Stéphanie Dumont

The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism

Mutations of clock genes can lead to diabetes and obesity. REV‐ERBα, a nuclear receptor involved in the circadian clockwork, has been shown to control lipid metabolism. To gain insight into the role of REV‐ERBα in energy homeostasis in vivo, we explored daily metabolism of carbohydrates and lipids in chow‐fed, unfed, or high‐fat‐fed Rev‐erbα−/− mice and their wild‐type littermates. Chow‐fed Rev‐erbα−/− mice displayed increased adiposity (2.5‐fold) and mild hyperglycemia (∼10%) without insulin resistance. Indirect calorimetry indicates that chow‐fed Rev‐erbα−/− mice utilize more fatty acids during daytime. A 24‐h nonfeeding period in Rev‐erbα−/− animals favors further fatty acid mobilization at the expense of glycogen utilization and gluconeogenesis, without triggering hypoglycemia and hypothermia. High‐fat feeding in Rev‐erbα−/− mice amplified metabolic disturbances, including expression of lipogenic factors. Lipoprotein lipase (Lpl) gene, critical in lipid utilization/storage, is triggered in liver at night and constitutively up‐regulated (∼ 2‐fold) in muscle and adipose tissue of Rev‐erbα−/− mice. We show that CLOCK, up‐regulated (2‐fold) at night in Rev‐erbα−/− mice, can transactivate Lpl. Thus, overexpression of Lpl facilitates muscle fatty acid utilization and contributes to fat overload. This study demonstrates the importance of clock‐driven Lpl expression in energy balance and highlights circadian disruption as a potential cause for the metabolic syndrome.—Delezie, J., Dumont, S., Dardente, H., Oudart, H., Gréchez‐Cassiau, A., Klosen, P., Teboul, M., Delaunay, F., Pévet, P., Challet, E. The nuclear receptor REV‐ERBα is required for the daily balance of carbohydrate and lipid metabolism. FASEB J. 26, 3321–3335 (2012). www.fasebj.org

Gradual caldera collapse at Bárdarbunga volcano, Iceland, regulated by lateral magma outflow

Driven to collapse Volcanic eruptions occur frequently, but only rarely are they large enough to cause the top of the mountain to collapse and form a caldera. Gudmundsson et al. used a variety of geophysical tools to monitor the caldera formation that accompanied the 2014 Bárdarbunga volcanic eruption in Iceland. The volcanic edifice became unstable as magma from beneath Bárdarbunga spilled out into the nearby Holuhraun lava field. The timing of the gradual collapse revealed that it is the eruption that drives caldera formation and not the other way around. Science, this issue p. 262 Magma flow from under the Bárdarbunga volcano drove caldera collapse during the 2014 eruption. INTRODUCTION The Bárdarbunga caldera volcano in central Iceland collapsed from August 2014 to February 2015 during the largest eruption in Europe since 1784. An ice-filled subsidence bowl, 110 square kilometers (km2) in area and up to 65 meters (m) deep developed, while magma drained laterally for 48 km along a subterranean path and erupted as a major lava flow northeast of the volcano. Our data provide unprecedented insight into the workings of a collapsing caldera. RATIONALE Collapses of caldera volcanoes are, fortunately, not very frequent, because they are often associated with very large volcanic eruptions. On the other hand, the rarity of caldera collapses limits insight into this major geological hazard. Since the formation of Katmai caldera in 1912, during the 20th century’s largest eruption, only five caldera collapses are known to have occurred before that at Bárdarbunga. We used aircraft-based altimetry, satellite photogrammetry, radar interferometry, ground-based GPS, evolution of seismicity, radio-echo soundings of ice thickness, ice flow modeling, and geobarometry to describe and analyze the evolving subsidence geometry, its underlying cause, the amount of magma erupted, the geometry of the subsurface caldera ring faults, and the moment tensor solutions of the collapse-related earthquakes. RESULTS After initial lateral withdrawal of magma for some days though a magma-filled fracture propagating through Earth’s upper crust, preexisting ring faults under the volcano were reactivated over the period 20 to 24 August, marking the onset of collapse. On 31 August, the eruption started, and it terminated when the collapse stopped, having produced 1.5 km of basaltic lava. The subsidence of the caldera declined with time in a near-exponential manner, in phase with the lava flow rate. The volume of the subsidence bowl was about 1.8 km3. Using radio-echo soundings, we find that the subglacial bedrock surface after the collapse is down-sagged, with no indications of steep fault escarpments. Using geobarometry, we determined the depth of magma reservoir to be ~12 km, and modeling of geodetic observations gives a similar result. High-precision earthquake locations and moment tensor analysis of the remarkable magnitude M5 earthquake series are consistent with steeply dipping ring faults. Statistical analysis of seismicity reveals communication over tens of kilometers between the caldera and the dike. CONCLUSION We conclude that interaction between the pressure exerted by the subsiding reservoir roof and the physical properties of the subsurface flow path explain the gradual near-exponential decline of both the collapse rate and the intensity of the 180-day-long eruption. By combining our various data sets, we show that the onset of collapse was caused by outflow of magma from underneath the caldera when 12 to 20% of the total magma intruded and erupted had flowed from the magma reservoir. However, the continued subsidence was driven by a feedback between the pressure of the piston-like block overlying the reservoir and the 48-km-long magma outflow path. Our data provide better constraints on caldera mechanisms than previously available, demonstrating what caused the onset and how both the roof overburden and the flow path properties regulate the collapse. The Bárdarbunga caldera and the lateral magma flow path to the Holuhraun eruption site. (A) Aerial view of the ice-filled Bárdarbunga caldera on 24 October 2014, view from the north. (B) The effusive eruption in Holuhraun, about 40 km to the northeast of the caldera

Setting the main circadian clock of a diurnal mammal by hypocaloric feeding

•  Timed hypocaloric feeding alters the main circadian clock, the suprachiasmatic nucleus (SCN), in nocturnal rodents. •  The endogenous oscillatory mechanism in the SCN is similar between nocturnal and diurnal mammals. •  In this study we report that in the diurnal rodent Arvicanthis ansorgei, a timed hypocaloric feeding (HF) entrains and shifts behavioural and molecular circadian rhythms in the SCN. Nevertheless, instead of phase advancing the clock as in nocturnal rodents, HF phase delays the Arvicanthis SCN pacemaker. •  Thus, HF modifies the circadian system of the diurnal rodent Arvicanthis ansorgei differentially from nocturnal rodents. •  The present results will help us to better understand the circadian system in diurnal species and how feeding cues can synchronize daily rhythms.

Pineal melatonin is a circadian time-giver for leptin rhythm in Syrian hamsters

Nocturnal secretion of melatonin from the pineal gland may affect central and peripheral timing, in addition to its well-known involvement in the control of seasonal physiology. The Syrian hamster is a photoperiodic species, which displays gonadal atrophy and increased adiposity when adapted to short (winter-like) photoperiods. Here we investigated whether pineal melatonin secreted at night can impact daily rhythmicity of metabolic hormones and glucose in that seasonal species. For that purpose, daily variations of plasma leptin, cortisol, insulin and glucose were analyzed in pinealectomized hamsters, as compared to sham-operated controls kept under very long (16 h light/08 h dark) or short photoperiods (08 h light/16 h dark). Daily rhythms of leptin under both long and short photoperiods were blunted by pinealectomy. Furthermore, the phase of cortisol rhythm under a short photoperiod was advanced by 5.6 h after pinealectomy. Neither plasma insulin, nor blood glucose displays robust daily rhythmicity, even in sham-operated hamsters. Pinealectomy, however, totally reversed the decreased levels of insulin under short days and the photoperiodic variations in mean levels of blood glucose (i.e., reduction and increase in long and short days, respectively). Together, these findings in Syrian hamsters show that circulating melatonin at night drives the daily rhythmicity of plasma leptin, participates in the phase control of cortisol rhythm and modulates glucose homeostasis according to photoperiod-dependent metabolic state.

Rev-erbα in the brain is essential for circadian food entrainment

Foraging is costly in terms of time and energy. An endogenous food-entrainable system allows anticipation of predictable changes of food resources in nature. Yet the molecular mechanism that controls food anticipation in mammals remains elusive. Here we report that deletion of the clock component Rev-erbα impairs food entrainment in mice. Rev-erbα global knockout (GKO) mice subjected to restricted feeding showed reduced elevations of locomotor activity and body temperature prior to mealtime, regardless of the lighting conditions. The failure to properly anticipate food arrival was accompanied by a lack of phase-adjustment to mealtime of the clock protein PERIOD2 in the cerebellum, and by diminished expression of phosphorylated ERK 1/2 (p-ERK) during mealtime in the mediobasal hypothalamus and cerebellum. Furthermore, brain-specific knockout (BKO) mice for Rev-erbα display a defective suprachiasmatic clock, as evidenced by blunted daily activity under a light-dark cycle, altered free-running rhythm in constant darkness and impaired clock gene expression. Notably, brain deletion of Rev-erbα totally prevented food-anticipatory behaviour and thermogenesis. In response to restricted feeding, brain deletion of Rev-erbα impaired changes in clock gene expression in the hippocampus and cerebellum, but not in the liver. Our findings indicate that Rev-erbα is required for neural network-based prediction of food availability.

Circadian desynchronization triggers premature cellular aging in a diurnal rodent

Chronic jet lag or shift work is deleterious to human metabolic health, in that such circadian desynchronization is associated with being overweight and the prevalence of altered glucose metabolism. Similar metabolic changes are observed with age, suggesting that chronic jet lag and accelerated cell aging are intimately related, but the association remains to be determined. We addressed whether jet lag induces metabolic and cell aging impairments in young grass rats (2–3 mo old), using control old grass rats (12–18 mo old) as an aging reference. Desynchronized young and control old subjects had impaired glucose tolerance (+60 and +280%) when compared with control young animals. Despite no significant variation in liver DNA damage, shorter telomeres were characterized, not only in old animal liver cells (–18%), but also at an intermediate level in desynchronized young rats (–9%). The same pattern was found for deacetylase sirtuin (SIRT)‐1 (–57 and –29%), confirming that jet‐lagged young rats have an intermediate aging profile. Our data indicate that an experimental circadian desynchronization in young animals is associated with a precocious aging profile based on 3 well‐known markers, as well as a prediabetic phenotype. Such chronic jet lag‐induced alterations observed in a diurnal species constitute proof of principle of the need to develop preventive treatments in jet‐lagged persons and shift workers.—Grosbellet, E., Zahn, S., Arrivé, M., Dumont, S., Gourmelen, S., Pévet, P., Challet, E., Criscuolo, F. Circadian desynchronization triggers premature cellular aging in a diurnal rodent. FASEB J. 29, 4794–4803 (2015). www.fasebj.org

Ultradian feeding in mice not only affects the peripheral clock in the liver, but also the master clock in the brain

ABSTRACT Restricted feeding during the resting period causes pronounced shifts in a number of peripheral clocks, but not the central clock in the suprachiasmatic nucleus (SCN). By contrast, daily caloric restriction impacts also the light-entrained SCN clock, as indicated by shifted oscillations of clock (PER1) and clock-controlled (vasopressin) proteins. To determine if these SCN changes are due to the metabolic or timing cues of the restricted feeding, mice were challenged with an ultradian 6-meals schedule (1 food access every 4 h) to abolish the daily periodicity of feeding. Mice fed with ultradian feeding that lost <10% body mass (i.e. isocaloric) displayed 1.5-h phase-advance of body temperature rhythm, but remained mostly nocturnal, together with up-regulated vasopressin and down-regulated PER1 and PER2 levels in the SCN. Hepatic expression of clock genes (Per2, Rev-erbα, and Clock) and Fgf21 was, respectively, phase-advanced and up-regulated by ultradian feeding. Mice fed with ultradian feeding that lost >10% body mass (i.e. hypocaloric) became more diurnal, hypothermic in late night, and displayed larger (3.5 h) advance of body temperature rhythm, more reduced PER1 expression in the SCN, and further modified gene expression in the liver (e.g. larger phase-advance of Per2 and up-regulated levels of Pgc-1α). While glucose rhythmicity was lost under ultradian feeding, the phase of daily rhythms in liver glycogen and plasma corticosterone (albeit increased in amplitude) remained unchanged. In conclusion, the additional impact of hypocaloric conditions on the SCN are mainly due to the metabolic and not the timing effects of restricted daytime feeding.

Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei, were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect. SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic entrainment in nocturnal animals. How these stimuli act in diurnal species remains to be established. Our study in a diurnal rodent, the Grass rat, indicates that sleep deprivation in the early rest period induces phase delays of circadian locomotor activity rhythm. Contrary to nocturnal rodents, both sleep deprivation and caffeine-induced arousal potentiate the photic entrainment in a diurnal rodent. Such enhanced light-induced circadian responses could be relevant for developing chronotherapeutic strategies.

Post-emplacement cooling and contraction of lava flows: InSAR observations and a thermal model for lava fields at Hekla volcano, Iceland†

Lava flows contract as they cool, causing progressive subsidence of the flow surface. Here we study this process by measuring and modelling the deformation of emplaced lava flows and the surrounding substrate. The temporal trend of vertical lava movements was investigated using interferometric analysis of synthetic aperture radar (InSAR) images from the 1991 and 2000 Hekla eruptions, covering periods of 23 and 12 years, respectively. Data from six tracks from three satellites, including both ascending and descending passes, were used to create 99 interferograms, from which trends of accumulated subsidence and subsidence velocities were derived. Subsidence rates are similar for both lava flows and decay approximately exponentially from about 20 mm/year five years after emplacement to about 2 mm/year 15 years after emplacement. A one-dimensional, semi-analytical model was fitted to the observed subsidence rates, with subsidence due to phase change calculated analytically, and subsidence due to thermal contraction calculated numerically using dilatometic constraints obtained experimentally. The initial thicknesses of the 1991 and 2000 lava fields, D1991 and D2000, scaled thermal expansivity, γα, and thermal diffusivity, κ, are the crucial parameters influencing lava subsidence and subsidence rate. Inversion for these parameters reveal linear correlations between them. Best fitting results of inversions for D1991 range from 10 m to 27 m, for D2000 from 10 m to 30 m, γα = (9 − 24) × 10−6K−1, and κ = (1 − 7) × 10−7m2s−1.

Expression of the clock gene Rev‐erbα in the brain controls the circadian organization of food intake and locomotor activity, but not daily variations of energy metabolism

The nuclear receptor REV‐ERBα is part of the molecular clock mechanism and is considered to be involved in a variety of biological processes within metabolically active peripheral tissues as well. To investigate whether Rev‐erbα (also known as Nr1d1) in the brain plays a role in the daily variations of energy metabolism, feeding behaviour and the sleep‐wake cycle, we studied mice with global (GKO) or brain (BKO) deletion of Rev‐erbα. Mice were studied both in a light/dark cycle and in constant darkness, and then 24‐hour variations of Respiratory quotient (RQ) and energy expenditure, as well as the temporal patterns of rest‐activity and feeding behaviour, were recorded. The RQ increase of GKO mice was not detected in BKO animals, indicating a peripheral origin for this metabolic alteration. Arrhythmic patterns of locomotor activity were only found in BKO mice. By contrast, the circadian rhythm of food intake was lost both in GKO and BKO mice, mostly by increasing the number of daytime meals. These changes in the circadian pattern of feeding behaviour were, to some extent, correlated with a loss of rhythmicity of hypothalamic Hcrt (also named Orx) mRNA levels. Taken together, these findings highlight that Rev‐erbα in the brain is involved in the temporal partitioning of feeding and sleep, whereas its effects on energy metabolism are mainly exerted through its peripheral expression.