The main findings of this study were: 1) a four-week resveratrol supplementation had significant effects on energy metabolism in the mouse lemur, characterized by a reduction in seasonal body-mass gain associated with an increase in resting metabolic rate and a decrease in food intake; 2) the response to resveratrol supplementation mainly involved a strong reduction of daily heterothermia expression with no change in the daily amount of locomotor activity; 3) despite the fact that glucose-dependent insulinotropic polypeptide (GIP) values increased during resveratrol supplementation, no correlation was evidenced between the other tested gut hormones and changes in energy balance parameters.
Resveratrol supplementation was given to mouse lemurs at the very time of seasonal fattening induced by exposure to short day lengths. This period corresponds to an increase in both spontaneous food intake and frequency of deep torpor, leading to fast body mass gain through fat accumulation. Moreover, the resting metabolic rate and locomotor activity decrease, reinforcing the energy saving processes. Resveratrol supplementation appeared to limit all these energy saving mechanisms by acting more specifically on food intake and daily hypothermia bouts without change in locomotor activity.
The observed decrease in food intake in mouse lemurs cannot be related to the palatability of resveratrol as the mouse lemurs were not found to be averse to resveratrol prior to the experiment. It is more likely that an aversive palatability of resveratrol would have led to an immediate reduction in food intake which was not observed. However, the effects on food intake might have been related to the dose of resveratrol given. The dosage level administered in this study (200 mg/kg) was selected from studies in the literature on rodents, and was intermediate between the 40 mg/kg of Baur et al. [14
] and the 400 mg/kg of Lagouge et al. [12
]. This dose was carefully mixed in the food and, since the animals tended to eat less than provided, the actual ingested dose of resveratrol was below 200 mg/kg. The amount of resveratrol ingested by the animals was 96.1% in the first week and 84% in the fourth week (corresponding to an equivalent of 192 mg/kg/day and 168 mg/kg/day, respectively). These amounts, based on the existing literature, appeared sufficiently high to be effective in mammals [21
]. However, the observed satiety in resveratrol-supplemented mouse lemurs may be a sensibility response specific to this species or to primates.
Although the change in food intake could explain the reduction of seasonal body-mass gain, resveratrol supplementation significantly affected the body temperature patterns in the mouse lemur. Average values of energy savings by daily torpor in this species have been estimated to be about 40-70% as compared to the maintenance of normothermia [24
]. Under resveratrol supplementation, the depth and the duration of daily torpor decreased and were associated with an increase in both body temperature and resting metabolic rate during the daily resting period. In contrast, body temperature values during the night active phase were not modified, and nor was locomotor activity. The decrease in energy savings during the daily diurnal rest would thus contribute to the reduction in body-mass gain under resveratrol supplementation.
No such effect of resveratrol has been shown in mice, for which no change in food intake or body temperature was observed [11
]. However, these data originate from experimentally-induced obesity and it is likely that the responses observed in mouse lemurs rely on specific life-history traits of this primate, which has developed high seasonal energy saving mechanisms and exhibits pre-wintering spontaneous obesity.
Resveratrol activates mammalian sirtuins, more specifically SIRT1, which is involved in glucose homeostasis and lipid metabolism. In mice exposed to a high-fat diet or in ob/ob mice, resveratrol was shown to protect mice from diet-induced metabolic disorders [12
] by mimicking some effects of caloric restriction. Likewise, resveratrol and assimilated SIRT1 activators have been proposed as potential treatments for type 2 diabetes in mice models [14
]. The effects of resveratrol have been suggested to depend on an increase in oxidative mitochondrial metabolism [14
] and on enhanced fat oxidation [11
], leading to an increase in energy expenditure. Interestingly, SRT1720, which activates SIRT1 by four fold in comparison to resveratrol, induces a significant decrease in fat mass without a change in food intake in mice [11
]. In the mouse lemur, concomitantly to an increase in energy expenditure through decreasing hypothermia bouts and increasing metabolism, resveratrol might have a direct negative effect on fat storage.
Due to their involvement in satiety and satiation processes [18
], several gut hormones have been measured in resveratrol-supplemented mouse lemurs. No significant change was recorded after four weeks for the glucagon-like peptide 1 and the peptide YY, two gut hormones involved in the reduction of food intake and energy expenditure [31
]. Conversely, the two other gut hormones are known to induce an increase in energy expenditure. The pancreatic polypeptide increases satiety, thus leading to a loss in body mass [20
] and the glucose-dependent insulinotropic polypeptide (GIP) was shown to induce an increase in exploratory behaviour and performance in some motor function tests in a transgenic mouse that over-expressed GIP [35
]. Only GIP significantly increased with resveratrol supplementation. Data emerging from studies in animal models and cultured human fat cells support a physiological role for GIP in fat cell metabolism, leading to the mobilization of fat stores [17
]. Such effects might have contributed to the reduction in body-mass gain by limiting fat storage in supplemented mouse lemurs. The observed effect of resveratrol on food intake in the mouse lemur appears to be independent of changes in anorexic gut hormones, but the high observed inter-individual variability in our study does not allow definite conclusions to be reached. Moreover, because sampling was performed at a single point in fasted animals during the diurnal rest, changes may have been missed.
Resveratrol has been studied as a potential mimetic of caloric restriction [4
]. However, caloric restriction decreases the metabolic rate [37
], whereas resveratrol had the opposite effect [12
]. From previous studies using moderate caloric restriction in wintering mouse lemurs [17
], the effects of resveratrol significantly differed from changes observed in caloric-restricted animals. In the mouse lemurs, caloric restriction led to an increase in the duration and depth of daily torpor bouts. These body temperature adjustments were efficient at preventing body-mass loss and were not associated with changes in gut hormones [17