Coupling circadian rhythms of metabolism and chromatin remodelling.

The circadian clock controls a large variety of neuronal, endocrine, behavioural and physiological responses in mammals. This control is exerted in large part at the transcriptional level on genes expressed in a cyclic manner. A highly specialized transcriptional machinery based on clock regulatory factors organized in feedback autoregulatory loops governs a significant portion of the genome. These oscillations in gene expression are paralleled by critical events of chromatin remodelling that appear to provide plasticity to circadian regulation. Specifically, the nicotinamide adenine dinucleotide (NAD)(+) -dependent deacetylases SIRT1 and SIRT6 have been linked to circadian control of gene expression. This, and additional accumulating evidence, shows that the circadian epigenome appears to share intimate links with cellular metabolic processes and has remarkable plasticity showing reprogramming in response to nutritional challenges. In addition to SIRT1 and SIRT6, a number of chromatin remodellers have been implicated in clock control, including the histone H3K4 tri-methyltransferase MLL1. Deciphering the molecular mechanisms that link metabolism, epigenetic control and circadian responses will provide valuable insights towards innovative strategies of therapeutic intervention.

Epigenetic control and the circadian clock: linking metabolism to neuronal responses.

Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape.

The time of metabolism: NAD+, SIRT1, and the circadian clock.

The mammalian cell contains a molecular clock that contributes, within each organism, to circadian rhythms and variety of physiological and metabolic processes. The clock machinery is constituted by interwined transcriptional-translational feedback loops that, through the action of specific transcription factors, modulate the expression of clock-controlled genes. These oscillations in gene expression necessarily implicate events of chromatin remodeling on a relatively large, global scale, considering that as many 10% of cellular transcripts oscillate in a circadian manner. CLOCK, a transcription factor crucial for circadian function, has intrinsic histone acetyltransferase activity and operates within a large nuclear complex with other chromatin remodelers. CLOCK directs the cyclic acetylation of the histone H3 and of its own partner BMAL1. A search for the histone deacetylase (HDAC) that counterbalanced CLOCK activity revealed that SIRT1, a nicotinamide adenine dinucleotide (NAD(+))-dependent HDAC, functions in a circadian manner. Importantly, SIRT1 is a regulator of several metabolic processes and was found to interact with CLOCK and to be recruited to circadian promoters in a cyclic manner. As many transcripts that oscillate in mammalian peripheral tissues encode proteins that have central roles in metabolic processes, these findings establish a functional and molecular link among energy balance, chromatin remodeling, and circadian physiology.

Nutrient restriction during early life reduces cell proliferation in the hippocampus at adulthood but does not impair the neuronal differentiation process of the new generated cells.

Maternal malnutrition results in learning deficits and predisposition to anxiety and depression in the offspring that extend into adulthood. At the cellular level, learning and memory rely on the production of new neurons in the dentate gyrus (DG) of the hippocampus, and hippocampal neurogenesis has been associated with the etiology and treatment of depression, but whether adult neurogenesis is affected by malnutrition during early life is not known. To investigate the effects of perinatal undernutrition on neurogenesis at adulthood, pregnant Sprague-Dawley rats were fed either ad libitum (C) or were undernourished by reducing their daily food intake by 50% in relation to the C group during gestation and lactation (FR/FR). At birth, one subset of control pups was cross-fostered to food-restricted dams to constitute a third group of animals that were undernourished during the lactation period only (AdLib/FR). At 90 days of age, pups were injected with bromodeoxyuridine (BrdU) and sacrificed 2 h, 1 week, or 3 weeks later. The number of BrdU-labeled cells in the DG was significantly reduced in the offspring of FR/FR dams in relation to controls at all the time points examined. However, the proportion of new cells exhibiting a neuronal phenotype was higher in FR/FR rats than in controls as revealed by the colabeling at 3 weeks of the BrdU-labeled cells with neuron-specific nuclear protein (NeuN). AdLib/FR animals exhibited also reduced BrdU labeling at 2 h and 1 week. Nevertheless, we found no significant differences at 3 weeks in either the number of BrdU-labeled cells or in the proportion of new neurons between controls and AdLib/FR rats. These results indicate that the decreased number of hippocampal neurons in perinatally undernourished rats is due to the deleterious effects of early nutrient restriction on cell proliferation but not on the neuronal differentiation process of the new generated cells.

Perinatal nutrient restriction induces long-lasting alterations in the circadian expression pattern of genes regulating food intake and energy metabolism.

OBJECTIVE: Several lines of evidence indicate that nutrient restriction during perinatal development sensitizes the offspring to the development of obesity, insulin resistance and cardiovascular disease in adulthood via the programming of hyperphagia and reduced energy expenditure. Given the link between the circadian clock and energy metabolism, and the resetting action of food on the circadian clock, in this study, we have investigated whether perinatal undernutrition affects the circadian expression rhythms of genes regulating food intake in the hypothalamus and energy metabolism in the liver. DESIGN: Pregnant Sprague-Dawley rats were fed ad libitum either a control (20% protein) or a low-protein (8% protein) diet throughout pregnancy and lactation. At weaning, pups received a standard diet and at 17 and 35 days of age, their daily patterns of gene expression were analyzed by real-time quantitative PCR experiments. RESULTS: 17-day-old pups exposed to perinatal undernutrition exhibited significant alterations in the circadian expression profile of the transcripts encoding diverse genes regulating food intake, the metabolic enzymes fatty acid synthase and glucokinase as well as the clock genes BMAL1 and Period1. These effects persisted after weaning, were associated with hyperphagia and mirrored the results of the behavioral analysis of feeding. Thus, perinatally undernourished rats exhibited an increased hypothalamic expression of the orexigenic peptides agouti-related protein and neuropeptide Y. Conversely, the mRNA levels of the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-related transcripts were decreased. CONCLUSION: These observations indicate that the circadian clock undergoes nutritional programming. The programming of the circadian clock may contribute to the alterations in feeding and energy metabolism associated with malnutrition in early life, which might promote the development of metabolic disorders in adulthood.