Metabolic and genomic adaptations to winter fattening in a primate species, the grey mouse lemur (Microcebus murinus).

AIM: To understand the mechanisms underlying the development of metabolic changes leading to obesity remains a major world health issue. Among such mechanisms, seasonality is quite underestimated although it corresponds to the manifestation of extreme metabolic flexibility in response to a changing environment. Nevertheless, the changes induced by such flexibility are far to be understood, especially at the level of insulin signaling, genomic stability or inflammation. METHODS: Here, we investigated the metabolic regulations displayed by a seasonal primate species, the grey mouse lemur (Microcebus murinus) that exhibits pronounced changes in body mass during the 6-month winter season: a fattening period followed by a spontaneous fat loss, without ever reaching pathological stages. RESULTS: Such body weight modulations result from a combination of behavioral (food intake) and physiological (endocrine changes, switch between carb and lipid oxidation) adjustments that spontaneously operate during winter. Conversely to classical models of obesity, insulin sensitivity is paradoxically preserved during the obesogenic phase. Fat loss is associated with increased metabolic activity, especially in brown adipose tissue, and induced increased oxidative stress associated with telomere length dynamic. Furthermore, liver gene expression analysis revealed regulations in metabolic homeostasis (beta-oxidation, insulin signaling, cholesterol and lipid metabolism) but not for genes involved in inflammatory process (for example, Ifng, Tnf, Nfkb1). CONCLUSION: Altogether, these results show that mouse lemurs undergo deep physiological and genomic seasonal changes, without ever reaching a pathological stage. Further investigation is needed to decipher the underlying mechanisms, which may well be highly relevant for human therapeutic strategies.

Thyroid hormone signaling and homeostasis during aging.

Studies in humans and in animal models show negative correlations between thyroid hormone (TH) levels and longevity. TH signaling is implicated in maintaining and integrating metabolic homeostasis at multiple levels, notably centrally in the hypothalamus but also in peripheral tissues. The question is thus raised of how TH signaling is modulated during aging in different tissues. Classically, TH actions on mitochondria and heat production are obvious candidates to link negative effects of TH to aging. Mitochondrial effects of excess TH include reactive oxygen species and DNA damage, 2 factors often considered as aging accelerators. Inversely, caloric restriction, which can retard aging from nematodes to primates, causes a rapid reduction of circulating TH, reducing metabolism in birds and mammals. However, many other factors could link TH to aging, and it is these potentially subtler and less explored areas that are highlighted here. For example, effects of TH on membrane composition, inflammatory responses, stem cell renewal and synchronization of physiological responses to light could each contribute to TH regulation of maintenance of homeostasis during aging. We propose the hypothesis that constraints on TH signaling at certain life stages, notably during maturity, are advantageous for optimal aging.

[Evolution of electrohysterogram signals synchronization according to term of pregnancy: interest for preterm labor diagnosis]. / Évolution de la synchronisation des signaux de l'électromyogramme utérin en fonction du terme de grossesse, et intérêt pour la détection précoce de la menace d'accouchement prématuré

OBJECTIVES: Our study focuses on the analysis of the uterine electromyogram recorded on women during pregnancy. We were interested in evaluating the synchronization of this electrical signal at various terms in order to follow evolution of synchronization as labor approaches. This study attempts to deepen our understanding of the myometrial maturation close to labor and to provide reliable parameters for improving preterm labor diagnosis. PATIENTS AND METHODS: We performed a prospective study by recording the electrical signals of physiological uterine contractions (causing no delivery) on 16 pregnant women. We then calculated the non-linear correlation coefficient h(2) to estimate synchronization between EMG signals collected for each contraction. We expressed the results by grouping synchronization values by class of term in order to study the evolution of this coefficient along gestation. This study has been approved by the ethical committee of our hospital. RESULTS: Our results show a non-significant increase of the h(2) value along term. There is however a trend towards an increase of the synchronization of EMG signals as labor approaches but not enough to conclude definitively. DISCUSSION AND CONCLUSION: With a confirmation of the increase of h(2) along term, the study of the synchronization of uterine electrical activity could be an important clue to support the notion of myometrial maturation close to labor. Synchronization analysis could also be a promising parameter for reliable diagnosis of preterm labor.

The grey mouse lemur: a non-human primate model for ageing studies.

The use of non-human primate models is required to understand the ageing process and evaluate new therapies against age-associated pathologies. The present article summarizes all the contributions of the grey mouse lemur Microcebus murinus, a small nocturnal prosimian primate, to the understanding of the mechanisms of ageing. Results from studies of both healthy and pathological ageing research on the grey mouse lemur demonstrated that this animal is a unique model to study age-dependent changes in endocrine systems, biological rhythms, thermoregulation, sensorial, cerebral and cognitive functions.

Physiological responses to chronic heat exposure in an aging non-human primate species, the gray mouse lemur (Microcebus murinus).

Epidemiological evidence related to increased death from hyperthermia suggests higher frailty in the elderly when exposed to high ambient temperatures. Despite the recent awareness of such public health problems, integrative studies investigating the effects of age on the physiological responses to heat wave thermal conditions remain scarce. Daily rhythmicity of core temperature (T(c)) and locomotor activity (LA), as well as parameters representative of energy balance and IGF-1 levels which are involved in the aging process and stress resistance, were monitored in a non-human primate species, the gray mouse lemur (Microcebus murinus). Adult and aged animals, acclimated to long days (LD) or short days (SD), were monitored during 8-day periods of exposure to 25 ° C and 34 ° C. Adult animals displayed efficient coping with heat exposure, regardless of the photoperiod. Hence, efficient responses resulted in decrease of energy intake, energy expenditure, IGF-1 levels and LA levels, promoting hyperthermia avoidance. Positive energy balance was maintained and water turnover did not change significantly after heat exposure. In contrast, while aged animals acclimated to LD responded similarly to adults, aged mouse lemurs acclimated to SD showed great difficulties coping with heat exposure. Indeed, in this group, normothermia impairment was associated with increased T(c) levels, alterations in daily rhythmicity, negative energy balance and increased IGF-1 levels. Impaired responses to heat exposure were seen in aged mouse lemurs acclimated to SD only. The main effects were observed during diurnal resting periods, suggesting decreased capacities with age to dissipate excess body heat. Taken together, these data highlight daily rhythmicity and IGF-1 pathway as main targets in the impaired response to heat exposure in the elderly.

Improving the classification rate of labor vs. normal pregnancy contractions by using EHG multichannel recordings.

Most of the studies on the synchronization between EHG signals, recorded during the same contractions at different locations, are limited to the use of only two channels. Multichannel techniques have however been widely applied to EEG signals but rarely to EHG. In this paper, we investigate the use of multichannel uterine EMG signals for classifying contractions. We compare the performance of phase synchronization in distinguishing between labor and normal pregnancy contractions by using either only two channels or a 4x4 matrix positioned on the woman's abdomen. We used two indexes to measure the phase synchronization: mean phase coherence and phase entropy. ROC curves indicate that the use of multichannel signals can significantly improve the classification rate of pregnancy and labor contractions.

Nonlinearity of EHG signals used to distinguish active labor from normal pregnancy contractions.

Labor prediction using the electrohysterogram has immediate clinical applications and has been the aim of several studies in recent years. Studies using various linear methods such as classic spectral analysis do not give clinically useful results. In this paper we present the use of two methods that investigate nonlinearity to predict normal labor. We show the comparison between a linear method that is known from the literature (mean power frequency) and two nonlinear methods (approximate entropy and time reversibility) using ROC analysis. The comparison indicates that the best method for pretreatment to classify pregnancy and labor signals is time reversibility. The results indicate that time reversibility is a very promising tool for distinguishing between labor and physiological contractions during pregnancy. This could be the first step in developing a clinical application method to predict preterm labor.

Evolution of phase synchronization of the two frequency components of the electrohysterogram (EHG): application to the detection of human labor.

The analysis of the electrical activity of the uterus recorded externally, the electrohysterogram (EHG), may find an application in the prediction of labor. In the literature parameters that are supposed to be related to the excitability of the uterine cells have almost exclusively been used for this purpose. In the present paper we evaluate the possible use of synchronization parameters for EHG measured in several places on the uterus for this prediction. The EHG is mainly composed of two frequency components called FWL and FWH. These components may be related to the synchronization and the excitability phenomenon respectively. In order to study independently these frequency components, we extracted the corresponding ridges of the wavelet transform of the EHG using the GVF-snake method. For each frequency component we computed parameters that are related to the frequency content of the signals and parameters that consider the synchronization relationship between signals. The synchronization parameters used were the mean phase coherence and the phase entropy. The values of the different parameters were compared during pregnancy and labor by statistical analysis. The detection quality of each parameter was evaluated using ROC curves. Our results suggest that synchronization parameters could be used for the detection of labor in addition to the classical previously published parameters. Another important result of our study is that both FWH and FWL seem related to excitability but only FWL seems to be related to the synchronization of the uterus at term.

Gender markedly modulates behavioral thermoregulation in a non-human primate species, the mouse lemur (Microcebus murinus).

Age and gender are known to significantly modulate thermoregulatory capacities in mammals, suggesting strong impacts on behavioral adjustments, which are used to minimize the energy costs of thermoregulation. We tested the effects of sex and age on spontaneous choice of ambient temperature (Ta) in a non-human primate species, the mouse lemur (Microcebus murinus). The animals acclimated to both winter and summer photoperiods, two seasons significantly modifying thermoregulation function, were experimented in a thermal gradient device. During winter, adult males did not show preference for warm Tas whereas old males did. In contrast, female mouse lemurs of both age categories exhibited great preferences for warm Tas. Acclimation to summer revealed that males selected colder Ta for the day than during the night. Such behavior did not exist in females. Old females explored and selected warmer nests than adult ones. This study raised novel issues on the effect of gender on thermoregulatory capacities in the mouse lemur. Females probably use behavioral adjustments to limit energy expenditure and might prefer to preserve energy for maternal investment by anticipation of and during the breeding season. Further experiments focusing on female thermoregulatory capacities are needed to better understand the energy challenge that may occur during winter and summer in female mouse lemurs, and whether this trade-off changes during aging.

Non-shivering thermogenesis activation and maintenance in the aging gray mouse lemur (Microcebus murinus).

The cold-induced enhancement of non-shivering thermogenesis (NST), involving brown-adipose tissue (BAT) metabolism, could participate to impair energy balance in the aged gray mouse lemur (Microcebus murinus). We first investigated the age-related modulations of cold-stimulated BAT cell morphology and contents. Then, NST was pharmacologically stimulated to assess whether aging impaired NST activation in the mouse lemur. In reference conditions, the ability to activate NST was preserved during aging in the mouse lemur as BAT morphology and UCP-1 presence did not differ between adult and aged mouse lemurs. Also, the pharmacological activation of NST revealed similar increased levels of O(2) consumption in adult and aged animals, confirming that no age effect could be evidenced on NST activation at 25 degrees C. However, preliminary histological data revealed a lack of lipid resources in one aged individual during cold exposure. Surprisingly, the pharmacological activation of NST revealed an impaired evacuation of the excess body heat in aged animals, associated with increased energy expenditure. Thus, aging seems to be related to decreased capacities in the maintenance of NST rather than in its activation. Energy mobilization could be impaired in the aging mouse lemur but remains to be demonstrated.

Leg muscles activities during hyperventilation following a cycling exercise.

The goal of this study was to establish how increased ventilation modifies postural stability, as characterized by body sway and leg muscle activities. Twelve healthy subjects had to perform six 30-second postural tests: one pre-exercise test while breathing gently and then one test every minute for the five minutes immediately following a maximum-intensity, incremental cycling exercise test. Subjects were asked to maintain an upright stance on a force plate for 30 s, with their eyes open. Movement of the centre of pressure in the sagittal plane was monitored in the time and spectral domains. Myoelectric activities of the soleus and tibialis anterior muscles were recorded using surface electromyography. Ventilatory parameters were measured with a portable, telemetric device. Postural changes related to respiratory variations were quantified by coherence analysis. The results showed that hyperventilation induced by exercise was accompanied by a significant increase in postural parameters, indicating a reduction in postural stability following a change in ventilatory drive. Coherence analysis confirmed the ventilatory origin of the postural oscillations. The results suggest that ventilation may be an important factor in postural disturbance during physical activity. The observed increases in leg muscle activities were most likely related to musculo-articular stiffening.

Nonlinearity testing in the case of non Gaussian surrogates, applied to improving analysis of synchronicity in uterine contraction.

Surrogates are commonly used to test a particular hypothesis on time series. The parameter commonly used in the literature to test these hypotheses is the z score. The z score assumes that the distribution of the statistics obtained on the surrogates is Gaussian. In this paper, we propose the use of a more general parameter than the z score that will also work in the case of non-Gaussian distribution of the statistics. We also derive a statistical test, based on the fitting of the distribution of the surrogate measure profile, in order to test the initial hypothesis. We validate the proposed approach on both synthetic signals and real uterine EMG signals by using the nonlinear correlation coefficient as initial statistic. We further show that this corrected nonlinear correlation coefficient can discriminate between pregnancy contractions and labor in a monkey, but the uncorrected nonlinear correlation coefficient cannot. This makes the corrected nonlinear correlation coefficient a promising candidate in a future application for preterm labor prediction in humans.

Spatial analysis of uterine EMG signals: evidence of increased in synchronization with term.

Evaluation of synchronization between signals can give new insights into the functioning of the related systems. Methods that can detect synchronization or coupling between signals can be divided two types: linear and non linear methods. In this paper we use the non linear correlation coefficient (h(2)) to show the difference in synchronization between efficient uterine contractions during labor and normal physiological contractions during pregnancy, in uterine activity bursts recorded at different places on the pregnant abdomen. Our interest in the non linear correlation coefficient is based on the fact that the propagation mechanism of uterine EMG signal may be strongly non linear. The results obtained from estimating the synchronization between 16 uterine EMG channels indicate that synchronization between contractions as measured by h(2) is stronger in labor than in pregnancy. Limited data indicates that the h(2) value increases markedly with term when expressed in duration before spontaneous labor.

Effects of age on thermoregulatory responses during cold exposure in a nonhuman primate, Microcebus murinus.

Cold resistance appears altered with aging. Among existing hypotheses, the impaired capacity in response to cold could be related to an altered regulation of plasma IGF-1 concentration. The combined effects of age and cold exposure were studied in a short-living primate, the gray mouse lemur (Microcebus murinus), which adjusts its energy balance using a daily torpor phase, to avoid high energy cost of normothermia maintenance. Changes in body mass, core temperature, locomotor activity, and caloric intake were monitored under 9-day exposures to 25 degrees C and 12 degrees C in captive animals in winter conditions. Short-term (after 2 days) and long-term (after 9 days) cold-induced changes in IGF-1 levels were also evaluated. In thermoneutral conditions (25 degrees C), general characteristics of the daily rhythm of core temperature were preserved with age. At 12 degrees C, age-related changes were mainly characterized by a deeper hypothermia and an increased frequency of torpor phases, associated with a loss of body mass. A short-term cold-induced decrease in plasma IGF-1 levels was observed. IGF-1 levels returned to basal values after 9 days of cold exposure. No significant effect of age could be evidenced on IGF-1 response. However, IGF-1 levels of cold-exposed aged animals were negatively correlated with the frequency of daily torpor. Responses exhibited by aged mouse lemurs exposed to cold revealed difficulties in the maintenance of normothermia and energy balance and might involve modulations of IGF-1 levels.

Use of piecewise stationary segmentation as a pre-treatment for synchronization measures.

The analysis of the synchronization between biological signals can be helpful for the characterization of biological functions. Biological signals are however often strongly non stationary. This is in contradiction to the assumption of commonly used synchronization measures which assume that the signal is stationary. We propose to use a piecewise stationary pre-segmentation (PSP) of the signals of interest, before the computation of synchronization measures. We show on synthetic as well as real biological signals (EEG and uterine EMG) that the proposed piecewise stationary pre-segmentation approach increases the accuracy of the measures by making a good tradeoff between the stationary assumption and length of the analyzed segments, when compared to the classical windowing method.

Spectral characterization of human EHG frequency components based on the extraction and reconstruction of the ridges in the scalogram.

Numerous studies have observed and analyzed the external electrical activity of the uterus, the so-called electrohysterogram (EHG), associated with contractions during pregnancy and labor. The EHG is mainly composed of two distinct frequency components, FWL (Fast Wave Low, low frequency component) and FWH (Fast Wave High, high frequency component). It has been suggested that FWH is mainly associated with uterine cell excitability and FWL with the propagation of this activity. This hypothesis is still unproven. We compared two procedures for ridge extraction/reconstruction of the EHG scalogram, with the objective of analyzing the propagation of the EHG on FWH and FWL separately. The performance of the methods under investigation was tested on both synthetic and real signals. The results indicate that the EHG can be characterized by two distinct continuous ridges, supposed to be FWH and FWL, with a low reconstruction error. We have also shown that the extracted ridges have different energy, temporal characteristics and bandwidths.

Plasma D-dimer and peritoneal CA-125 levels as predictors of disease status in ovarian carcinoma.

Although serum CA-125 has improved our ability to monitor tumor response in ovarian carcinoma, approximately 50% of patients with normalization of CA-125 have persistent disease at second look laparotomy. Peritoneal CA-125 and plasma D-Dimer levels were studied to determine if their use could increase the sensitivity for persistent ovarian carcinoma in a population of patients with normal physical examinations, radiologic studies, and serum CA-125 values. Plasma D-Dimer levels were obtained prior to second look laparotomy. The results of peritoneal CA-125 and plasma D-Dimer studies were compared to second look laparotomy results. Differences were evaluated with a one-way analysis of variance. Twenty-seven patients were studied. Peritoneal CA-125 was evaluated in 23 patients and ranged from < 6.3-223 U/ml. There was no statistical difference in peritoneal CA-125 levels between patients whose second look laparotomies were negative, or microscopically or macroscopically positive. D-Dimer was elevated in three patients, all of whom had macroscopically positive second look findings. The sensitivity for positive second look findings was only 27%. Minimally elevated plasma D-Dimer levels were specific but not sensitive for persistent disease and peritoneal CA-125 was not predictive of disease status.