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Food entrainment of circadian gene expression altered in PPARalpha-/- brown fat and heart.

ABSTRACT: The circadian clock is subject to food entrainment. Since PPARalpha exhibits a circadian expression profile, we hypothesized that PPARalpha deficiency would alter the food entrainable response of adipose, cardiac, and liver tissues. Wild-type and PPARalpha null mice were compared under ad libitum or restricted food access for the expression of circadian transcription factor-encoding mRNAs. Temporally restricted food access caused between a mean 5.8-11.5 h phase shift in the expression profiles of the circadian genes Bmal1, Per3, and Rev-erbalpha in all tissues of control mice. In contrast, these same conditions phase shifted the circadian genes in tissues of PPARalpha null mice between a mean of 10.8-14.2 h with amplitude attenuation. The food entrained phase shifts in the brown adipose and cardiac tissue circadian transcription factors of the PPARalpha null mice were prolonged significantly relative to wild-type controls. Likewise, PPARalpha responsive genes in the livers of PPARalpha null mice exhibited a significantly prolonged phase shift relative to control mice. These findings confirm and extend recent observations in the literature.

SUBMITTER: Goh BC

PROVIDER: S-EPMC2277508 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Food entrainment of circadian gene expression altered in PPARalpha-/- brown fat and heart.

Goh Brian C BC Wu Xiying X Evans Ann E AE Johnson Meagan L ML Hill Molly R MR Gimble Jeffrey M JM

Biochemical and biophysical research communications 20070705 4

The circadian clock is subject to food entrainment. Since PPARalpha exhibits a circadian expression profile, we hypothesized that PPARalpha deficiency would alter the food entrainable response of adipose, cardiac, and liver tissues. Wild-type and PPARalpha null mice were compared under ad libitum or restricted food access for the expression of circadian transcription factor-encoding mRNAs. Temporally restricted food access caused between a mean 5.8-11.5 h phase shift in the expression profiles o ...[more]

PMID: 17624301

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Project description:Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10-15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is dependent on the chronicity and circadian phase of RF but independent of body weight. Given that LS involves reorganization of DA-regulated motor circuitry, our work provides indirect support for the role of DA in the food entrainment pathway of RF. The findings also suggest differences in neuronal pathways involved in LS from AMPH sensitization and LS from RF.

Project description:Retinoic acid induced 1 ( RAI1 ) encodes a dosage-sensitive gene that when haploinsufficient results in Smith-Magenis syndrome (SMS) and when overexpressed results in Potocki-Lupski syndrome (PTLS). Phenotypic and molecular evidence illustrates that haploinsufficiency of RAI1 disrupts circadian rhythm through the dysregulation of the master circadian regulator, circadian locomotor output cycles kaput ( CLOCK) , and other core circadian components, contributing to prominent sleep disturbances in SMS. However, the phenotypic and molecular characterization of sleep features in PTLS has not been elucidated. Using the Pittsburgh Sleep Quality Index (PSQI), caregivers of 15 school-aged children with PTLS reported difficulties in initiating sleep. Indeed, more than 70% of individuals manifested moderate to severe sleep latency, as defined by the PSQI. Moreover, these individuals manifested difficulties in sleep maintenance, with middle of the night and early morning awakenings. When assessing daytime sleepiness through the Epworth Sleepiness Scale, approximately 21% of the individuals manifested excessive daytime somnolence. This indicates that mild dyssomnia characterizes the majority of the sleep phenotype, with occasionally problematic daytime somnolence, a phenotype different than that expressed by individuals with SMS, where daytime sleepiness is a chronic problem. Gene expression analysis of the core circadian machinery in the hypothalamus of the PTLS mouse model ( Rai1 -Tg) found significant dysregulation of the transcriptional activators, Clock and Arntl , and the transcriptional repressors, Per1-3 and Cry1/2 , during both light and dark phases. These findings suggest a partial loss of circadian entrainment typically evoked by environmental photic cues. Examination of circadian clock gene expression in the Rai1- Tg mouse heart, liver, and kidney found unchanged expression of Clock and most of its downstream targets during both light and dark phases, suggesting an asynchronized circadian rhythm. Furthermore, examination of circadian gene expression in synchronized PTLS lymphoblasts revealed reduced transcripts of the Period ( PER1-3 ) family and normal expression of CRY1/2 . The finding that central circadian gene expression was altered while many peripheral circadian components were intact suggests a tissue-specific circadian uncoupling of the circadian machinery due to Rai1 overexpression. Overall, our results demonstrate that overexpression of RAI1 results in sleep deficiencies in individuals with PTLS due to a lack of properly regulated circadian machinery gene expression and highlight the importance of evaluating sleep concerns in individuals with PTLS.

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Food entrainment of circadian gene expression altered in PPARalpha-/- brown fat and heart.

Publications

Food entrainment of circadian gene expression altered in PPARalpha-/- brown fat and heart.

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