, gain in body mass and fat accretion have been observed after only 1 month (Fukuchi et al., 2004) or longer duration of sucrose access (Fukuchi et al., 2004; Galic and Persinger, 2007). As a putative obesogenic environmental factor, photoperiod may affect these parameters in rats. The photoperiodic environment could indeed exaggerate metabolic responses to dietary fat or sucrose. To test this hypothesis in the perspective of modelling SAD, fat accretion and sucrose consumption were measured in rats fed with a HFD — combined or not with sucrose access — and exposed to short or long day for 4 weeks.
2. Materials and methods 2.1. Ethics The experiment was performed in accordance with the rules of the European Committee Council Directive of 24 November
N. Sinitskaya et al. 1986 (86/609/EEC) and the French Department of Agriculture (license no. 67-88).
2.2. Animals Sixty-four male Sprague—Dawley rats (Charles River Laboratories, L’Arbresle, France) weighing around 120 g upon their arrival (age: 4 weeks), were housed individually, kept at 21 1 8C under a 12:12 h light—dark cycle (lights on at 07:00 h) and had ad libitum access to food (standard lowfat diet, 105, SAFE, 89290 Augy, France) and tap water for 2 weeks.
2.3. Experimental design On the first day of the experiment, 6-weeks-old rats were distributed equally in two rooms: one half (n = 32) was exposed to a short (i.e., winter-like) photoperiod with a 10:14 h light—dark cycle (lights on at 0700 h); the other half (n = 32) was exposed to a long (i.e., summer-like) photoperiod with a 14:10 h light—dark cycle (lights on at 07:00 h). For each photoperiodic condition, rats were divided into two groups: the first group of 16 rats was fed a standard highcarbohydrate, low-fat pelleted diet (high-carbohydrate diet (HCD); 15.5 kJ/g (3.7 kcal/g); 229H, SAFE: distribution of metabolizable energy content in %: 24% protein, 64% carbohydrate and 12% fat derived from corn oil only), while the second group of 16 rats received a high-fat, medium-carbohydrate pelleted diet (HFD; 19.7 kJ/g (4.7 kcal/g), SAFE: energy content distribution in %: 17% protein, 30% carbohydrate and 53% fat, including 6% derived from corn oil and 47% saturated fat from lard). This diet has been shown to increase fat accretion and to reduce sensitivity to insulin (Sinitskaya et al., 2007). Composition of HCD and HFD is shown in Table 1. For each feeding regimen, half of the animals had ad libitum access to tap water (n = 8), while the other half had free access to 10% sucrose solution in addition to water supply (n = 8). Diets were vacuum-packed and stored in a fresh (8 8C) room before use. Animals were given fresh food (200 g) and beverages every week. Body mass and food consumption (remaining pellets) were measured in early morning, every week. Diets were given as dry pellets so to limit spillage. After 4 weeks of experimental diet, rats were fasted overnight and deeply anesthetized in early morning with isoflurane and their body mass were determined before decapitation. After trunk blood was collected, one drop was sampled for glucose assay and the remaining blood centrifugated for further ELISA analysis. Epididymal fat pads Table 1
Centesimal composition (in 100 g of chow)
Protein Carbohydrate Fat (corn oil) Fat (lard) Fibres Minerals, ash Vitamins Binder (silica)
229H (HCD)
HFD
22.5 59.5 5 — 5 7 1 —
20 37 3 25 5 7 1 2
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were dissected and weighed. The mass of epididymal fat expressed as percentage of body mass was used as an index of adiposity.
2.4. Methods of analysis Blood glucose was immediately determined (Glucotrend premium kit, Roche Diagnostics, Meylan, France). Plasma insulin was determined by an ELISA kit for rats (EZRMI-13 K, Linco Research Inc., St. Charles, MO, USA) with intra- and inter-assay coefficients of variation (%CV) of 1.9 0.6 and 7.6 0.8%, respectively. The limit of sensitivity of insulin assay was 0.2 ng/ml. Plasma leptin was determined by an ELISA kit for rats (EZRL-83 K, Linco Research) with 2.2 0.2 intra- and 3.4 0.3 inter-assay %CV. The limit of sensitivity of leptin assay was 0.04 ng/ml. Plasma adiponectin was determined by an ELISA kit for rats (EZRADP-62 K, Linco Research) with 1.3 0.2 intra- and 7.0 0.4 inter-assay %CV. The limit of sensitivity of adiponectin assay was 0.155 ng/ml. Homeostatic model assessment (HOMA) was used to assess B-cell function and insulin resistance (IR), and calculated as follows: HOMA-IR = (fasting plasma glucose fasting plasma insulin)/22.5 as described by Matthews et al. (1985).
2.5. Statistical analysis To test the effects of nutritional condition (HCD water, HCD + sucrose, HFD water or HFD + sucrose), photoperiod (short vs. long) or time (week 1—4), data were processed with analyses of variance (ANOVA) with repeated measures or not, depending on the parameter considered. If significant main effects or significant interactions were detected ( p < 0.05), post hoc comparisons were performed with Tukey HSD test. Values are means S.E.M.
3. Results
Figure 1 Changes in body mass in rats fed either with low-fat, high carbohydrate diet (HCD, circles) or high-fat, medium-carbohydrate diet (HFD, squares) under short (A) or long photoperiods (B). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 (post hoc test after 2-way ANOVA) for HFD+ group compared to the HCD, HCD+ and HFD groups.
3.1. Body mass and adiposity At the end of experiment, body mass was significantly affected by the nutritional condition [F(3, 56) = 19.66; p < 0.001], independently of the photoperiod [F(1, 56) = 0.97, p = 0.33]. More specifically, HFD rats drinking sucrose had a lower body mass compared to the three other groups under both short- and long photoperiod (post hoc test, p < 0.001; Fig. 1A and B). With respect to the time-course of these changes, they appear from 2 to 3 weeks after the beginning to the end of the treatment (as analyzed with [nutritional condition time] ANOVA for each photoperiodic condition: see Fig. 1A and B). There was a significant [nutritional condition photoperphotoperiod] interaction [F(3, 56) = 3.08, p < 0.05] for adiposity index (i.e., epididymal white fat as percentage of body mass) while the main effects of nutritional condition or photoperiod were not significant [F(3, 56) = 1.69, p = 0.18 and F(1, 56) = 0.28, p = 0.60, respectively]. Of note, adiposity index was greater in HFD-fed animals drinking sucrose under a short photoperiod compared not only to rats drinking sucrose and fed with the control (HCD) diet under the same photoperiod (post hoc test, p < 0.01), but also to animals fed
with the same regimen under a long photoperiod (post hoc test, p < 0.05; Fig. 2A and B).
3.2. Sucrose consumption In rats exposed to a short photoperiod, 10% sucrose intake (in volume) was affected by the nutritional condition [F(1, 42) = 8.11, p = 0.01] and time [F(3, 42) = 24.95, p < 0.001]. Interestingly, sucrose consumption was greater in HFD than HCD groups, as soon as the second week of treatment (post hoc test, p < 0.05) up to the fourth experimental week (post hoc test, p < 0.05; Fig. 3A). In rats exposed to a long photoperiod, sucrose consumption (in volume) was affected by time [F(3, 42) = 24.95, p < 0.001], but not by the nutritional condition [F(1, 42) = 1.99, p = 0.18]. Moreover, there was a significant [time nutritional condition] interaction for sucrose intake in long photoperiod [F(3, 42) = 6.08, p < 0.01]. In contrast to what happens in short photoperiod, sucrose intake tended to be opposite (i.e., HCD > HFD) when rats were exposed to a long photoperiod. This difference was significant only by the fourth week of experiment (post hoc test, p < 0.01; Fig. 3B).
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N. Sinitskaya et al. ing the first experimental week, food intake in HCD rats was greater than that in HCD+, HFD and HFD+ groups (post hoc test, p < 0.05). During the following 3 weeks, food intake in both HCD and HFD groups (i.e., without sucrose) was larger than that in HCD+ and HFD+ rats (i.e., with sucrose access; Fig. 3D). Total energy intake over the experiment was significantly affected by the nutritional condition [F(3, 56) = 4.63, p < 0.01], independently of the photoperiod [F(1, 56) = 0.24, p = 0.63]. While total energy intake under a long-photoperiod remained unaltered between the nutritional groups (Fig. 4B), it was significantly increased under a short photoperiod in animals drinking sucrose and fed with HFD in comparison with rats drinking only water and fed with the control (HCD) diet (post hoc test, p < 0.01; Fig. 4A). Energy intake derived from chow pellets was affected by sucrose consumption [F(3, 56) = 63.00, p < 0.001], independently of the photoperiod [F(1, 56) = 0.06, p = 0.81]. Accordingly, when rats had free access to a sucrose solution and fed with or without HFD, they proportionally reduced their energy intake from chow (Fig. 4C and D). There was a significant [photoperiod nutritional condition] interaction [F(1, 28) = 10.19, p < 0.01] for voluntary intake of 10% sucrose solution (Fig. E and F), while the main effects of the photoperiod and nutritional condition were not significant [F(1, 28) = 1.02, p = 0.32 and F(1,28) = 0.06, p = 0.79, respectively].
3.4. Blood glucose, insulinemia, homeostatic model assessment and insulin resistance (HOMAIR) Figure 2 Adiposity, as determined by the ratio of abdominal (i.e., epididymal and retroperitoneal) white fat and body mass, in rats fed either with low-fat, high carbohydrate diet (HCD) or high-fat, medium-carbohydrate diet (HFD, squares) under short (A) or long photoperiods (B). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 (post hoc test after 2-way ANOVA) between HFD+ and HCD+ groups. ap < 0.05 (post hoc test after 2-way ANOVA) for HFD+ under short vs. long photoperiods.
3.3. Food, chow-derived and sucrose-derived energy intake Food intake (in grams) in rats exposed to a short photoperiod was affected by the nutritional condition [F(3, 84) = 52.47, p < 0.001] but not by time [F(3, 84) = 0.79, p = 0.50]. There was also a significant [time nutritional condition] interaction [F(9, 84) = 6.13, p < 0.001]. Food intake in HCD rats was always greater than in the three other groups (HCD+, HFD and HFD+; post hoc test, p < 0.05), except for the fourth experimental week during which HFD and HCD groups were no longer different between each other (Fig. 3C). In rats exposed to a long photoperiod, food intake (in grams) was significantly changed by the nutritional condition [F(3, 84) = 32.44, p < 0.001] and time [F(3, 84) = 3.49, p < 0.05]. In addition, the [time nutritional condition] interaction was significant [F(9, 84) = 4.76, p < 0.001]. Dur-
Two-way ANOVA did not detect any significant effect for photoperiod [F(1, 56) = 0.19, p = 0.66] or nutritional condition [F(3, 56) = 1.93, p = 0.13] on values of fasting blood glucose. When we considered only the rats exposed to a short photoperiod, blood glucose determined in the morning (i.e., 2 h after the onset of light) did not differ significantly between the nutritional conditions [F(3, 28) = 0.79, p = 0.51] (Fig. 5A). By contrast, in rats exposed to a long photoperiod, fasting blood glucose was significantly affected by the nutritional conditions [F(3, 28) = 3.27, p < 0.05]. Post hoc test revealed a greater concentration of blood glucose in HFD-fed animals drinking sucrose compared to control animals ( p < 0.05; Fig. 5B). Morning levels of plasma insulin in fasted rats were not significantly affected by the nutritional condition [F(3, 56) = 1.70, p = 0.18] or photoperiodic conditions [F(1, 56) = 0.36, p = 0.55] (Fig. 5C and D). Similarly, HOMA-IR was not significantly affected by the nutritional condition [F(3, 56) = 1.12, p = 0.35] or the photoperiod [F(1, 56) = 0.13, p = 0.72] (Fig. 5E and F), thus, suggesting that the rats were not exposed to nutritional conditions for a duration long enough to alter b-cell function.
3.5. Leptinemia and adiponectinemia Plasma leptin was significantly affected by the nutritional condition [F(3, 56) = 4.20, p = 0.01], independently of the
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Figure 3 Consumption of 10% sucrose solution (A and B) and food intake (C and D) in rats fed with low-fat, high carbohydrate diet (HCD+, circles) or high-fat, medium-carbohydrate diet (HFD+, squares) under short (A and C) or long photoperiods (B and D). *p < 0.05 (post hoc test after 1-way ANOVA) in HCD+ vs. HFD+ for a given time point. ap < 0.05 (post hoc test after 1-way ANOVA) with HCD values greater than those in HCD+, HFD or HFD+ for a given time point. bp < 0.05 (post hoc test after 1-way ANOVA) with HCD values not different from HFD ones and greater than those in HCD+ or HFD+ for a given time point.
photoperiod [F(1, 56) = 0.01, p = 0.98]. The [photoperiod nutritional condition] interaction was close to the threshold of significance [F(3, 56) = 2.48.19, p = 0.07]. When only rats exposed to a short photoperiod were considered, plasma leptin was significantly affected by nutritional condition [F(3, 28) = 4.85, p < 0.01]. In particular, plasma leptin in HFD rats drinking sucrose rats was higher than that in HCD rats drinking sucrose or not (post hoc test, p < 0.05; Fig. 6A). By contrast, in rats under a long photoperiod, plasma leptin was not significantly affected by nutritional condition [F(3, 28) = 1.20, p = 0.33] (Fig. 6B). Plasma adiponectin was significantly affected by the nutritional condition [F(3, 56) = 14.33, p < 0.001], independently of the photoperiod [F(1, 56) = 2.99, p = 0.09]. When only rats exposed to a short photoperiod were considered, plasma adiponectin was markedly modified by nutritional condition [F(3, 28) = 6.83, p = 0.001]. More specifically, adiponectonemia was increased in rats fed with HFD and drinking sucrose compared to the HCD and HFD animals without access to sucrose (post hoc test, p < 0.001; Fig. 6C). In rats under a long photoperiod, plasma adiponectin was also affected by the nutritional condition [F(3, 28) = 13.32, p < 0.001]. The lowest values of plasma adiponectin were found in HFD rats. These values were significantly lower than those in rats drinking sucrose and fed with HCD or HFD (post hoc test, p < 0.05; Fig. 6D). Furthermore, plasma adiponectin was increased in rats fed with HFD and drinking sucrose
compared to the control HCD group without access to sucrose (post hoc test, p < 0.05; Fig. 6C).
4. Discussion The present study shows that free access to liquid sucrose and HFD in rats enhanced sucrose consumption and relative visceral adiposity. These changes were dependent on the day-length, as they were detected only in animals exposed to a short photoperiod. As already mentioned in Section 1, some animal species are defined as photoperiodic because their physiology is regulated on a seasonal basis via the nocturnal secretion of pineal melatonin that transmits seasonal cues to the whole body (Malpaux et al., 2001; Pe ´vet, 2003). This kind of seasonal responses typically takes weeks or months to occur in photoperiodic rodents, such as Siberian or Syrian hamsters.
4.1. Adiposity and adipokine levels according to photoperiod Chronic HFD feeding leads to increased body mass and relative adiposity in rats exposed to a standard (12 h light:12 h dark) photoperiod (e.g., He ´lie `s et al., 2005; Sinitskaya et al., 2007). These effects, however, were detected after at least 6
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Figure 4 Total, chow-derived and sucrose-derived energy intake during 4 weeks in rats fed either with low-fat, high carbohydrate diet (HCD) or high fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 between groups exposed to a given photoperiod. ap < 0.05 for the same nutritional group under short vs. long photoperiods.
experimental weeks. In the present study, the final body mass was still very close between HFD and HCD rats in both photoperiods, indicating that HFD alone did not speed up any photoperiod-dependent increase of body mass after only 4 weeks of treatment. Moreover, contrary to what we expected, when HFD rats had the possibility to drink a 10% sucrose solution, they displayed a lower body mass compared to the other groups under both short- and long-photoperiods. Surprisingly, visceral adiposity, defined here as the ratio of epididymal fat pads and body mass, was specifically increased in HFD rats drinking sucrose, but only in those animals kept under a short photoperiod. There are several explanations as to why these changes occurred. HFD contains a bit less protein content (in energy) than HCD. Thus, because HFD rats drinking sucrose ate less chow pellets, they may ingest less protein than HFD rats having access to water only. However, we have previously shown that high-fat feeding in young rats (same age
and strain) did not modify regular growth (Sinitskaya et al., 2007). Similarly, chronic sucrose intake does not impair body length or carcass protein in young rats (Diniz et al., 2006; Novelli et al., 2007). As plasma leptin, which is another reliable parameter of adiposity, is increased only in the fattiest and lightest group (i.e., HFD rats with sucrose access in short days), we interpret these data as reflecting increased adiposity rather than decreased protein synthesis. Physical activity is known to affect overall energy balance. Even if exposure to short days does not change the level of locomotor activity in chow-fed rats (Zhang et al., 2000; Benstaali et al., 2002), it remains possible that HFD with sucrose affects (increases?) physical activity in rats under short days. Is there a causal link between increased sucrose consumption and increased adiposity/leptinemia under short days? Leptin, an hormone synthesized by the adipocytes, is believed to signal, on short- and long-term basis, satiety
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Figure 5 Plasma glucose (A and B), plasma insulin (C and D) as well as homeostatic model assessment and insulin resistance (HOMAIR; panels E and F) in rats fed either with low-fat, high carbohydrate diet (HCD) or high-fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). * p < 0.05 between groups exposed to a given photoperiod.
and peripheral metabolic status to the brain, respectively (Harris, 2000; Ahima, 2006; Klok et al., 2007). In keeping with this view, circulating leptin levels can be correlated to adiposity (Sinitskaya et al., 2007; this study). In rats, leptin is secreted during nighttimes (Bodosi et al., 2004). The longer night under short-photoperiod may be associated with larger daily peak of leptin. Its exogenous administration increases sucrose intake in rats exposed to chronic unpredictable stress (Lu et al., 2006), while otherwise leptin is generally considered as a satiety signal (Harris, 2000; Ahima, 2006). Moreover, it cannot be fully excluded that hypothalamic sensitivity to leptin, that can be reduced by high-fat feeding (Widdowson et al., 1997), is also changed by photoperiodic conditions. Therefore, the putative longer duration of leptin secretion under short days may somehow enhance sucrose consumption. Our
experimental data, however, do not support this hypothesis because both HCD and HFD groups with access to sucrose under short photoperiods would then display these changes. This was not the case. Furthermore, the fact that sucrose was given as liquid may have reduced satiety signals (Malik et al., 2006; Drewnowski and Bellisle, 2007; Mourao et al., 2007). Thus, the longer night under short days may have lengthened the daily duration of sucrose intake compared to long days. This argument, however, does not explain why the intake of sucrose solution under exposure to short days was elevated in HFD rats, but not in control rats fed with HCD. This continuously greater intake of sucrose in HFD rats was associated with the highest energy intake and plasma leptin. On a long-term scale (months), chronic sucrose intake is well known to induce body mass gain and obesity in rats (Fukuchi et al., 2004;
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Figure 6 Plasma leptin (A and B) and adiponectin (C and D) in rats fed either with low-fat, high carbohydrate diet (HCD) or high fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 between groups exposed to a given photoperiod.
Galic and Persinger, 2007). Thus, the most likely explanation is that under short days, the combination of two obesogenic factors, namely HFD feeding and high sucrose consumption, selectively enhances adipogenesis. Adiponectin is another hormone synthesized by the adipocytes with anti-diabetic, anti-atherogenic and antiinflammatory effects (Ahima, 2006; Okamoto et al., 2006). Contrary to leptin, its plasma levels are known to be reduced in obese patients. Thus, hypoadiponectinemia has been proposed to be an indicator of the metabolic syndrome (Weyer et al., 2001; Santaniemi and Kesaniemi, 2006). Accordingly, under both short and long photoperiods, low levels of plasma adiponectin in HFD rats drinking only water were associated with relatively high plasma leptin. The opposite trend can be seen in HCD rats drinking only water. By contrast, these relationships between plasma adiponectin and leptin were totally absent in the rats having access to sucrose. Independently of the photoperiod, both HCD and HFD rats drinking sucrose had greater adiponectinemia compared to rats drinking water only. This unexpected finding has been already described in Sprague— Dawley rats fed with a sucrose-enriched diet (Kamari et al., 2007). With respect to blood glucose, it was significantly increased in HFD rats having free access to sucrose under a long photoperiod. A trend for similar results is observable under a short photoperiod. In view of the values for plasma insulin and HOMA-IR, these rats treated for 4 weeks cannot be considered as being insulin-resistant. Nevertheless, it is more than likely that longer exposure to these nutritional conditions would lead to altered b-cell function.
4.2. Sucrose consumption according to photoperiod and feeding regimen In contrast to the diet that was imposed to all the rats, two groups of animals per photoperiod had the possibility to choose between water and 10% sucrose solution. Overall, total energy intake was maintained constant, as rats drinking the sweetened solution proportionally reduced their calorie intake from chow pellets (HCD or HFD). One salient exception is the group of HFD rats drinking sucrose solution under a short-photoperiod. Those rats indeed had a greater total intake of energy compared to HCD animals under the same photoperiod. Interestingly, the quantity of sucrose ingestion depended on both diet and photoperiod. Sucrose consumption was not markedly modified by the day-length in animals fed with the control diet (HCD). Incidentally, in rats exposed to long photoperiods, there was an increase in sucrose consumption in the HCD rats compared to the HFD group. However, the difference was only significantly during the last experimental week and seems due rather to a relative (unexplained) decrease in the HFD rats. Overall, this effect on sucrose consumption under long days was much smaller than that observed under short days. Indeed, under a short-photoperiod, rats fed with HFD displayed sustained larger intake of sucrose. Because rats are nocturnal animals, one can argue that a longer night may allow them to drink sucrose solution for a longer daily period. If so, both HCD and HFD rats exposed to short days would then have a greater sucrose intake compared to individuals exposed to long days. This was not the case,
Photoperiod affects sucrose and calorie intake in ratst as only rats with HFD selectively increased sucrose consumption in short days. Consumption of sweet solutions has long been used in animals to assess hedonia and responsiveness to reward (Willner, 1984). Accordingly, animal models of depression and anhedonia, such as chronic unpredictable stress, are associated with reduced sucrose consumption, an effect that can be reversed by tricyclic antidepressants (Willner, 1984; Monleon et al., 1995). Of interest, exposure to a short photoperiod has anxiogenic effects not only in the Siberian hamster, a photoperiodic species (Prendergast and Nelson, 2005), but also in the laboratory Wistar rat (Benabid et al., 2008). Moreover, a short day-length triggers depressive-like responses in two photoperiodic species, the Siberian hamster and the fat sand rat (Prendergast and Nelson, 2005; Einat et al., 2006). At a first glance, it may thus appear surprising that our rats increase, and not decrease, sucrose consumption when exposed to a shortphotoperiod. In this context, it is noteworthy that SAD patients during winter depressive episodes may have excessive sweets intake, often with food associating carbohydrate and fat (Wurtman and Wurtman, 1995; Kra ¨uchi et al., 1997; Friedman et al., 2006). New curative strategies taking into account nutrient content and nutrient timing are under investigation in SAD patients (Danilenko et al., 2008). To better understand the underlying mechanisms, further studies will aim at investigating the metabolic responses to HFD and sucrose in photoperiodic species. If exposure to short-photoperiod facilitates expression of altered affective responses, then increases of sucrose intake and relative adiposity in HFD rats under short-days may help to develop new animal models of winter depression. Furthermore, these altered metabolic responses according to daylength opens new avenues for investigating the physiological mechanisms underlying diet-induced obesity and metabolic syndrome.
Role of the funding sources Funding for this study was provided by the Institut de Recherches Internationales Servier, France.
Conflict of interest None declared.
Acknowledgment We wish to thank Dr. D. Ciocca for her valuable assistance during data collection. Contributors: C.S.K., B.G.L., P.P. and E.C. designed research; N.S., S.G. and E.C. performed research; N.S. and E.C. analyzed data; P.P. and E.C. wrote the paper.
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1277 Allen, N.H., Kerr, D., Smythe, P.J., Martin, N., Osola, K., Thompson, C., 1992. Insulin sensitivity after phototherapy for seasonal affective disorder. Lancet 339, 1065—1066. Astrup, A., 2005. The role of dietary fat in obesity. Semin. Vasc. Med. 5, 40—47. Bartness, T.J., Wade, G.N., 1985. Photoperiodic control of seasonal body weight cycles in hamsters. Neurosci. Biobehav. Rev. 95, 599—612. Benabid, N., Mesfioui, A., Ouichou, A., 2008. Effects of photoperiod regimen on emotional behaviour in two tests for anxiolytic activity in Wistar rat. Brain Res. Bull. 75, 53—59. Benstaali, C., Bogdan, A., Touitou, Y., 2002. Effect of a short photoperiod on circadian rhythms of body temperature and motor activity in old rats. Pflu ¨gers Arch. 444, 73—79. Bodosi, B., Gardi, J., Hajdu, I., Szentirmai, E., Obal Jr., F., Krueger, J.M., 2004. Rhythms of ghrelin, leptin, and sleep in rats: effects of the normal diurnal cycle, restricted feeding, and sleep deprivation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1071—R1079. Bowers, R.R., Gettys, T.W., Prpic, V., Harris, R.B., Bartness, T.J., 2005. Short photoperiod exposure increases adipocyte sensitivity to noradrenergic stimulation in Siberian hamsters. Am. J. Physiol. Regul. Integr. Comp. Physiol. 288, R1354—R1360. Danilenko, K.V., Plisov, I.L., He ¨uchi, K., Wirz-Justice, ´bert, M., Kra A., 2008. Influence of timed nutrient diet on depression and light sensitivity in seasonal affective disorder. Chronobiol. Int. 25, 51—64. de Castro, J.M., 1991. Seasonal rhythms of human nutrient intake and meal pattern. Physiol. Behav. 50, 243—248. Diniz, Y.S., Rocha, K.K., Souza, G.A., Galhardi, C.M., Ebaid, G.M., Rodrigues, H.G., JL, N.F., Cicogna, A.C., Novelli, E.L., 2006. Effects of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia, dyslipidemia and oxidative stress in rats. Eur. J. Pharmacol. 543, 151—157. Drewnowski, A., Bellisle, F., 2007. Liquid calories, sugar, and body weight. Am. J. Clin. Nutr. 85, 651—661. Einat, H., Kronfeld-Schor, N., Eilam, D., 2006. Sand rats see the light: short photoperiod induces a depression-like response in a diurnal rodent. Behav. Brain Res. 173, 153—157. Faulconnier, Y., Bonnet, M., Bocquier, F., Leroux, C., Chilliard, Y., 2001. Effects of photoperiod and feeding level on adipose tissue and muscle lipoprotein lipase activity and mRNA level in dry nonpregnant sheep. Br. J. Nutr. 85, 299—306. Friedman, S., Even, C., Thuile, J., Rouillon, F., Guelfi, J.D., 2006. Night eating syndrome and winter seasonal affective disorder. Appetite 47, 119—122. Fukuchi, S., Hamaguchi, K., Seike, M., Himeno, K., Sakata, T., Yoshimatsu, H., 2004. Role of fatty acid composition in the development of metabolic disorders in sucrose-induced obese rats. Exp. Biol. Med. (Maywood) 229, 486—493. Galic, M.A., Persinger, M.A., 2007. Diverse physiological consequences of long-term sucrose consumption in female rats. Nutr. Neurosci. 10, 59—66. Harris, R.B., 2000. Leptin-much more than a satiety signal. Annu. Rev. Nutr. 20, 45—75. He ´lie `s, J.M., Diane, A., Langlois, A., Larue-Achagiotis, C., Fromentin, G., Tome ´, D., Morme `de, P., Marissal-Arvy, N., 2005. Comparison of fat storage between Fischer 344 and obesity-resistant Lou/ C rats fed different diets. Obes. Res. 13, 3—10. Kamari, Y., Grossman, E., Oron-Herman, M., Peleg, E., Shabtay, Z., Shamiss, A., Sharabi, Y., 2007. Metabolic stress with a high carbohydrate diet increases adiponectin levels. Horm. Metab. Res. 39, 384—388. Klok, M.D., Jakobsdottir, S., Drent, M.L., 2007. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes. Rev. 8, 21—34. Kra ¨uchi, K., Reich, S., Wirz-Justice, A., 1997. Eating style in seasonal affective disorder: who will gain weight in winter? Compr. Psychiatry 38, 80—87.
1278 Kra ¨uchi, K., Keller, U., Leonhardt, G., Brunner, D.P., van der Velde, P., Haug, H.J., Wirz-Justice, A., 1999. Accelerated post-glucose glycaemia and altered alliesthesia-test in seasonal affective disorder. J. Affect. Disord. 53, 23—26. Lu, X.Y., Kim, C.S., Frazer, A., Zhang, W., 2006. Leptin: a potential novel antidepressant. Proc. Natl. Acad. Sci. U.S.A. 103, 1593— 1598. Ma, Y., Olendzki, B.C., Li, W., Hafner, A.R., Chiriboga, D., Hebert, J.R., Campbell, M., Sarnie, M., Ockene, I.S., 2006. Seasonal variation in food intake, physical activity, and body weight in a predominantly overweight population. Eur. J. Clin. Nutr. 60, 519—528. Malik, V.S., Schulze, M.B., Hu, F.B., 2006. Intake of sugar-sweetened beverages and weight gain: a systematic review. Am. J. Clin. Nutr. 84, 274—288. Malpaux, B., Migaud, M., Tricoire, H., Chemineau, P., 2001. Biology of mammalian photoperiodism and the critical role of the pineal gland and melatonin. J. Biol. Rhythms 16, 336—347. Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., 1985. Homeostasis model assessment: insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412—419. Monleon, S., D’Aquila, P., Parra, A., Simon, V.M., Brain, P.F., Willner, P., 1995. Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine. Psychopharmacology (Berlin) 117, 453—457. Mourao, D.M., Bressan, J., Campbell, W.W., Mattes, R.D., 2007. Effects of food form on appetite and energy intake in lean and obese young adults. Int. J. Obes. (London) 31, 1688—1695. Novelli, E.L., Diniz, Y.S., Galhardi, C.M., Ebaid, G.M., Rodrigues, H.G., Mani, F., Fernandes, A.A., Cicogna, A.C., Novelli Filho, J.L., 2007. Anthropometrical parameters and markers of obesity in rats. Lab. Anim. 41, 111—119. Okamoto, Y., Kihara, S., Funahashi, T., Matsuzawa, Y., Libby, P., 2006. Adiponectin: a key adipocytokine in metabolic syndrome. Clin. Sci. (London) 110, 267—278. Pe ´vet, P., 2003. Melatonin: from seasonal to circadian signal. J. Neuroendocrinol. 15, 422—426. Prendergast, B.J., Nelson, R.J., 2005. Affective responses to changes in day-length in Siberian hamsters (Phodopus sungorus). Psychoneuroendocrinology 30, 438—452.
N. Sinitskaya et al. Rintama ¨ki, R., Grimaldi, S., Englund, A., Haukka, J., Partonen, T., Reunanen, A., Aromaa, A., Lonnqvist, J., 2008. Seasonal changes in mood and behavior are linked to metabolic syndrome. PLoS ONE 3, e1482. Santaniemi, M., Kesaniemi, Y.A., Ukkola, O., 2006. Low plasma adiponectin concentration is an indicator of the metabolic syndrome. Eur. J. Endocrinol. 155, 745—750. Sinitskaya, N., Gourmelen, S., Schuster-Klein, C., Guardiola-Lemaitre, B., Pe ´vet, P., Challet, E., 2007. Increasing the fat-to-carbohydrate ratio in a high-fat diet prevents the development of obesity but not a prediabetic state in rats. Clin. Sci. (London) 113, 417—425. Wade, G.N., 1983. Dietary obesity in golden hamsters: reversibility and effects of sex and photoperiod. Physiol. Behav. 30, 131—137. Watson, P.E., McDonald, B.W., 2007. Seasonal variation of nutrient intake in pregnancy: effects on infant measures and possible influence on diseases related to season of birth. Eur. J. Clin. Nutr. 61, 1271—1280. Wehr, T.A., Giesen, H.A., Schulz, P.M., Anderson, J.L., Joseph-Vanderpool, J.R., Kelly, K., Kasper, S., Rosenthal, N.E., 1991. Contrasts between symptoms of summer depression and winter depression. J. Affect. Disord. 23, 173—183. Weyer, C., Funahashi, T., Tanaka, S., Hotta, K., Matsuzawa, Y., Pratley, R.E., Tataranni, P.A., 2001. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J. Clin. Endocrinol. Metab. 86, 1930—1935. Widdowson, P.S., Upton, R., Buckingham, R., Arch, J., Williams, G., 1997. Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes 46, 1782—1785. Willner, P., 1984. The validity of animal models of depression. Psychopharmacology (Berlin) 83, 1—16. Wurtman, R.J., Wurtman, J.J., 1995. Brain serotonin, carbohydratecraving, obesity and depression. Obes. Res. 3, 477S—480S. Yanovski, S., 2003. Sugar and fat: cravings and aversions. J. Nutr. 133, 835S—837S. Zhang, B.L., Zannou, E., Sannajust, F., 2000. Effects of photoperiod reduction on rat circadian rhythms of BP, heart rate, and locomotor activity. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R169—R178.
a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m
j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / p s y n e u e n
Short day-length increases sucrose consumption and adiposity in rats fed a high-fat diet ´atrice Guardiola-Lemaitre b, Natalia Sinitskaya a, Carole Schuster-Klein b, Be ´vet a, Etienne Challet a,* Sylviane Gourmelen a, Paul Pe a
´partement de Neurobiologie des Rythmes, Institut de Neurosciences Cellulaires et Inte ´gratives, CNRS, Universite ´ Louis Pasteur, 5 De rue Blaise Pascal, 67084 Strasbourg, France b ´iades, 92415 Courbevoie cedex, France Institut de Recherches Internationales Servier (IRIS-Servier), 6 Place des Ple Received 27 February 2008; received in revised form 13 June 2008; accepted 3 July 2008
KEYWORDS Obesity; Leptin; Adiponectin; Carbohydrate craving; Winter depression
Summary Background: Photoperiod, i.e., the relative day-length per 24 h, may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption. Methods: To test this hypothesis, hormonal changes, fat accretion and sucrose intake were measured in rats exposed to short- or long-day for 4 weeks and fed with a standard highcarbohydrate low-fat pelleted diet (high-carbohydrate diet (HCD)) or a high-fat, mediumcarbohydrate pelleted diet (HFD), with or without free access to 10% sucrose solution in addition to water available ad libitum. Results: Plasma leptin and adiposity index, defined as epididymal white fat expressed as percentage of body mass, were markedly increased only in HFD-fed animals drinking sucrose under short, but not long, photoperiods. Voluntary ingestion of sucrose under short days was greater in HFD rats compared with HCD animals over the experiment, while a trend for the opposite effect was visible under long days. Total energy intake was not changed overall, as rats proportionally decreased chow intake when they drank sucrose. A noteworthy exception was the HFD group with sucrose access under short days that significantly increased their total calorie intake. Fasting blood glucose was generally unaltered, except for an increase in HFD-fed animals drinking sucrose under long days compared to control animals, suggesting a decrease in glucose tolerance. Insulin resistance was not yet affected by nutritional or photoperiodic conditions after 4 experimental weeks. Conclusions: Even if photoperiod cannot be considered as an obesogenic environmental factor per se, the metabolic effects resulting from the combination of high-fat feeding and voluntary intake of sucrose were dependent on day-length. Exposure to short days triggers a larger increase of sucrose ingestion and hyperleptinemia in rats fed with HFD compared to the control diet. Considering that the cardinal symptoms of winter depression include carbohydrate craving and increased adiposity, the present data provide an experimental basis for developing new animal models of seasonal affective disorder. # 2008 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +33 3 88456693; fax: +33 3 88456654. E-mail address: [email protected] (E. Challet). 0306-4530/$ — see front matter # 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.psyneuen.2008.07.003
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1. Introduction In humans, dietary fat and sugar-rich beverages are major risks of developing visceral obesity, type 2 diabetes, and cardiovascular disease, these symptoms together defining the so-called metabolic syndrome (e.g., Astrup, 2005). Of note, epidemiologic analyses suggest that the human metabolic syndrome could be linked in part to seasonality (Rintama ¨ki et al., 2008). Moreover, a few previous reports have mentioned possible seasonal fluctuations of energy intake in humans (e.g., de Castro, 1991; Ma et al., 2006; Watson and McDonald, 2007). Thus, photoperiod (i.e., the relative daylength per 24 h depending on seasons) may modulate the metabolic responses to high-fat diet (HFD) and sucrose consumption. The seasonal affective disorder (SAD, also known as socalled winter depression) typically occurs under short photoperiods and is often associated with carbohydrate craving (Wurtman and Wurtman, 1995; Kra ¨uchi et al., 1997; Yanovski, 2003). There are indications that SAD is associated with altered glucose metabolism (Allen et al., 1992; Kra ¨uchi et al., 1999). Besides carbohydrate craving, another cardinal symptom of SAD is gain in body mass and fat (Wehr et al., 1991). Classical animal models of major depression are associated with reduced sucrose intake (Willner, 1984; Monleon et al., 1995). By contrast, an appropriate animal model of SAD would aim at combining increases in sucrose intake and adiposity, possibly depending on photoperiod. Photoperiod may by itself directly or indirectly affect energy metabolism. Natural fluctuations of food intake and/or body mass and adiposity are well known to occur according to the seasons in photoperiodic species (Bartness and Wade, 1985; Adam and Mercer, 2004). In those animals, physiology is specifically and reversibly regulated on a seasonal basis. In particular, metabolism of white adipose tissue is influenced by day-length in photoperiodic species (Faulconnier et al., 2001; Bowers et al., 2005). The photoperiodic information is transduced into neuroendocrine changes via the nocturnal secretion of melatonin by the pineal gland (Malpaux et al., 2001; Pe ´vet, 2003). Interestingly, in photoperiodic rodents such as Syrian hamsters, the metabolic effects of HFD are exaggerated when animals are housed in short days (Wade, 1983). In rats under 12:12 photoperiod, gain in body mass and fat accretion have been observed after only 1 month (Fukuchi et al., 2004) or longer duration of sucrose access (Fukuchi et al., 2004; Galic and Persinger, 2007). As a putative obesogenic environmental factor, photoperiod may affect these parameters in rats. The photoperiodic environment could indeed exaggerate metabolic responses to dietary fat or sucrose. To test this hypothesis in the perspective of modelling SAD, fat accretion and sucrose consumption were measured in rats fed with a HFD — combined or not with sucrose access — and exposed to short or long day for 4 weeks.
2. Materials and methods 2.1. Ethics The experiment was performed in accordance with the rules of the European Committee Council Directive of 24 November
N. Sinitskaya et al. 1986 (86/609/EEC) and the French Department of Agriculture (license no. 67-88).
2.2. Animals Sixty-four male Sprague—Dawley rats (Charles River Laboratories, L’Arbresle, France) weighing around 120 g upon their arrival (age: 4 weeks), were housed individually, kept at 21 1 8C under a 12:12 h light—dark cycle (lights on at 07:00 h) and had ad libitum access to food (standard lowfat diet, 105, SAFE, 89290 Augy, France) and tap water for 2 weeks.
2.3. Experimental design On the first day of the experiment, 6-weeks-old rats were distributed equally in two rooms: one half (n = 32) was exposed to a short (i.e., winter-like) photoperiod with a 10:14 h light—dark cycle (lights on at 0700 h); the other half (n = 32) was exposed to a long (i.e., summer-like) photoperiod with a 14:10 h light—dark cycle (lights on at 07:00 h). For each photoperiodic condition, rats were divided into two groups: the first group of 16 rats was fed a standard highcarbohydrate, low-fat pelleted diet (high-carbohydrate diet (HCD); 15.5 kJ/g (3.7 kcal/g); 229H, SAFE: distribution of metabolizable energy content in %: 24% protein, 64% carbohydrate and 12% fat derived from corn oil only), while the second group of 16 rats received a high-fat, medium-carbohydrate pelleted diet (HFD; 19.7 kJ/g (4.7 kcal/g), SAFE: energy content distribution in %: 17% protein, 30% carbohydrate and 53% fat, including 6% derived from corn oil and 47% saturated fat from lard). This diet has been shown to increase fat accretion and to reduce sensitivity to insulin (Sinitskaya et al., 2007). Composition of HCD and HFD is shown in Table 1. For each feeding regimen, half of the animals had ad libitum access to tap water (n = 8), while the other half had free access to 10% sucrose solution in addition to water supply (n = 8). Diets were vacuum-packed and stored in a fresh (8 8C) room before use. Animals were given fresh food (200 g) and beverages every week. Body mass and food consumption (remaining pellets) were measured in early morning, every week. Diets were given as dry pellets so to limit spillage. After 4 weeks of experimental diet, rats were fasted overnight and deeply anesthetized in early morning with isoflurane and their body mass were determined before decapitation. After trunk blood was collected, one drop was sampled for glucose assay and the remaining blood centrifugated for further ELISA analysis. Epididymal fat pads Table 1
Centesimal composition (in 100 g of chow)
Protein Carbohydrate Fat (corn oil) Fat (lard) Fibres Minerals, ash Vitamins Binder (silica)
229H (HCD)
HFD
22.5 59.5 5 — 5 7 1 —
20 37 3 25 5 7 1 2
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were dissected and weighed. The mass of epididymal fat expressed as percentage of body mass was used as an index of adiposity.
2.4. Methods of analysis Blood glucose was immediately determined (Glucotrend premium kit, Roche Diagnostics, Meylan, France). Plasma insulin was determined by an ELISA kit for rats (EZRMI-13 K, Linco Research Inc., St. Charles, MO, USA) with intra- and inter-assay coefficients of variation (%CV) of 1.9 0.6 and 7.6 0.8%, respectively. The limit of sensitivity of insulin assay was 0.2 ng/ml. Plasma leptin was determined by an ELISA kit for rats (EZRL-83 K, Linco Research) with 2.2 0.2 intra- and 3.4 0.3 inter-assay %CV. The limit of sensitivity of leptin assay was 0.04 ng/ml. Plasma adiponectin was determined by an ELISA kit for rats (EZRADP-62 K, Linco Research) with 1.3 0.2 intra- and 7.0 0.4 inter-assay %CV. The limit of sensitivity of adiponectin assay was 0.155 ng/ml. Homeostatic model assessment (HOMA) was used to assess B-cell function and insulin resistance (IR), and calculated as follows: HOMA-IR = (fasting plasma glucose fasting plasma insulin)/22.5 as described by Matthews et al. (1985).
2.5. Statistical analysis To test the effects of nutritional condition (HCD water, HCD + sucrose, HFD water or HFD + sucrose), photoperiod (short vs. long) or time (week 1—4), data were processed with analyses of variance (ANOVA) with repeated measures or not, depending on the parameter considered. If significant main effects or significant interactions were detected ( p < 0.05), post hoc comparisons were performed with Tukey HSD test. Values are means S.E.M.
3. Results
Figure 1 Changes in body mass in rats fed either with low-fat, high carbohydrate diet (HCD, circles) or high-fat, medium-carbohydrate diet (HFD, squares) under short (A) or long photoperiods (B). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 (post hoc test after 2-way ANOVA) for HFD+ group compared to the HCD, HCD+ and HFD groups.
3.1. Body mass and adiposity At the end of experiment, body mass was significantly affected by the nutritional condition [F(3, 56) = 19.66; p < 0.001], independently of the photoperiod [F(1, 56) = 0.97, p = 0.33]. More specifically, HFD rats drinking sucrose had a lower body mass compared to the three other groups under both short- and long photoperiod (post hoc test, p < 0.001; Fig. 1A and B). With respect to the time-course of these changes, they appear from 2 to 3 weeks after the beginning to the end of the treatment (as analyzed with [nutritional condition time] ANOVA for each photoperiodic condition: see Fig. 1A and B). There was a significant [nutritional condition photoperphotoperiod] interaction [F(3, 56) = 3.08, p < 0.05] for adiposity index (i.e., epididymal white fat as percentage of body mass) while the main effects of nutritional condition or photoperiod were not significant [F(3, 56) = 1.69, p = 0.18 and F(1, 56) = 0.28, p = 0.60, respectively]. Of note, adiposity index was greater in HFD-fed animals drinking sucrose under a short photoperiod compared not only to rats drinking sucrose and fed with the control (HCD) diet under the same photoperiod (post hoc test, p < 0.01), but also to animals fed
with the same regimen under a long photoperiod (post hoc test, p < 0.05; Fig. 2A and B).
3.2. Sucrose consumption In rats exposed to a short photoperiod, 10% sucrose intake (in volume) was affected by the nutritional condition [F(1, 42) = 8.11, p = 0.01] and time [F(3, 42) = 24.95, p < 0.001]. Interestingly, sucrose consumption was greater in HFD than HCD groups, as soon as the second week of treatment (post hoc test, p < 0.05) up to the fourth experimental week (post hoc test, p < 0.05; Fig. 3A). In rats exposed to a long photoperiod, sucrose consumption (in volume) was affected by time [F(3, 42) = 24.95, p < 0.001], but not by the nutritional condition [F(1, 42) = 1.99, p = 0.18]. Moreover, there was a significant [time nutritional condition] interaction for sucrose intake in long photoperiod [F(3, 42) = 6.08, p < 0.01]. In contrast to what happens in short photoperiod, sucrose intake tended to be opposite (i.e., HCD > HFD) when rats were exposed to a long photoperiod. This difference was significant only by the fourth week of experiment (post hoc test, p < 0.01; Fig. 3B).
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N. Sinitskaya et al. ing the first experimental week, food intake in HCD rats was greater than that in HCD+, HFD and HFD+ groups (post hoc test, p < 0.05). During the following 3 weeks, food intake in both HCD and HFD groups (i.e., without sucrose) was larger than that in HCD+ and HFD+ rats (i.e., with sucrose access; Fig. 3D). Total energy intake over the experiment was significantly affected by the nutritional condition [F(3, 56) = 4.63, p < 0.01], independently of the photoperiod [F(1, 56) = 0.24, p = 0.63]. While total energy intake under a long-photoperiod remained unaltered between the nutritional groups (Fig. 4B), it was significantly increased under a short photoperiod in animals drinking sucrose and fed with HFD in comparison with rats drinking only water and fed with the control (HCD) diet (post hoc test, p < 0.01; Fig. 4A). Energy intake derived from chow pellets was affected by sucrose consumption [F(3, 56) = 63.00, p < 0.001], independently of the photoperiod [F(1, 56) = 0.06, p = 0.81]. Accordingly, when rats had free access to a sucrose solution and fed with or without HFD, they proportionally reduced their energy intake from chow (Fig. 4C and D). There was a significant [photoperiod nutritional condition] interaction [F(1, 28) = 10.19, p < 0.01] for voluntary intake of 10% sucrose solution (Fig. E and F), while the main effects of the photoperiod and nutritional condition were not significant [F(1, 28) = 1.02, p = 0.32 and F(1,28) = 0.06, p = 0.79, respectively].
3.4. Blood glucose, insulinemia, homeostatic model assessment and insulin resistance (HOMAIR) Figure 2 Adiposity, as determined by the ratio of abdominal (i.e., epididymal and retroperitoneal) white fat and body mass, in rats fed either with low-fat, high carbohydrate diet (HCD) or high-fat, medium-carbohydrate diet (HFD, squares) under short (A) or long photoperiods (B). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 (post hoc test after 2-way ANOVA) between HFD+ and HCD+ groups. ap < 0.05 (post hoc test after 2-way ANOVA) for HFD+ under short vs. long photoperiods.
3.3. Food, chow-derived and sucrose-derived energy intake Food intake (in grams) in rats exposed to a short photoperiod was affected by the nutritional condition [F(3, 84) = 52.47, p < 0.001] but not by time [F(3, 84) = 0.79, p = 0.50]. There was also a significant [time nutritional condition] interaction [F(9, 84) = 6.13, p < 0.001]. Food intake in HCD rats was always greater than in the three other groups (HCD+, HFD and HFD+; post hoc test, p < 0.05), except for the fourth experimental week during which HFD and HCD groups were no longer different between each other (Fig. 3C). In rats exposed to a long photoperiod, food intake (in grams) was significantly changed by the nutritional condition [F(3, 84) = 32.44, p < 0.001] and time [F(3, 84) = 3.49, p < 0.05]. In addition, the [time nutritional condition] interaction was significant [F(9, 84) = 4.76, p < 0.001]. Dur-
Two-way ANOVA did not detect any significant effect for photoperiod [F(1, 56) = 0.19, p = 0.66] or nutritional condition [F(3, 56) = 1.93, p = 0.13] on values of fasting blood glucose. When we considered only the rats exposed to a short photoperiod, blood glucose determined in the morning (i.e., 2 h after the onset of light) did not differ significantly between the nutritional conditions [F(3, 28) = 0.79, p = 0.51] (Fig. 5A). By contrast, in rats exposed to a long photoperiod, fasting blood glucose was significantly affected by the nutritional conditions [F(3, 28) = 3.27, p < 0.05]. Post hoc test revealed a greater concentration of blood glucose in HFD-fed animals drinking sucrose compared to control animals ( p < 0.05; Fig. 5B). Morning levels of plasma insulin in fasted rats were not significantly affected by the nutritional condition [F(3, 56) = 1.70, p = 0.18] or photoperiodic conditions [F(1, 56) = 0.36, p = 0.55] (Fig. 5C and D). Similarly, HOMA-IR was not significantly affected by the nutritional condition [F(3, 56) = 1.12, p = 0.35] or the photoperiod [F(1, 56) = 0.13, p = 0.72] (Fig. 5E and F), thus, suggesting that the rats were not exposed to nutritional conditions for a duration long enough to alter b-cell function.
3.5. Leptinemia and adiponectinemia Plasma leptin was significantly affected by the nutritional condition [F(3, 56) = 4.20, p = 0.01], independently of the
Photoperiod affects sucrose and calorie intake in ratst
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Figure 3 Consumption of 10% sucrose solution (A and B) and food intake (C and D) in rats fed with low-fat, high carbohydrate diet (HCD+, circles) or high-fat, medium-carbohydrate diet (HFD+, squares) under short (A and C) or long photoperiods (B and D). *p < 0.05 (post hoc test after 1-way ANOVA) in HCD+ vs. HFD+ for a given time point. ap < 0.05 (post hoc test after 1-way ANOVA) with HCD values greater than those in HCD+, HFD or HFD+ for a given time point. bp < 0.05 (post hoc test after 1-way ANOVA) with HCD values not different from HFD ones and greater than those in HCD+ or HFD+ for a given time point.
photoperiod [F(1, 56) = 0.01, p = 0.98]. The [photoperiod nutritional condition] interaction was close to the threshold of significance [F(3, 56) = 2.48.19, p = 0.07]. When only rats exposed to a short photoperiod were considered, plasma leptin was significantly affected by nutritional condition [F(3, 28) = 4.85, p < 0.01]. In particular, plasma leptin in HFD rats drinking sucrose rats was higher than that in HCD rats drinking sucrose or not (post hoc test, p < 0.05; Fig. 6A). By contrast, in rats under a long photoperiod, plasma leptin was not significantly affected by nutritional condition [F(3, 28) = 1.20, p = 0.33] (Fig. 6B). Plasma adiponectin was significantly affected by the nutritional condition [F(3, 56) = 14.33, p < 0.001], independently of the photoperiod [F(1, 56) = 2.99, p = 0.09]. When only rats exposed to a short photoperiod were considered, plasma adiponectin was markedly modified by nutritional condition [F(3, 28) = 6.83, p = 0.001]. More specifically, adiponectonemia was increased in rats fed with HFD and drinking sucrose compared to the HCD and HFD animals without access to sucrose (post hoc test, p < 0.001; Fig. 6C). In rats under a long photoperiod, plasma adiponectin was also affected by the nutritional condition [F(3, 28) = 13.32, p < 0.001]. The lowest values of plasma adiponectin were found in HFD rats. These values were significantly lower than those in rats drinking sucrose and fed with HCD or HFD (post hoc test, p < 0.05; Fig. 6D). Furthermore, plasma adiponectin was increased in rats fed with HFD and drinking sucrose
compared to the control HCD group without access to sucrose (post hoc test, p < 0.05; Fig. 6C).
4. Discussion The present study shows that free access to liquid sucrose and HFD in rats enhanced sucrose consumption and relative visceral adiposity. These changes were dependent on the day-length, as they were detected only in animals exposed to a short photoperiod. As already mentioned in Section 1, some animal species are defined as photoperiodic because their physiology is regulated on a seasonal basis via the nocturnal secretion of pineal melatonin that transmits seasonal cues to the whole body (Malpaux et al., 2001; Pe ´vet, 2003). This kind of seasonal responses typically takes weeks or months to occur in photoperiodic rodents, such as Siberian or Syrian hamsters.
4.1. Adiposity and adipokine levels according to photoperiod Chronic HFD feeding leads to increased body mass and relative adiposity in rats exposed to a standard (12 h light:12 h dark) photoperiod (e.g., He ´lie `s et al., 2005; Sinitskaya et al., 2007). These effects, however, were detected after at least 6
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Figure 4 Total, chow-derived and sucrose-derived energy intake during 4 weeks in rats fed either with low-fat, high carbohydrate diet (HCD) or high fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 between groups exposed to a given photoperiod. ap < 0.05 for the same nutritional group under short vs. long photoperiods.
experimental weeks. In the present study, the final body mass was still very close between HFD and HCD rats in both photoperiods, indicating that HFD alone did not speed up any photoperiod-dependent increase of body mass after only 4 weeks of treatment. Moreover, contrary to what we expected, when HFD rats had the possibility to drink a 10% sucrose solution, they displayed a lower body mass compared to the other groups under both short- and long-photoperiods. Surprisingly, visceral adiposity, defined here as the ratio of epididymal fat pads and body mass, was specifically increased in HFD rats drinking sucrose, but only in those animals kept under a short photoperiod. There are several explanations as to why these changes occurred. HFD contains a bit less protein content (in energy) than HCD. Thus, because HFD rats drinking sucrose ate less chow pellets, they may ingest less protein than HFD rats having access to water only. However, we have previously shown that high-fat feeding in young rats (same age
and strain) did not modify regular growth (Sinitskaya et al., 2007). Similarly, chronic sucrose intake does not impair body length or carcass protein in young rats (Diniz et al., 2006; Novelli et al., 2007). As plasma leptin, which is another reliable parameter of adiposity, is increased only in the fattiest and lightest group (i.e., HFD rats with sucrose access in short days), we interpret these data as reflecting increased adiposity rather than decreased protein synthesis. Physical activity is known to affect overall energy balance. Even if exposure to short days does not change the level of locomotor activity in chow-fed rats (Zhang et al., 2000; Benstaali et al., 2002), it remains possible that HFD with sucrose affects (increases?) physical activity in rats under short days. Is there a causal link between increased sucrose consumption and increased adiposity/leptinemia under short days? Leptin, an hormone synthesized by the adipocytes, is believed to signal, on short- and long-term basis, satiety
Photoperiod affects sucrose and calorie intake in ratst
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Figure 5 Plasma glucose (A and B), plasma insulin (C and D) as well as homeostatic model assessment and insulin resistance (HOMAIR; panels E and F) in rats fed either with low-fat, high carbohydrate diet (HCD) or high-fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). * p < 0.05 between groups exposed to a given photoperiod.
and peripheral metabolic status to the brain, respectively (Harris, 2000; Ahima, 2006; Klok et al., 2007). In keeping with this view, circulating leptin levels can be correlated to adiposity (Sinitskaya et al., 2007; this study). In rats, leptin is secreted during nighttimes (Bodosi et al., 2004). The longer night under short-photoperiod may be associated with larger daily peak of leptin. Its exogenous administration increases sucrose intake in rats exposed to chronic unpredictable stress (Lu et al., 2006), while otherwise leptin is generally considered as a satiety signal (Harris, 2000; Ahima, 2006). Moreover, it cannot be fully excluded that hypothalamic sensitivity to leptin, that can be reduced by high-fat feeding (Widdowson et al., 1997), is also changed by photoperiodic conditions. Therefore, the putative longer duration of leptin secretion under short days may somehow enhance sucrose consumption. Our
experimental data, however, do not support this hypothesis because both HCD and HFD groups with access to sucrose under short photoperiods would then display these changes. This was not the case. Furthermore, the fact that sucrose was given as liquid may have reduced satiety signals (Malik et al., 2006; Drewnowski and Bellisle, 2007; Mourao et al., 2007). Thus, the longer night under short days may have lengthened the daily duration of sucrose intake compared to long days. This argument, however, does not explain why the intake of sucrose solution under exposure to short days was elevated in HFD rats, but not in control rats fed with HCD. This continuously greater intake of sucrose in HFD rats was associated with the highest energy intake and plasma leptin. On a long-term scale (months), chronic sucrose intake is well known to induce body mass gain and obesity in rats (Fukuchi et al., 2004;
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Figure 6 Plasma leptin (A and B) and adiponectin (C and D) in rats fed either with low-fat, high carbohydrate diet (HCD) or high fat, medium-carbohydrate diet (HFD, squares) under short (left column) or long photoperiods (right column). Free access to 10% sucrose is denoted by a + symbol (HCD+ or HFD+). *p < 0.05 between groups exposed to a given photoperiod.
Galic and Persinger, 2007). Thus, the most likely explanation is that under short days, the combination of two obesogenic factors, namely HFD feeding and high sucrose consumption, selectively enhances adipogenesis. Adiponectin is another hormone synthesized by the adipocytes with anti-diabetic, anti-atherogenic and antiinflammatory effects (Ahima, 2006; Okamoto et al., 2006). Contrary to leptin, its plasma levels are known to be reduced in obese patients. Thus, hypoadiponectinemia has been proposed to be an indicator of the metabolic syndrome (Weyer et al., 2001; Santaniemi and Kesaniemi, 2006). Accordingly, under both short and long photoperiods, low levels of plasma adiponectin in HFD rats drinking only water were associated with relatively high plasma leptin. The opposite trend can be seen in HCD rats drinking only water. By contrast, these relationships between plasma adiponectin and leptin were totally absent in the rats having access to sucrose. Independently of the photoperiod, both HCD and HFD rats drinking sucrose had greater adiponectinemia compared to rats drinking water only. This unexpected finding has been already described in Sprague— Dawley rats fed with a sucrose-enriched diet (Kamari et al., 2007). With respect to blood glucose, it was significantly increased in HFD rats having free access to sucrose under a long photoperiod. A trend for similar results is observable under a short photoperiod. In view of the values for plasma insulin and HOMA-IR, these rats treated for 4 weeks cannot be considered as being insulin-resistant. Nevertheless, it is more than likely that longer exposure to these nutritional conditions would lead to altered b-cell function.
4.2. Sucrose consumption according to photoperiod and feeding regimen In contrast to the diet that was imposed to all the rats, two groups of animals per photoperiod had the possibility to choose between water and 10% sucrose solution. Overall, total energy intake was maintained constant, as rats drinking the sweetened solution proportionally reduced their calorie intake from chow pellets (HCD or HFD). One salient exception is the group of HFD rats drinking sucrose solution under a short-photoperiod. Those rats indeed had a greater total intake of energy compared to HCD animals under the same photoperiod. Interestingly, the quantity of sucrose ingestion depended on both diet and photoperiod. Sucrose consumption was not markedly modified by the day-length in animals fed with the control diet (HCD). Incidentally, in rats exposed to long photoperiods, there was an increase in sucrose consumption in the HCD rats compared to the HFD group. However, the difference was only significantly during the last experimental week and seems due rather to a relative (unexplained) decrease in the HFD rats. Overall, this effect on sucrose consumption under long days was much smaller than that observed under short days. Indeed, under a short-photoperiod, rats fed with HFD displayed sustained larger intake of sucrose. Because rats are nocturnal animals, one can argue that a longer night may allow them to drink sucrose solution for a longer daily period. If so, both HCD and HFD rats exposed to short days would then have a greater sucrose intake compared to individuals exposed to long days. This was not the case,
Photoperiod affects sucrose and calorie intake in ratst as only rats with HFD selectively increased sucrose consumption in short days. Consumption of sweet solutions has long been used in animals to assess hedonia and responsiveness to reward (Willner, 1984). Accordingly, animal models of depression and anhedonia, such as chronic unpredictable stress, are associated with reduced sucrose consumption, an effect that can be reversed by tricyclic antidepressants (Willner, 1984; Monleon et al., 1995). Of interest, exposure to a short photoperiod has anxiogenic effects not only in the Siberian hamster, a photoperiodic species (Prendergast and Nelson, 2005), but also in the laboratory Wistar rat (Benabid et al., 2008). Moreover, a short day-length triggers depressive-like responses in two photoperiodic species, the Siberian hamster and the fat sand rat (Prendergast and Nelson, 2005; Einat et al., 2006). At a first glance, it may thus appear surprising that our rats increase, and not decrease, sucrose consumption when exposed to a shortphotoperiod. In this context, it is noteworthy that SAD patients during winter depressive episodes may have excessive sweets intake, often with food associating carbohydrate and fat (Wurtman and Wurtman, 1995; Kra ¨uchi et al., 1997; Friedman et al., 2006). New curative strategies taking into account nutrient content and nutrient timing are under investigation in SAD patients (Danilenko et al., 2008). To better understand the underlying mechanisms, further studies will aim at investigating the metabolic responses to HFD and sucrose in photoperiodic species. If exposure to short-photoperiod facilitates expression of altered affective responses, then increases of sucrose intake and relative adiposity in HFD rats under short-days may help to develop new animal models of winter depression. Furthermore, these altered metabolic responses according to daylength opens new avenues for investigating the physiological mechanisms underlying diet-induced obesity and metabolic syndrome.
Role of the funding sources Funding for this study was provided by the Institut de Recherches Internationales Servier, France.
Conflict of interest None declared.
Acknowledgment We wish to thank Dr. D. Ciocca for her valuable assistance during data collection. Contributors: C.S.K., B.G.L., P.P. and E.C. designed research; N.S., S.G. and E.C. performed research; N.S. and E.C. analyzed data; P.P. and E.C. wrote the paper.
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