Food in synchrony with melatonin and corticosterone relieves constant light disturbed metabolism

Abstract

Circadian disruption is associated with metabolic disturbances such as hepatic steatosis (HS), obesity and type 2 diabetes. We hypothesized that HS, resulting from constant light (LL) exposure is due to an inconsistency between signals related to food intake and endocrine-driven suprachiasmatic nucleus (SCN) outputs. Indeed, exposing rats to LL induced locomotor, food intake and hormone arrhythmicity together with the development of HS. We investigated whether providing temporal signals such as 12-h food availability or driving a corticosterone plus melatonin rhythm could restore rhythmicity and prevent the metabolic disturbances under LL conditions in male rats. Discrete metabolic improvements under these separate treatments stimulated us to investigate whether the combination of hormone treatment together with mealtime restriction (12-h food during four weeks) could prevent the metabolic alterations. LL exposed arrhythmic rats, received daily administration of corticosterone (2.5 µg/kg) and melatonin (2.5 mg/kg) in synchrony or out of synchrony with their 12-h meal. HS and other metabolic alterations were importantly ameliorated in LL-exposed rats receiving hormonal treatment in synchrony with 12-h restricted mealtime, while treatment out of phase with meal time did not. Interestingly, liver bile acids, a major indication for HS, were only normalized when animals received hormones in synchrony with food indicating that disrupted bile acid metabolism might be an important mechanism for the HS induction under LL conditions. We conclude that food-elicited signals, as well as hormonal signals, are necessary for liver synchronization and that HS arises when there is conflict between food intake and the normal pattern of melatonin and corticosterone.

Differential Effects of Constant Light and Dim Light at Night on the Circadian Control of Metabolism and Behavior

“…In rats, shortly after LL exposure, the rhythm of the locomotor activity became free-running with a longer period, but this rhythmicity was gradually lost, until, after approximately one month, the behavior was absolutely arrhythmic in all individuals [65,66,78], which is in agreement with other studies [54,57,76,78,79,94]. The displayed changes are comparable with changes in the behavior of mice; however, the interindividual differences are far more pronounced in mice.…”

“…Unlike mice, rats produce melatonin, and its synthesis is highly sensitive to light exposure [52,53] (Table 1). Nocturnal, but not daytime, plasma melatonin levels are suppressed in LL, resulting in a loss of melatonin rhythm [54][55][56][57][58][59]. The same pattern is observed in urine 6-sulfatoxymelatonin concentrations [60].…”

“…The effects of LL on CORT in rats are diverse. In rats, its rhythm is abolished due to either the suppression of the peak [57,60] or the elevation of levels during the subjective day [59,[64][65][66]. The effects do not seem to be strain-dependent since both changes are observed in Sprague-Dawley and Wistar rats, as shown in Table 1.…”

“…The locomotor activity might be re-entrained by other stimuli than light. For example, the rhythmic hormonal treatment with CORT and melatonin restored the rhythmicity of locomotor activity [57]. Another way to restore rhythmic behavior is through restricted feeding that synchronizes locomotor activity with the time of food access.…”

“…Even though the distribution of food intake was altered, the body weight was not affected in rats [54][55][56]58,76,77], but still, the higher visceral adiposity was found [55], as indicated in Table 1. Only one study reported increased body weight and fat mass in Wistar rats after LL exposure [57].…”