Autophagy and circadian rhythms:interactions and clinical implications

Autophagy is a widespread biological process that controls cellular growth,survival,development,and death.Circadian rhythm is a recurring reaction of living organisms and behaviors to variations in surrounding brightness and obscurity.Most of the fundamental physiological processes in mammals,such as the sleep-wake pattern and the rhythm of nutrition and energy metabolism,are governed by circadian rhythms.Research has indicated that autophagy exhibits a specific circadian pattern in both normal and abnormal conditions.Autophagy can modulate circadian rhythms by breaking down proteins that regulate the circadian clock.The potential regulatory connection between the two has been a popular subject of clinical and fundamental research.Understanding the interaction between circadian rhythm and autophagy could potentially lead to the development of novel approaches for disease treatment in the future.The present analysis presented a summary of the molecular processes implicated in the interplay between autophagy and circadian rhythm,as well as the pathological importance of the disrupted regulatory association between these two phenomena.

Interaction between adolescent sleep rhythms and gender in an obese population

BACKGROUND The obesity rate of adolescents is gradually increasing,which seriously affects their mental health,and sleep plays an important role in adolescent obesity.AIM To investigate the relationship between sleep rhythm and obesity among adolescents and further explores the interactive effect of sleep rhythm and gender on adolescent obesity,providing a theoretical basis for developing interventions for adolescent obesity.METHODS Research data source Tianjin Mental Health Promotion Program for Students.From April to June 2022,this study selected 14201 students from 13 middle schools in a certain district of Tianjin as the research subject using the convenient cluster sampling method.Among these students,13374 accepted and completed the survey,with an effective rate of 94.2%.The demographic data and basic information of adolescents,such as height and weight,were collected through a general situation questionnaire.The sleep rhythm of adolescents was evaluated using the reduced version of the morningness-eveningness questionnaire.RESULTS A total of 13374 participants(6629 females,accounting for 49.56%;the average age is 15.21±1.433 years)were analyzed.Among them,the survey showed that 2942 adolescent were obesity,accounting for 22%and 2104 adolescent were overweight,accounting for 15.7%.Among them,1692 male adolescents are obese,with an obesity rate of 25.1%,higher than 18.9%of female adolescents.There is a statistically significant difference between the three groups(χ2=231.522,P<0.000).The obesity group has the smallest age(14.94±1.442 years),and there is a statistical difference in age among the three groups(F=69.996,P<0.000).Obesity rates are higher among individuals who are not-only-child,have residential experience within six months,have family economic poverty,and have evening-type sleep(P<0.05).Logistic regression analysis shows a correlation between sleep rhythm and adolescent obesity.Evening-type sleep rhythm can increase the risk of obesity in male adolescents[1.250(1.067-1.468)],but the effect on female obesity is not remarkable.Further logistic regression analysis in the overall population demonstrates that the interaction between evening-type sleep rhythm and the male gender poses a risk of adolescent obesity[1.122(1.043-1.208)].CONCLUSION Among adolescents,the incidence of obesity in males is higher than in females.Evening-type sleep rhythm plays an important role in male obesity but has no significant effect on female obesity.Progressive analysis suggests an interactive effect of sleep rhythm and gender on adolescent obesity,and the combination of evening-type sleep and the male gender promotes the development of adolescent obesity.In formulating precautions against adolescent obesity,obesity in male adolescents with evening-type sleep should be a critical concern.

Photoacoustic treatment mitigates cognitive dysfunction in a model of sleep-wake rhythm disturbance

Sleep-wake rhythm disturbances,which are characterized by abnormal sleep timing or duration,are associated with cognitive dysfunction.Photoacoustic treatments including light and sound stimulation have been found to be effective in modulating sleep patterns and improving cognitive behavior in abnormal sleep-wake pattern experiments.In this study,we examined whether light and sound interventions could reduce sleep-wake pattern disturbances and memory deficits in a sleep rhythm disturbance model.We established a model of sleep rhythm disturbance in C57 BL/6 J mice via a sleep deprivation method involving manual cage tapping,cage jostling,and nest disturbance.We used a Mini Mitter radio transmitter device to monitor motor activity in the mice and fear conditioning tests to assess cognitive function.Our results indicated that an intervention in which the mice were exposed to blue light(40-Hz flickering frequency)for 1 hour during their subjective daytime significantly improved the 24-hour-acrophase shift and reduced the degree of memory deficit induced by sleep deprivation.However,interventions in which the mice were exposed to a 40-Hz blue light at offset time or subjective night time points,as well as 2 Hz-blue light at 3 intervention time points(subjective day time,subjective night time,and offset time points),had no positive effects on circadian rhythm shift or memory deficits.Additionally,a 2000-Hz sound intervention during subjective day time attenuated the24-hour-acrophase shift and memory decline,while 440-Hz and 4000-Hz sounds had no effect on circadian rhythms.Overall,these results demonstrate that photoacoustic treatment effectively corrected abnormal sleep-wake patterns and cognitive dysfunction associated with sleep-deprivation-induced disturbances in sleep-wake rhythm.All animal experiments were approved by the Experimental Animal Ethics Committee of Drum Tower Hospital Affiliated to the Medical College of Nanjing University,China(approval No.20171102)on November20,2017.

Effects of constant light and dark conditions on the locomotor activity,body mass,and body temperature rhythms of Eurasian Tree Sparrows(Passer montanus)

Light is an essential environmental cue influencing the endogenous circadian clocks that regulate behavioral and physiological processes in animals.Despite extensive research on the circadian rhythms of avian behavior and physiology,the mechanisms by which they adapt and adjust to abnormal photoperiod conditions,such as artificial light,have yet to be fully elucidated.Here,the circadian rhythms of the body mass,activity,and core and peripheral body temperatures of the Eurasian Tree Sparrow(Passer montanus,ETS)-a diurnal passerine-were examined under three different lighting conditions:constant light(LL),constant darkness(DD),and normal light-dark cycles(LD).Our results showed that the activity,body mass,core,tarsometatarsus,and eye temperatures of the ETSs varied significantly with treatment,time,and the interaction between treatment and time;however,there was no significant change in body mass in response to the interaction between time and treatment.Under LD conditions,the ETSs exhibited significant circadian rhythms in activity and core,tarsometatarsus,and eye temperatures.Under LL conditions,only the core temperature exhibited significant rhythmicity.Under DD conditions,there were no significant circadian rhythms in activity,body mass,and eye temperature;however,the core and tarsometatarsus temperatures remained rhythmic.Our results indicate that the core body temperature rhythm of ETS is endogenous and can be maintained under abnormal photoperiods.In contrast,the activity and body surface temperature,uncoupled from the core body temperature under abnormal photoperiod conditions,strongly depend on light.These results differ from those of other diurnal avian species,suggesting a unique coping mechanism of ETS in response to an abnormal photoperiod.

Effect of Wearing a Maxillofacial Prosthesis on Masticatory Rhythm Improvement in Mandibulectomy Patients

Background: Recording jaw movement rhythms in patients with jaw defects is challenging using conventional tracking devices. However, masticatory rhythm is crucial for masticatory performance and nutritional intake. This study aimed to explore the impact of using a maxillofacial prosthesis to restore masticatory rhythm in mandibulectomy patients with a novel wearable device. Methods: Twelve patients who underwent mandibulectomy and were rehabilitated with maxillofacial prosthesis were recruited. Chewing rate, cycle durations, coefficient of variation of cycle durations (CV), changing times of skin morphology on the back of the ear pinna area (SM), and masticatory performance were measured during gum chewing without and with a denture using a wearable jaw movement rhythm tracking device. A paired t-test and the Pearson correlation coefficient were used for statistical analysis. Results: The chewing rate increased by 8.6 cycles/min with dentures (P P = 0.01). The CV and SM decreased with dentures (P = 0.004 and P = 0.01, respectively). Significant correlations were found between the CV and SM without dentures (P = 0.004). Conclusion: 1. Wearing maxillofacial prostheses can improve masticatory rhythm in patients who undergo mandibulectomy with Eichner B2 occlusal supports. 2. The wearable device is available for measuring masticatory rhythm in patients with jaw defects in clinics. 3. Changing times of the skin morphology on the back of the ear pinna indicate jaw movement stability through a simpler process than the coefficient of variation of cycle durations.

Probiotics administration alleviates cognitive impairment and circadian rhythm disturbance induced by sleep deprivation

Gut microbiome is indispensable for maintaining normal brain function.Specifically,gut microbiota plays a causal role in sleep deprivation(SD)-induced cognitive impairment.In this study,neurobehavioral effects of the Bifidobacterium breve strain(CCFM1025)were assessed in sleep-deprived mice.CCFM1025 improved the body weight and food and water intake of the mice.It also alleviated SD-induced cognitive behavioural abnormalities(in the novel object recognition test),but did not show beneficial effects on mood-and spatial memory-related behaviours.CCFM1025 significantly altered the gut microbial composition and genome function.Key microbial metabolites that may regulate sleep function were also identified,such as isovaleric acid andγ-aminobutyric acid in the gut and purine metabolites in the serum.Those metabolites may participate in gutbrain communication by acting on the striatal melatonin system,for example to increase melatonin levels,and by regulating the expression of circadian clock genes such as those encoding the adenosine A2A receptor and period circadian regulator 1.Collectively,administration of probiotics alleviated cognitive impairment and circadian rhythm disturbance induced by SD via modulation of gut microbiome and its metabolites.These findings may help guide the treatment of insomnia or other sleep disorders via dietary strategies.

Circadian rhythm disruption and retinal dysfunction:a bidirectional link in Alzheimer’s disease?

Dysfunction in circadian rhythms is a common occurrence in patients with Alzheimer’s disease.A predominant function of the retina is circadian synchronization,carrying information to the brain through the retinohypothalamic tract,which projects to the suprachiasmatic nucleus.Notably,Alzheimer’s disease hallmarks,including amyloid-β,are present in the retinas of Alzheimer’s disease patients,followed/associated by structural and functional disturbances.However,the mechanistic link between circadian dysfunction and the pathological changes affecting the retina in Alzheimer’s disease is not fully understood,although some studies point to the possibility that retinal dysfunction could be considered an early pathological process that directly modulates the circadian rhythm.

The modulatory effect of oolong tea polyphenols on intestinal flora and hypothalamus gene expression in a circadian rhythm disturbance mouse model

The interaction between host circadian rhythm and gut microbes through the gut-brain axis provides new clues for tea polyphenols to improve host health.Our present research showed that oolong tea polyphenols(OTP)improved the structural disorder of the intestinal flora caused by continuous darkness,thereby modulating the production of metabolites related to pyruvate metabolism,glycolysis/gluconeogenesis,and tryptophan metabolism to alleviate the steady-state imbalance.After fecal microbiota transplantation from the OTP group,the single-cell transcriptomic analysis revealed that OTP significantly increased the number of hypothalamus cell clusters,up-regulated the number of astrocytes and fibroblasts,and enhanced the expression of circadian rhythm genes Cry2,Per3,Bhlhe41,Nr1d1,Nr1d2,Dbp and Rorb in hypothalamic cells.Our results confirmed that OTP can actively improve the intestinal environmental state as well as internal/peripheral circadian rhythm disorders and cognitive impairment,with potential prebiotic functional characteristics to notably contribute to host health.

Unraveling links between aging,circadian rhythm and cancer:Insights from evidence-based analysis

Aging and circadian rhythms have been connected for decades,but their molecular interaction has remained unknown,especially for cancers.In this situation,we summarized the current research actuality and problems in this field using the bibliometric analysis.Publications in the PubMed and Web of Science databases were retrieved.Overall,there is a rising trend in the publication volume regarding aging and circadian rhythms in the field of cancer.Researchers from USA,Germany,Italy,China and England have greater studies than others.Top three publication institutions are University of California System,UDICE-French Research Universities and University of Texas System.Current research hotspots include oxidative stress,breast cancer,melatonin,cell cycle,calorie restriction,prostate cancer and NF-κB.In conclusion,results generated by bibliometric analysis indicate that many approaches involve in the complex interactions between aging and circadian rhythm in cancer.These established and emerging research directions guide our exploration of the regulatory mechanisms of aging and circadian rhythms in cancer and provide a reference for developing new research avenues.

Genetically engineered systems revealed the roles of basal ganglia in sleep-wake regulation

The basal ganglia(BG) act as a cohesive functional unit that regulates motor function,habit formation,and reward/addictive behaviors. However,it is still not well understood how the BG maintains wakefulness and suppresses sleep to achieve al these fundamental functions until genetical y engineered systems developed these years. Significant research efforts have recently been directed at developing genetic-molecular tools to achieve reversible and cell-type specific in vivo silencing or activation of neurons in behaving animals. Optogenetic tools can be used both to specifically activate or inhibit neurons of interest and identify functional synaptic connectivity between specific neuronal populations,both in vivo and in brain slices. Another recently developed system by Roth and colleagues permits the selective and ″remote″ manipulation(activation and silencing) of neuronal activity via all 3 major GPCR signaling pathways(G_i,G_s and G_q). These so-called ″ designer receptors exclusively activated by designer drugs″(DREADD) involve mutant GPCRs that do not respond to their endogenous ligands but are responsive to otherwise inert biological compounds. Recently,we demonstrated the essential roles and the neural pathways of the neurons expressing adenosine A_(2A) receptors or dopamine D_1 receptors in the BG for sleep-wake regulation using the genetically engineered systems including optogenetics and DREADD. We proposed a plausible model in which the caudate-putamen and the nucleus accumbens integrates behavioral processes with sleep/wakefulness through adenosine and dopamine receptors.

Circadian rhythms in the pathogenesis of gastrointestinal diseases

The etiology of digestive pathologies such as irritable bowel syndrome(IBS), inflammatory bowel diseases(IBD) and cancer is not yet fully understood. In recent years, several studies have evidenced circadian variations in mechanisms involved in digestive health. In situations of disturbed circadian rhythms(chronodisruption) where the central clock and the peripheral clocks receive incoherent signals, the synchronicity is lost producing implications for health. This lack of coordination could alter the tissue function and cause long term damage to the organs. Life habits such as sleep, physical exercise, social interaction, and feeding times are determinants for stability and integrity of circadian rhythms. In recent years, experimental and clinical studies have consistently evidenced that the alteration of circadian rhythms is associated with the development of digestive pathologies mainly linked to dismotility or changes in microbiota composition. Likewise, it seems reasonable to deep into the importance of chronodisruption as a factor that may participate in the development of pathologies such as IBS, IBD and digestive cancers. Moreover, life habits respecting circadian rhythms should be promoted for the prevention of these diseases. Further studies will allow us a better understanding of the mechanisms acting at molecular level, and the development of new therapeutic targets.

Sedimentation Rate Rhythms:Evidence from Filling of the Tarim Basin,Northwest China

Variations of sedimentation rate within a basin over geologic time are a time series that can be filtered into several cyclic wave curves. Based on back-stripping and the empirical mode decomposition method, the cores from 14 wells in the Tarim Basin were selected to do filtering analysis. Four cycles or quasi-cycles （33 Ma, 64.4 Ma, 103.6 Ma, and 224 Ma） were obtained. Among these, the 33 Ma period, which was related to the internal earth activity, an external force, or a combination of the two, was the most obvious. The 64.4 Ma period corresponded to the solar system crossing the galaxy plane or the periodic melting of inner-earth material. The 103.6 Ma period was related with plate collisional tectonism around the Tarim Plate. The 224 Ma period was related to one galaxy year and may also be related to the aesthenospherical convection cycle.

Circadian rhythms in the growth and reproduction of the brown alga Undaria pinnatifida and gametogenesis under different photoperiods

Circadian growth rhythm of the juvenile sporophyte of the brown alga Undaria pinnatifida was measured with the computer-aided image analysis system in constant florescent white light under constant temperature （ 10 ℃ ）. The growth rhythm persisted for 4 d in constant light with a free-running period of 25.6 h. Egg release from filamentous gametophytes pre-cultured in the light - dark regime was evaluated for six consecutive days at fixed time intervals in constant white light and 12 h light per day. Egg release rhythm persisted for 3 d in both regimes, indicating the endogenous nature. Temporal scale of egg release and gametogenesis in 18, 16, 12 and 8 h light per day were evaluated respectively using vegetatively propagated filamentous gametophytes. Egg release occurred 2 h after the onset of dark phase and peaked at midnight. Evaluation of the rates of oogonium formation, egg release or fertilization revealed no significant differences in four light-dark regimes, indicating the great plasticity of sexual reproduction. No photoperiodic effect in gametogenesis in terms of oogonium formation and egg release was found, but fertilization in short days was significantly higher than in long days. Results of this investigation further confirmed the general occurrence of circadian rhythms in intertidal seaweed species.

Devonian Sea-Level Change Rhythms in South China and Coupling Relationships Among the Earth-spheres

Twenty orthosequences and their corresponding sea-level change (SLC) cycles have been recognized in the Devonian overlying the Caledonian unconformity, of which 9, 5.5 and 5.5 occurred in the Lower, Middle and Upper Devonian respectively. They can be grouped into 4 orthosequence sets, in which the maximum flooding surfaces lie in the sulcutus Zone (D12), perbonus Zone (D13), Middle and Upper varcus Zone (D22) and gigas Zone (D21) respectively. Four instant palaeogeographical reconstructions of South China have been made in the Emsian and Givetian. Devonian sea-level change rhythms of South China can be divided into 3 categories: the autorhythmic, the worldwide and regional allorhythmic, and the coupling-rhythmic. They developed respectively in the Famennian, Pragian, Eifelian, Lochkovian, Emsian, Givetian, Frasnian and the F / F (between the Frasnian and Famennian) event. The cause of the worldwide allorhythmic SLC of the Pragian and Eifelian under comparatively dry, warm and tranquil conditions may be related to the pulsating expanding and contracting of the oceanic basin volume or the earth volume pulsation, rather than the common glaciation and plate tectonism. The coupling-rhythmic SLC related to the F/ F event is a sensitive indicator of the interaction between terrestrial and extraterrestrial factors, and coordinated action among the earth-spheres.

Bone Loss Induced by Simulated Microgravity,Ionizing Radiation and/or Ultradian Rhythms in the Hindlimbs of Rats

Objective To better understand the pathological causes of bone loss in a space environment, including microgravity, ionizing radiation, and ultradian rhythms.Methods Sprague Dawley （SD） rats were randomly divided into a baseline group, a control group, a hindlimb suspension group, a radiation group, a ultradian rhythms group and a combined-three-factor group. After four weeks of hindlimb suspension followed by X-ray exposure and/or ultradian rhythms, biomechanical properties, bone mineral density, histological analysis, microstructure parameters, and bone turnover markers were detected to evaluate bone loss in hindlimbs of rats.Results Simulated microgravity or combined-three factors treatment led to a significant decrease in the biomechanical properties of bones, reduction in bone mineral density, and deterioration of trabecular parameters. Ionizing radiation exposure also showed adverse impact while ultradian rhythms had no significant effect on these outcomes. Decrease in the concentration of the turnover markers bone alkaline phosphatase （bALP）, osteocalcin （OCN）, and tartrate-resistant acid phosphatase-5b （TRAP-Sb） in serum was in line with the changes in trabecular parameters.Conclusion Simulated microgravity is the main contributor of bone loss. Radiation also results in deleterious effects but ultradian rhythms has no significant effect. Combined-three factors treatment do not exacerbate bone loss when compared to simulated microgravity treatment alone.

Effects of Exposure to Extremely Low Frequency Electro-magnetic Fields on Circadian Rhythms and Distribution of Some Leukocyte Differentiation Antigens in Dairy Cows

Objective To investigate the effects of extremely low frequency magnetic and electric fields （ELFEMFs） emitted from 380 kV transmission lines on some leukocyte differentiation antigens in dairy cows. Methods The study was carded out in 5 cows exposed to 1.98-3.28 μT of ELFEMFs and in 5 control cows exposed to 0.2-0.7 μT of ELFEMFs. Following haematological and immunologic parameters were measured in both groups： WBC, CD45R, CD6, CD4, CD8, CD21, and CD11B leukocyte antigen expression. Results Some of the haematological and immunologic parameters under investigation were similar in both groups. However, CD8 （T lymphocyte surface antigen） was higher in the exposed group （1.35 ±0.120 vs 0.50 ±0.14×10^3/mL）. Furthermore, the CD4/CD8 ratio （0.84 ±0.05 and 2.19±0.16 for exposed and not exposed cows respectively） and circadian rhythm were different between the two groups. Conclusion Exposure to ELFEMFs is responsible of the abnormal temporal variations and distribution of some haematological and immunological parameters in dairy cows.

The role of pineal microRNA-325 in regulating circadian rhythms after neonatal hypoxic-ischemic brain damage

Circadian rhythm disorder is a common,but often neglected,consequence of neonatal hypoxic-ischemic brain damage(HIBD).However,the underlying molecular mechanisms remain largely unknown.We previously showed that,in a rat model of HIBD,up-regulation of microRNA-325(miR-325)in the pineal gland is responsible for the suppression of Aanat,a key enzyme involved in melatonin synthesis and circadian rhythm regulation.To better understand the mechanism by which miR-325 affects circadian rhythms in neonates with HIBD,we compared clinical samples from neonates with HIBD and samples from healthy neonates recruited from the First Affiliated Hospital of Soochow University(Dushuhu Branch)in 2019.We found that circulating miR-325 levels correlated positively with the severity of sleep and circadian rhythm disorders in neonates with HIBD.Furthermore,a luciferase reporter gene assay revealed that LIM homeobox 3(LHX3)is a novel downstream target of miR-325.In addition,in miR-325 knock-down mice,the transcription factor LHX3 exhibited an miR-325-dependent circadian pattern of expression in the pineal gland.We established a neonatal mouse model of HIBD by performing doublelayer ligation of the left common carotid artery and exposing the pups to a low-oxygen environment for 2 hours.Lhx3 mRNA expression was significantly down-regulated in these mice and partially rescued in miR-325 knockout mice subjected to the same conditions.Finally,we showed that improvement in circadian rhythm-related behaviors in animals with HIBD was dependent on both miR-325 and LHX3.Taken together,our findings suggest that the miR-325-LHX3 axis is responsible for regulating circadian rhythms and provide novel insights into the identification of potential therapeutic targets for circadian rhythm disorders in patients with neonatal HIBD.The clinical trial was approved by Institutional Review Board of Children’s Hospital of Soochow University(approval No.2015028)on July 20,2015.Animal experiments were approved by Animal Care and Use Committee,School of Medicine,Soochow University,China(approval No.XD-2016-1)on January 15,2016.

Circatidal rhythms of locomotion in the American horseshoe crab Limulus polyphemus: Underlying mechanisms and cues that influence them

While eye sensitivity in the American horseshoe crab Limulus polyphemus has long been known to be under the controlof an endogenous circadian clock, only recently has horseshoe crab locomotion been shown to be controlled by a separateclock system. In the laboratory, this system drives clear activity rhythms throughout much of the year, not just during the matingseason when horseshoe crabs express clear tidal rhythms in the field. Water temperature is a key factor influencing the expressionof these rhythms: at 17℃ tidal rhythms are expressed by most animals, while at 11℃ expression of circatidal rhythms is rarelyseen, and at 4℃ rhythms are suppressed. Neither long (16:8 Light:Dark) nor short (8:16) photoperiods modify this behavior atany of these temperatures. Synchronization of these circatidal rhythms can be most readily effected by water pressure cycles bothin situ and in the lab, while temperature and current cycles play lesser, but possibly contributory, roles. Interestingly, Light:Darkcycles appear to have synchronizing as well as 'masking' effects in some individuals. Evidence that each of two daily bouts ofactivity are independent suggests that the Limulus circatidal rhythm of locomotion is driven by two (circalunidian) clocks, eachwith a period of 24.8h. While the anatomical locations of either the circadian clock, that drives fluctuations in visual sensitivity, orthe circatidal clock, that controls tidal rhythms of locomotion, are currently unknown, preliminary molecular analyses have shownthat a 71 kD protein that reacts with antibodies directed against the Drosophila PERIOD (PER) protein is found in both the protocerebrumand the subesophageal

The Clock gene clone and its circadian rhythms in Pelteobagrus vachelli

The Clock gene,a key molecule in circadian systems,is widely distributed in the animal kingdom. We isolated a 936-bp partial c DNA sequence of the C lock gene( Pva- clock) from the darkbarbel catfish P elteobagrus vachelli that exhibited high identity with C lock genes of other species of fish and animals(65%–88%). The putative domains included a basic helix-loop-helix(b HLH) domain and two period-ARNT-single-minded(PAS) domains,which were also similar to those in other species of fish and animals. P va- Clock was primarily expressed in the brain,and was detected in all of the peripheral tissues sampled. Additionally,the pattern of P va- Clock expression over a 24-h period exhibited a circadian rhythm in the brain,liver and intestine,with the acrophase at zeitgeber time 21:35,23:00,and 23:23,respectively. Our results provide insight into the function of the molecular C lock of P. vachelli.

Circadian rhythms of hormone secretion and obesity

The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor(PPAR) γ(key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing's disease.