Biology subjects

Oster, H.

Publications and source records attributed to Oster, H..

13 recordsLinked to original sources

bioRxiv2026

C3a receptor signalling in ObRb-expressing neurons promotes leptin resistance and obesity-associated cardiac remodelling

Obesity is associated with hypothalamic inflammation, leptin resistance and increased cardiometabolic risk, but the neuroimmune signals linking nutrient excess to these outcomes remain incompletely defined. Here we show that diet-induced obesity is accompanied by local complement activation in the mouse hypothalamus, leading to C3a generation that signals through C3a receptor (C3aR) on leptin receptor (ObRb)-expressing neurons and blunts leptin signaling. Deletion of C3aR in ObRb-expressing neurons preserves leptin responsiveness, reduces food intake and weight gain, and improves glucose homeostasis during dietary challenge. Systemic pharmacological C3aR targeting induces weight loss and improves leptin responsiveness in established obesity. Genetic or pharmacological C3aR targeting also attenuates obesity-associated diastolic dysfunction and myocardial fibrosis; pair-feeding experiments reveal an additional component of cardiac protection beyond reduced weight gain, associated with lower cardiac sympathetic innervation. In humans, circulating complement activation markers are elevated in obesity and decline after bariatric surgery. Together, our findings identify C3aR signaling in ObRb-expressing neurons as a neuroimmune pathway contributing to hypothalamic leptin resistance and obesity-associated cardiac remodeling, highlighting complement signaling as a potential therapeutic target in cardiometabolic disease.

immunology↗

bioRxiv2026

Low-dose ketamine tilts the cortical excitation--inhibition balance irrespective of systemic physiological response

Non-invasive proxies of cortical excitation--inhibition (E:I) balance, are increasingly used to understand human neural dynamics; especially so the aperiodic (1/f) electroencephalographic (EEG) exponent. Ketamine, an NMDA-receptor antagonist, is thought to shift this balance toward excitation. Propofol, a GABAA-receptor agonist, should behave oppositely. Here we show that these pharmacological manipulations at low doses tilt the noninvasive read-out of E:I balance as predicted, and we demonstrate this effect to be robust against potential mediation by the ketamine-related systemic cardiovascular response. In a single-blind, placebo-controlled crossover study, 25 healthy adults received low, subanesthetic doses of ketamine, propofol, or placebo by target-controlled infusion during resting-state EEG. We further analyzed electrocardiogram (ECG) and dissociating ratings. Ketamine flattened the aperiodic exponent (i.e., a shift toward excitation) and raised heart rate and blood pressure; propofol exerted its effects in the opposite direction, while both agents reduced alpha oscillatory power. Critically, the cardiovascular response did not mediate the cortical E:I shift. Controlling for heart rate left the ketamine effect not only intact but numerically stronger, suggesting that E:I balance findings might even be underestimated when ignoring the systemic physiological response.

neuroscience↗

bioRxiv2025

Hepatocyte Circadian Clocks Control Cholesterol Metabolism and Protect From Metabolic Dysfunction-Associated Steatohepatitis (MASH)

The circadian clock synchronizes physiological processes with the 24-hour light-dark cycle. Clock disruption contributes to metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASH). Here, we investigated the role of the hepatocyte clock in MASH using hepatocyte-specific Bmal1 deletion (Hep-Bmal1KO) mice. Hep-Bmal1KO mice showed faster MASH progression with increased hepatic cholesterol, inflammation, and fibrosis. Transcriptomic and lipidomic analyses revealed dysregulated cholesterol metabolism in Hep-Bmal1KO mice, marked by reduced expression and disrupted rhythmicity of key cholesterol-related genes. Bioinformatic analyses identified Chrebp as a potential co-regulator of these transcriptional changes. In an in vitro model with palmitate exposure and gene silencing, we found that Bmal1, but not Chrebp, regulated cholesterol accumulation, indicating Bmal1s specific role in hepatic cholesterol metabolism. Translating our findings to a human patient cohort revealed a significantly shifted circadian phase, despite no marked effect on hepatic cholesterol levels in the livers of patients with more advanced liver disease (i.e., MASH) compared to simple steatosis. Taken altogether, our findings offer a roadmap to understand the hepatocyte clocks role in MASH and its potential as a therapeutic target.

pathology↗

bioRxiv2025

A systemic clock brake: Period1 stabilizes the circadian network under environmental stress

Precise alignment between internal circadian clocks and environmental light cycles is essential for physiological homeostasis and survival. However, the molecular mechanisms that preserve this synchrony across central and peripheral tissues remain poorly defined. Here, we uncover an unexpected role for the core clock gene Period1 (Per1) as a systemic modulator of circadian stability, regulating light-induced re-entrainment across the brain and body. In Per1-deficient mice, we show that loss of Per1 accelerates clock realignment, influencing transcriptomic, metabolic, hormonal, and behavioral indicators of circadian realignment across multiple organ systems, including the suprachiasmatic nucleus (SCN) and peripheral tissues such as the liver, adipose tissue, and adrenal glands. Notably, this accelerated adaptation confers protection against jetlag-induced sleep disturbances, weight gain, and metabolic imbalance, underscoring a systemic role for Per1 in maintaining circadian network stability. Mechanistically, unbiased spatial transcriptomics identified reduced expression of the arginine vasopressin (AVP), a key neuropeptide mediating SCN intercellular coupling, as the driver of circadian network instability. Weakened SCN synchrony permits enhanced flexibility of peripheral oscillator responses, expediting whole-body adaptation to shifted light-dark schedules. These findings position Per1 as a critical regulator of circadian robustness, a buffer against light over-responsiveness, identifying a potential molecular target for mitigating circadian misalignment in contexts such as jetlag, shift work, and metabolic disease. TeaserWhat if beating jetlag was as simple as switching off a gene? Researchers show that disabling Per1, a core circadian regulator, accelerates body clock realignment and protects against sleep and metabolic disruption--highlighting new therapeutic possibilities for jetlag and shift work.

neuroscience↗

bioRxiv2024

Time-of-day related fluctuations of self-belief formation

Time of day influences a variety of human cognitive processes, including attention, executive functions and memory formation, as well as affective experiences and mood. However, circadian modulations of self-related learning and belief formation, which are highly affected by emotional states, remain poorly understood. Here, we present results from exploratory post-hoc analyses on data aggregated from five studies assessing the formation of self-related ability beliefs. A total of N=242 healthy participants completed a validated learning task at different times of the day, during which they continuously received feedback on their performance. Computational modeling was applied to quantify participants learning behavior during the task. Results suggest an association between time-of-day and self-belief formation, showing that participants who were tested in the evening (7:00-9:59 p.m.) updated their self-beliefs more strongly in response to the received feedback compared to those tested in the afternoon (1:00-3:59 p.m.). Evidence from additional models indicated that these differences were driven by non-linear, rhythmic changes in self-belief formation across different times of the day. Future studies should systematically examine within-subject fluctuations in self-belief formation across the day and address the influence of individual factors such as chronotype, age, mood and sleep quality. Understanding circadian modulations of self-related belief formation could contribute to optimized interventions for conditions characterized by maladaptive self-beliefs, such as depression, as well as in academic contexts.

neuroscience↗

bioRxiv2024

Astrocytes in the mouse suprachiasmatic nuclei respond directly to glucocorticoids feedback

The circadian timing system anticipates daily recurring changes in the environment to synchronize physiology. In mammals, the master pacemaker is the hypothalamic suprachiasmatic nuclei (SCN), which synchronizes "wake" functions by inducing the circadian release of Glucocorticoids (GCs) from the adrenal gland. GCs peak right before the active phase and set the time of peripheral clocks, however, it is still unclear whether the SCN respond to GCs feedback. While GCs influence directly the SCN during the perinatal period, the adult circuit is considered to be resistant to them, suggesting a reduction of GCs-sensitivity along development. To understand this mechanism, we followed the expression of GC receptor (GR) along mouse SCN development with single-cell resolution and show that GR is up-regulated in astrocytes as the circuit matures. We provide in vivo and in vitro evidence that the adult SCN stays responsive to circulating GCs through the activation of GR in astrocytes. Astrocytes communication is necessary to induce the GC-dependent shift on the SCN clock. Our data provides insight into the development of the SCN and highlight a new role of astrocytes as time-keepers in the adult. This finding might shed light on how the circadian system adapts to jetlag or shift work.

developmental biology↗

bioRxiv2024

Thyroid hormone receptor beta (THRB) dependent regulation of diurnal hepatic lipid metabolism in adult male mice

Thyroid hormones (THs) are critical regulators of systemic energy metabolism and homeostasis. In the liver, high TH action protects against steatosis by enhancing cholesterol and triglyceride turnover, with thyroid hormone receptor beta (THRB) signaling playing a pivotal role. This study probed the potential interaction between THRB action and another critical regulator of liver energy metabolism, the circadian clock. Liver transcriptome analysis of THRB deficient (THRBKO) mice under normal chow conditions revealed a markedly modest impact of THRB deletion. Temporal transcriptome and lipidome profiling uncovered significant alterations in diurnal metabolic rhythms attributable to THRB deficiency pointing to a pro-steatotic state with elevated levels of cholesterol, tri- and diacylglycerides, and fatty acids. These findings were confirmed by THRB agonization in hepatocytes under steatosis-promoting conditions in vitro. Integration of transcriptome profiles from THRBKO mice and mice with induced high or low TH action identified a subset of TH responsive but THRB insensitive genes implicated in immune processes. In summary, our study reveals a complex time-of-day dependent interaction of different TH-related signals in the regulation of liver physiology indicating an opportunity for chronopharmacological approaches to TH/THR(B) manipulation in fatty liver diseases.

physiology↗

bioRxiv2023

Tuning of liver circadian transcriptome rhythms by thyroid hormone state in male mice

Thyroid hormones (THs) are important regulators of systemic energy metabolism. In the liver, they stimulate lipid and cholesterol turnover and increase systemic energy bioavailability. It is still unknown how the TH state interacts with the circadian clock, another important regulator of energy metabolism. We addressed this question using a mouse model of hypothyroidism and performed circadian analyses. Low TH levels decreased locomotor activity, food intake, and body temperature mostly in the active phase. Concurrently, liver transcriptome profiling showed only subtle effects compared to elevated TH conditions. Comparative circadian transcriptome profiling revealed alterations in mesor, amplitude, and phase of transcript levels in the livers of low-TH mice. Genes associated with cholesterol uptake, biosynthesis, and bile acid secretion showed reduced mesor. Increased and decreased cholesterol levels in the serum and liver were identified, respectively. Combining data from low- and high-TH conditions allowed the identification of 516 genes with mesor changes as molecular markers of the liver TH state. These genes participate in many known TH-associated processes. We further explored these genes and created a unique expression panel that can assess liver TH state in a time-of-day dependent manner. Our findings suggest that the liver has a low TH state under physiological conditions. Circadian profiling reveals genes as potential markers of liver TH state in one-time point studies.

physiology↗

bioRxiv2023

Non-alcoholic steatohepatitis disrupts diurnal liver transcriptome rhythms in mice

Background & AimsThe liver ensures organismal homeostasis through modulation of physiological functions over the course of the day. How liver diseases such as non-alcoholic steatohepatitis (NASH) affects daily transcriptome rhythms in the liver remains elusive. To start closing this gap, we evaluated the impact of NASH on the diurnal regulation of the liver transcriptome in mice. Along this, we investigated how stringent consideration of circadian rhythmicity affects the outcomes of NASH transcriptome analyses. Approach & ResultsComparative rhythm analysis of the liver transcriptome from diet-induced NASH and control mice revealed an almost 3h phase advance in global gene expression rhythms. Rhythmically expressed genes associated with DNA repair and cell cycle regulation showed increased overall expression and circadian amplitude. In contrast, lipid and glucose metabolism associated genes showed loss of circadian amplitude, reduced overall expression, and phase advances in NASH livers. Comparison of NASH-induced liver transcriptome responses between published studies revealed little overlap (12%) in differentially expressed genes (DEGs). However, by controlling for sampling time and using circadian analytical tools, a 7-fold increase in DEG detection was achieved compared to methods without time control. ConclusionsNASH had a strong effect on circadian liver transcriptome rhythms with phase- and amplitude-specific effects for key metabolic and cell repair pathways, respectively. Accounting for circadian rhythms in NASH transcriptome studies markedly improves DEGs detection and enhances reproducibility.

physiology↗

bioRxiv2022

Genetic and environmental circadian disruption induce metabolic impairment through changes in the gut microbiome

ObjectiveInternal clocks time behavior and physiology, including the gut microbiome in a circadian ([~]24 h) manner. Mismatch between internal and external time, e.g. during shift work, disrupts circadian system coordination promoting the development of obesity and type 2 diabetes (T2D). Conversely, body weight changes induce microbiota dysbiosis. The relationship between circadian disruption and microbiota dysbiosis in metabolic diseases, however, remains largely unknown. MethodsCore and accessory clock gene expression in different gastrointestinal (GI) tissues were determined by qPCR in two different models of circadian disruption - mice with Bmal1 deficiency in the circadian pacemaker, the suprachiasmatic nucleus (Bmal1SCNfl/-), and wild-type mice exposed to simulated shift work (SSW). Body composition and energy balance were evaluated by nuclear magnetic resonance (NMR), bomb calorimetry, food intake and running-wheel activity. Intestinal permeability was measured in an Ussing chamber. Microbiota composition and functionality were evaluated by 16S rRNA gene amplicon sequencing, PICRUST2.0 analysis and targeted metabolomics. Finally, microbiota transfer was conducted to evaluate the functional impact of SSW-associated microbiota on the hosts physiology. ResultsBoth chronodisruption models show desynchronization within and between peripheral clocks in GI tissues and reduced microbial rhythmicity, in particular in taxa involved in short-chain fatty acid (SCFA) fermentation and lipid metabolism. In Bmal1SCNfl/- mice, loss of rhythmicity in microbial functioning associates with previously shown increased body weight, dysfunctional glucose homeostasis and adiposity. Similarly, we observe an increase in body weight in SSW mice. Germ-free colonization experiments with SSW- associated microbiota mechanistically link body weight gain to microbial changes. Moreover, alterations in expression of peripheral clock genes as well as clock-controlled genes (CCGs) relevant for metabolic functioning of the host were observed in recipients, indicating a bidirectional relationship between microbiota rhythmicity and peripheral clock regulation. ConclusionsCollectively, our data suggest that loss of rhythmicity in bacteria taxa and their products, which likely originates in desynchronization of intestinal clocks, promotes metabolic abnormalities during shift work.

physiology↗

bioRxiv2022

Grape-seed proanthocyanidin extract (GSPE) modulates diurnal oscillations of key hepatic metabolic genes and metabolites alleviating hepatic lipid deposition in cafeteria-fed obese rats in a time-of-day-dependent manner

Metabolic syndrome (MS) and its related diseases, including obesity and non-alcoholic fatty liver disease (NAFLD), have become a public health issue due to their increasing prevalence. Polyphenols, such as grape seed proanthocyanidin extract (GSPE), are bioactive compounds present in fruits and vegetables that show promise for MS treatment. We have previously demonstrated that the efficacy of this phenolic extract in the modulation of liver circadian clocks was affected by the time of the day at which it was ingested. Thus, we wondered if the beneficial effects of GSPE consumption in NAFLD could be mediated by diurnal modulation of hepatic lipid and glucose metabolism and whether GSPE effects on liver metabolism are impacted by the timing of administration. Results from hepatic lipid profiling, expression rhythm analysis of metabolic genes together with liver metabolomics in rats revealed that the CAF diet impaired glucose homeostasis and enhanced lipogenesis in the liver, leading to the generation of hepatosteatosis. Chronic consumption of GSPE at the onset of the active phase was able to restore the daily oscillation of liver mass and of key lipogenic and glycogenic genes, along with the reestablishment of liver metabolite rhythms, demonstrating hepatoprotective properties by decreasing triglyceride accumulation and lipid droplet formation in the liver, thus mitigating the development of CAF-induced NAFLD. Furthermore, in vitro data suggest that catechin, one of the main phenolic compounds found in the GSPE extract, may be involved in the ameliorating effects of GSPE against NAFLD.

pharmacology and toxicology↗

bioRxiv2022

Rewiring of liver diurnal transcriptome rhythms by triiodothyronine (T3) supplementation

Diurnal (i.e., 24-hour) physiological rhythms depend on transcriptional programs controlled by a set of circadian clock genes/proteins. Systemic factors like humoral and neuronal signals, oscillations in body temperature, and food intake align physiological circadian rhythms with external time. Thyroid hormones (THs) are major regulators of circadian clock target processes such as energy metabolism, but little is known about how fluctuations in TH levels affect the circadian coordination of tissue physiology. In this study, a high triiodothyronine (T3) state was induced in mice by supplementing T3 in the drinking water, which affected body temperature, and oxygen consumption in a time-of-day dependent manner. 24-hour transcriptome profiling of liver tissue identified 37 robustly and time independently T3 associated transcripts as potential TH state markers in the liver. Such genes participated in xenobiotic transport, lipid and xenobiotic metabolism. We also identified 10 - 15 % of the liver transcriptome as rhythmic in control and T3 groups, but only 4 % of the liver transcriptome (1,033 genes) were rhythmic across both conditions - amongst these several core clock genes. In-depth rhythm analyses showed that most changes in transcript rhythms were related to mesor (50%), followed by amplitude (10%), and phase (10%). Gene set enrichment analysis revealed TH state dependent reorganization of metabolic processes such as lipid and glucose metabolism. At high T3 levels, we observed weakening or loss of rhythmicity for transcripts associated with glucose and fatty acid metabolism, suggesting increased hepatic energy turnover. In sum, we provide evidence that tonic changes in T3 levels restructure the diurnal liver metabolic transcriptome independent of local molecular circadian clocks.

physiology↗

bioRxiv2020

Circadian fluctuations in glucocorticoid level impact perceptual sensitivity

Slow neurobiological rhythms, such as the circadian secretion of glucocorticoid (GC) hormones, modulate a wide variety of body functions. Whether and how such endocrine fluctuations also exert an influence on perceptual abilities is largely uncharted. Here, we show that phasic, moderate increases in GC availability prove beneficial to auditory discrimination. In an age-varying sample of N = 68 healthy human participants, we characterise the covariation of saliva cortisol with perceptual sensitivity in an auditory pitch-discrimination task at five time points across the sleep--wake cycle. First, momentary saliva cortisol levels were captured well by the time relative to wake-up and overall sleep duration. Second, within individuals, higher cortisol level just prior to behavioural testing predicted better pitch discrimination ability, expressed as a steepened psychometric curve. This effect of glucocorticoids held under a set of statistical control models. Our results pave the way for more in-depth studies on neuroendocrinological determinants of sensory encoding and perception.

neuroscience↗