Biology subjects

Monsonego, A.

Publications and source records attributed to Monsonego, A..

5 recordsLinked to original sources

bioRxiv2026

Time-restricted feeding corrects aggravation of glucose intolerance and circadian disruption induced by weight cycling in obese young mice

Weight cycling (WC), defined as weight gain, loss, and regain, is common in obesity, but its metabolic consequences remain unclear. We tested whether WC-aggravated glucose intolerance in obesity is age-dependent and linked to circadian disruption. Young (7w) and mid-aged (12m) mice underwent a 15-week dietary intervention: Lean and Obese mice fed normal chow (NC) and high-fat diet (HFD) throughout, respectively. WC mice undergone HFD-induced weight gain, NC-induced weight loss, and a second HFD-induced weight regain. Late-onset obese (LO) mice ate HFD only paralleling weight regain of WC. In young, but not mid-aged mice, prior obesity accelerated weight regain upon HFD re-exposure, and aggravated glucose intolerance beyond that observed in Obese mice. This occurred without a worse adipose inflammatory profile. Rather, WC young mice exhibited blunting of light/dark-phase oscillation of feeding and energy metabolism, adipose and hepatic core clock gene oscillation, and increased hepatic expression of clock and gluconeogenic genes during the inactive phase. Restricting food availability to the active phase did not alter final weight regain, but improved glucose tolerance selectively in WC mice, normalized hepatic gluconeogenic and clock-genes expression in both liver and adipose tissue. These findings identify circadian disruption as a modifiable mediator of the adverse metabolic impact of WC in young-adulthood obesity. HighlightsO_LIWeight cycling is common in obesity, but whether it worsens metabolic dysfunction beyond persistent obesity remains unclear. C_LIO_LIWe asked whether weight cycling aggravates glucose intolerance in an age-dependent manner and whether circadian disruption contributes to this effect. C_LIO_LIIn young, but not mid-aged mice, weight cycling accelerated weight regain and worsened glucose intolerance, accompanied by blunted diurnal oscillation of behavioral parameters and core clock gene expression, without exaggerated adipose inflammation. C_LIO_LIActive-phase time-restricted feeding improved WC-induced aggravated glucose tolerance and circadian oscillation, identifying circadian disruption as a modifiable mechanism linking weight cycling adverse metabolic outcomes in young-adulthood obesity. C_LI

biochemistry↗

bioRxiv2025

Mid-aged mice rapidly normalize dysglycemia but aggravate obesity-induced hypothalamic and microglial changes upon dietary obesity reversal

ObjectiveObesity-induced-dysglycemia and hypothalamic-microgliosis coincide, but whether they remain linked upon obesity reversal, and what is the effect of age, remain unclear. Here we hypothesized that rapid normalization of dysglycemia upon obesity-reversal remains linked to microgliosis resolution, but differs between young and mid-aged mice. MethodsYoung (7w) and mid-aged (1y) mice were fed normal chow (NC) or high-fat diet (HFD,8w), then switched to NC (Rev,2w). ResultsCompared to young mice, NC-fed mid-aged mice were heavier and weight-stable, gained weight with HFD comparably, and lost less weight in Rev. HFD-induced dysglycemia was less severe in mid-aged compared to young mice, but similarly normalized by obesity-reversal. However, whole-hypothalamus RNA sequencing revealed 2,419 differentially expressed genes (DEGs) in mid-aged mice, [~]4-times more than in young mice, and in both age-groups [~]80% of DEGs obesity-induced changes were aggravated in Rev. Furthermore, compared with young mice, middle-aged mice showed greater obesity-induced microglial cyto-morphological changes in the arcuate nucleus (ARC), which associated with increased p-NF{kappa}B-(p-p65) nuclear staining. Only in middle-aged mice obesity-induced microglial changes were aggravated by obesity reversal, with cell volume correlating (Rho({rho})=0.691, p=0.001) with adipose tissue crown-like-structures. ConclusionsIn conclusion, rapid dysglycemia normalization is uncoupled to the resolution of hypothalamic microgliosis, more-so in mid-age.

cell biology↗

bioRxiv2024

TGFβ determines morphology and key cellular processes of activated CD4+ T cells

During an immune response, cells are simultaneously exposed to multiple cytokine signals that collectively determine their phenotype. Transforming growth factor {beta} (TGF{beta}) is a pleiotropic cytokine acting as a key regulator of T-cell differentiation with activating and suppressive effects on their immune function. Here, we systematically analyze the cellular responses of CD4+ T cells to TGF{beta} across diverse cytokine environments in the presence or absence of TGF{beta}. We found that TGF{beta} had a profound dominant effect independent of the presence of other cytokines, modulating the expression of more than 4,000 genes. In the presence of TGF{beta}, cells exhibit lower expression of translation-related and apoptosis-related genes, accompanied by increased survival of activated T cells. Notably, cells cultured in the presence of TGF{beta} were smaller in size while preserving their proliferative ability. Accordingly, we identified a dense network of transcription factors that were modulated by TGF{beta}, suggesting a core gene set connecting TGF{beta} signaling to the regulation of T-cell size. We found N-Myc to be at the center of this network, and we directly show that TGF{beta} regulates its gene expression level, protein level, and nuclear localization. Our work provides a system to study cell size control and demonstrate the profound effect of TGF{beta} in the modulation and regulation of T-cell properties, expanding its role beyond guiding their phenotype. Significance StatementTGF{beta} is a key determinant of CD4+ T-cell differentiation; however, understanding its effect on additional aspects of T-cell state is lacking. Here, we systematically studied the role of TGF{beta} in regulating T-cell physiology. Exposing cells to diverse combinations of cytokines enabled us to distill the core effect of TGF{beta}. We found TGF{beta} to have a profound effect on multiple cellular processes critical to T-cell function. Significantly, TGF{beta} induced smaller T-cells both in vitro and in vivo, suggesting that TGF{beta} could skew the population towards tissue infiltration and residency. Furthermore, TGF{beta} can be used to fine-tune T-cell size, providing a system for studying cell size control. Overall, our findings demonstrate the profound effect of TGF{beta} in the regulation of T-cell physiology.

immunology↗

bioRxiv2024

CD4 T Cells Acquire Cytotoxic Properties to Modulate Cellular Senescence and Aging

Aging is characterized by the progressive deterioration of tissue structure and function, leading to increased vulnerability to diseases and, eventually, death. One prominent process in aging is the accumulation of senescent cells. Although the immune system has been recognized as crucial for the elimination of senescent cells, the associated mechanisms remain incompletely understood. Here we show that CD4 T cells differentiate into cytotoxic T lymphocytes (CTLs) in a senescent cell-rich environment and that a reduction in the senescent cell load, achieved using chemical senolytic drugs, was sufficient to halt this differentiation. We further demonstrate that eliminating CD4 CTLs in the context of late aging by selectively deleting the Eomes transcription factor in CD4 T cells resulted in the increased accumulation of senescent cells, profound physical deterioration, and a decreased life span. In liver cirrhosis, a model of localized chronic inflammation, CD4 CTL elimination increased the senescent load and worsened the disease. Collectively, our findings demonstrate the fundamental role of CD4 CTLs in modulating tissue senescence and unveil a new aspect of age-related T-cell biology implicated in disease susceptibility and longevity.

immunology↗

bioRxiv2022

CausalCell: applying causal discovery to single-cell analyses

Correlation between objects does not answer many scientific questions because of the lack of causal but the excess of spurious information and is prone to happen by coincidence. Causal discovery infers causal relationships from data upon conditional independence test between objects without prior assumptions (e.g., variables have linear relationships and data follow the Gaussian distribution). Causal interactions within and between cells provide valuable information for investigating gene regulation, identifying diagnostic and therapeutic targets, and designing experimental and clinical studies. The rapid increase of single-cell data permits inferring causal interactions in many cell types. However, because no algorithms have been designed for handling abundant variables and few algorithms have been evaluated using real data, how to apply causal discovery to single-cell data remains a challenge. We report a pipeline and web server (http://www.gaemons.net/causalcell/causalDiscovery/) for accurately and conveniently performing causal discovery. The pipeline has been developed upon the benchmarking of 18 algorithms and the analyses of multiple datasets. Our applications indicate that only complicated algorithms can generate satisfactorily reliable results. Critical issues are discussed, and tips for best practices are provided.

bioinformatics↗