Sex differences in white adipose tissue expansion: emerging molecular mechanisms

Abstract The escalating prevalence of individuals becoming overweight and obese is a rapidly rising global health problem, placing an enormous burden on health and economic systems worldwide. Whilst obesity has well described lifestyle drivers, there is also a significant and poorly understood component that is regulated by genetics. Furthermore, there is clear evidence for sexual dimorphism in obesity, where overall risk, degree, subtype and potential complications arising from obesity all differ between males and females. The molecular mechanisms that dictate these sex differences remain mostly uncharacterised. Many studies have demonstrated that this dimorphism is unable to be solely explained by changes in hormones and their nuclear receptors alone, and instead manifests from coordinated and highly regulated gene networks, both during development and throughout life. As we acquire more knowledge in this area from approaches such as large-scale genomic association studies, the more we appreciate the true complexity and heterogeneity of obesity. Nevertheless, over the past two decades, researchers have made enormous progress in this field, and some consistent and robust mechanisms continue to be established. In this review, we will discuss some of the proposed mechanisms underlying sexual dimorphism in obesity, and discuss some of the key regulators that influence this phenomenon.

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Sex differences in virtual navigation influenced by visual factors and individual differences

10.31234/osf.io/za4gj ◽

2019 ◽

Author(s):

Lace Padilla

Keyword(s):

Sex Differences ◽

Individual Differences ◽

Mental Rotation ◽

Morris Water Maze ◽

Water Maze ◽

Large Scale ◽

Small Scale ◽

Standard Design ◽

Males And Females ◽

Virtual Morris Water Maze

The Morris water maze is a task adapted from the animal spatial cognition literature and has been studied in the context of sex differences in humans, particularly because of the standard design, which manipulates proximal (close) and distal (far) cues. However, there are mixed findings with respect to the interaction of cues and sex differences in virtual Morris water maze tasks, which may be attributed to variations in the scale of the space and previously unmeasured individual differences. We explore the question of scale and context by presenting participants with an outdoor virtual Morris water maze that is four times the size of the mazes previously tested. We also measured lifetime mobility and mental rotation skills. Results of this study suggest that for the small-scale environment, males and females performed similarly when asked to navigate with only proximal cues. However, males outperformed females when only distal cues were visible. In the large-scale environment, males outperformed females in both cue conditions. Additionally, greater mental rotation skills predicted better navigation performance with proximal cues only. Finally, we found that highly mobile females and males perform equally well when navigating with proximal cues.

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Skeletal Muscle Wasting: The Estrogen Side of Sexual Dimorphism

AJP Cell Physiology ◽

10.1152/ajpcell.00333.2021 ◽

2021 ◽

Author(s):

Shawna L. McMillin ◽

Everett C. Minchew ◽

Dawn A. Lowe ◽

Espen E. Spangenburg

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Muscle Wasting ◽

Physiological Mechanisms ◽

Skeletal Muscle Wasting ◽

Muscle Biology ◽

Experimental Approaches ◽

The Impact ◽

Equal Efficacy

The importance of defining sex differences across various biological and physiological mechanisms is more pervasive now than it has been over the last 15-20 years. As the muscle biology field pushes to identify small molecules and interventions to prevent, attenuate or even reverse muscle wasting, we must consider the effect of sex as a biological variable. It should not be assumed that a therapeutic will affect males and females with equal efficacy or equivalent target affinities under conditions where muscle wasting is observed. With that said, it is not surprising to find that we have an unclear or even a poor understanding of the effects of sex or sex hormones on muscle wasting conditions. Although recent investigations are beginning to establish experimental approaches that will allow investigators to assess the impact of sex-specific hormones on muscle wasting, the field still has not established enough published scientific tools that will allow the field to rigorously address critical hypotheses. Thus, the purpose of this review is to assemble a current summary of knowledge in the area of sexual dimorphism driven by estrogens with an effort to provide insights to interested physiologists on necessary considerations when trying to assess models for potential sex differences in cellular and molecular mechanisms of muscle wasting.

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CBMT-45. SEX-SPECIFIC METABOLIC ADAPTIONS IN GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noz175.167 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi42-vi43

Author(s):

Jasmin Sponagel ◽

Shanshan Zhang ◽

Prakash Chinnaiyan ◽

Joshua Rubin ◽

Joseph Ippolito

Keyword(s):

Sex Differences ◽

Sexual Dimorphism ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Tca Cycle ◽

Metabolic Reprogramming ◽

Mitochondrial Activity ◽

Male And Female ◽

Glutamine Deprivation ◽

Novel Treatment Strategies

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. GBM occurs more commonly in males, but female patients survive significantly longer. Understanding the molecular mechanisms that underlie those sex differences could support novel treatment strategies. In this regard, we found that male and female GBM patient samples differ in their metabolite abundance and that male patients exhibit a significantly higher abundance of TCA cycle metabolites. We confirmed those findings in a murine model of GBM, which has previously yielded important insights into sexual dimorphism in GBM. Strikingly, sex differences in TCA cycle flux were entirely driven by glutamine flux, not glucose flux, suggesting a sex-specific role for glutamine in GBM. Metabolic manipulation through glutamine deprivation resulted in a greater growth inhibition in male GBM cells. Glutamine itself can be utilized for anabolic reactions or it can be converted to glutamate by glutaminase. Only male GBM cells were sensitive to pharmacological glutaminase inhibition with BPTES or CB-839, suggesting that male GBM cells are glutamate dependent while female GBM cells are not. Concordantly, we found significantly higher glutaminase levels in male GBM cells. Furthermore, we found that numerous metabolites (including NADH, ATP, and glutathione) involved in cellular processes downstream of glutamate were more abundant in male GBM cells. In contrast, female GBM cells were resistant to low glutamine conditions and glutaminase inhibitors unless glutamine-synthase activity was disrupted, suggesting that glutamine synthesis might play a more prominent role in female GBM. Together, these data indicate that male and female GBM differ in their metabolic adaptions. Male GBM utilize glutamate to fuel the TCA cycle and mitochondrial activity while female GBM synthesize and utilize glutamine itself. This sexual dimorphism in metabolic reprogramming reveals novel sex specific metabolic targets for GBM and underlines the importance of considering sex in metabolic targeting approaches.

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Sex differences in severity and mortality from COVID-19: are males more vulnerable?

Biology of Sex Differences ◽

10.1186/s13293-020-00330-7 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Ajay Pradhan ◽

Per-Erik Olsson

Keyword(s):

Sex Differences ◽

Immune System ◽

Immune Responses ◽

Molecular Mechanisms ◽

Viral Infections ◽

Basic Research ◽

Contributing Factors ◽

High Infection ◽

Males And Females

Abstract Coronavirus disease 2019 (COVID-19) has shown high infection and mortality rates all over the world, and despite the global efforts, there is so far no specific therapy available for COVID-19. Interestingly, while the severity and mortality of COVID-19 are higher in males than in females, the underlying molecular mechanisms are unclear. In this review, we explore sex-related differences that may be contributing factors to the observed male-biased mortality from COVID-19. Males are considered the weaker sex in aspects related to endurance and infection control. Studies show that viral RNA clearance is delayed in males with COVID-19. A recent study has indicated that the testis can harbor coronavirus, and consequently, males show delayed viral clearance. However, the role of testis involvement in COVID-19 severity and mortality needs further research. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens. This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality. In addition, differences in sex hormone milieus could also be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects. The sex-specific severity of COVID-19 infections indicates that further research on understanding the sex differences is needed. Inclusion of both males and females in basic research and clinical trials is required to provide critical information on sex-related differences that may help to better understand disease outcome and therapy.

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Concept, Design and Implementation of a Cardiovascular Gene-Centric 50 K SNP Array for Large-Scale Genomic Association Studies

PLoS ONE ◽

10.1371/journal.pone.0003583 ◽

2008 ◽

Vol 3 (10) ◽

pp. e3583 ◽

Cited By ~ 294

Author(s):

Brendan J. Keating ◽

Sam Tischfield ◽

Sarah S. Murray ◽

Tushar Bhangale ◽

Thomas S. Price ◽

...

Keyword(s):

Large Scale ◽

Association Studies ◽

Snp Array ◽

Concept Design ◽

Design And Implementation ◽

Genomic Association

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Investigating tissue-relevant causal molecular mechanisms of complex traits using probabilistic TWAS analysis

10.1101/808295 ◽

2019 ◽

Cited By ~ 2

Author(s):

Yuhua Zhang ◽

Corbin Quick ◽

Ketian Yu ◽

Alvaro Barbeira ◽

Francesca Luca ◽

...

Keyword(s):

Gene Expression ◽

Complex Traits ◽

Large Scale ◽

Molecular Mechanisms ◽

Association Studies ◽

Complex Trait ◽

Causal Effects ◽

Biological Mechanisms ◽

Integrative Framework ◽

Eqtl Data

AbstractTranscriptome-wide association studies (TWAS), an integrative framework using expression quantitative trait loci (eQTLs) to construct proxies for gene expression, have emerged as a promising method to investigate the biological mechanisms underlying associations between genotypes and complex traits. However, challenges remain in interpreting TWAS results, especially regarding their causality implications. In this paper, we describe a new computational framework, probabilistic TWAS (PTWAS), to detect associations and investigate causal relationships between gene expression and complex traits. We use established concepts and principles from instrumental variables (IV) analysis to delineate and address the unique challenges that arise in TWAS. PTWAS utilizes probabilistic eQTL annotations derived from multi-variant Bayesian fine-mapping analysis conferring higher power to detect TWAS associations than existing methods. Additionally, PTWAS provides novel functionalities to evaluate the causal assumptions and estimate tissue- or cell-type specific causal effects of gene expression on complex traits. These features make PTWAS uniquely suited for in-depth investigations of the biological mechanisms that contribute to complex trait variation. Using eQTL data across 49 tissues from GTEx v8, we apply PTWAS to analyze 114 complex traits using GWAS summary statistics from several large-scale projects, including the UK Biobank. Our analysis reveals an abundance of genes with strong evidence of eQTL-mediated causal effects on complex traits and highlights the heterogeneity and tissue-relevance of these effects across complex traits. We distribute software and eQTL annotations to enable users performing rigorous TWAS analysis by leveraging the full potentials of the latest GTEx multi-tissue eQTL data.

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Sex differences in the human brain transcriptome of cases with schizophrenia

10.1101/2020.10.05.326405 ◽

2020 ◽

Author(s):

Gabriel E. Hoffman ◽

Yixuan Ma ◽

Kelsey S. Montgomery ◽

Jaroslav Bendl ◽

Manoj Kumar Jaiswal ◽

...

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Differential Expression ◽

Large Scale ◽

Molecular Mechanisms ◽

Age Of Onset ◽

Differential Expression Analysis ◽

Gene Expression Signature ◽

Synaptic Organization ◽

Expression Signature

AbstractWhile schizophrenia differs between males and females in age of onset, symptomatology and the course of the disease, the molecular mechanisms underlying these differences remain uncharacterized. In order to address questions about the sex-specific effects of schizophrenia, we performed a large-scale transcriptome analysis of RNA-seq data from 437 controls and 341 cases from two distinct cohorts from the CommonMind Consortium. Analysis across the cohorts identifies a reproducible gene expression signature of schizophrenia that is highly concordant with previous work. Differential expression across sex is reproducible across cohorts and identifies X- and Y-linked genes, as well as those involved in dosage compensation. Intriguingly, the sex expression signature is also enriched for genes involved in neurexin family protein binding and synaptic organization. Differential expression analysis testing a sex-by-diagnosis interaction effect did not identify any genome-wide signature after multiple testing corrections. Gene coexpression network analysis was performed to reduce dimensionality and elucidate interactions among genes. We found enrichment of co-expression modules for sex-by-diagnosis differential expression signatures, which were highly reproducible across the two cohorts and involve a number of diverse pathways, including neural nucleus development, neuron projection morphogenesis, and regulation of neural precursor cell proliferation. Overall, our results indicate that the effect size of sex differences in schizophrenia gene expression signatures is small and underscore the challenge of identifying robust sex-by-diagnosis signatures, which will require future analyses in larger cohorts.

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Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-κB–driven inflammation and cardiovascular risk

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1816847116 ◽

2019 ◽

Vol 116 (23) ◽

pp. 11370-11379 ◽

Cited By ~ 35

Author(s):

Anthony S. Zannas ◽

Meiwen Jia ◽

Kathrin Hafner ◽

Jens Baumert ◽

Tobias Wiechmann ◽

...

Keyword(s):

Cardiovascular Risk ◽

Gene Networks ◽

Large Scale ◽

Molecular Mechanisms ◽

Replicative Senescence ◽

Disease Risk ◽

Human Fibroblasts ◽

Epigenetic Effects ◽

Inflammatory Processes ◽

History Of

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB–related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stress-driven FKBP5–NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

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Use of Wrapper Algorithms Coupled with a Random Forests Classifier for Variable Selection in Large-Scale Genomic Association Studies

Journal of Computational Biology ◽

10.1089/cmb.2008.0037 ◽

2009 ◽

Vol 16 (12) ◽

pp. 1705-1718 ◽

Cited By ~ 15

Author(s):

Andrei S. Rodin ◽

Anatoliy Litvinenko ◽

Kathy Klos ◽

Alanna C. Morrison ◽

Trevor Woodage ◽

...

Keyword(s):

Variable Selection ◽

Random Forests ◽

Large Scale ◽

Association Studies ◽

Genomic Association

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Sex Differences in the Genetics of Sarcoidosis Across European and African Ancestry Populations

10.21203/rs.3.rs-382787/v1 ◽

2021 ◽

Author(s):

Ying Xiong ◽

Susanna Kullberg ◽

Lori Garman ◽

Nathan Pezant ◽

David Ellinghaus ◽

...

Keyword(s):

Sex Differences ◽

Molecular Mechanisms ◽

Association Studies ◽

The United States ◽

Genetic Variations ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Genome Wide ◽

A Genome ◽

Löfgren’S Syndrome

Abstract Background: Sex differences in the susceptibility of sarcoidosis are unknown. The study aims to identify sex-dependent genetic variations in two sarcoidosis clinical phenotypes: Löfgren's syndrome (LS) and non- Löfgren's syndrome (non-LS).Methods: A meta-analysis of genome-wide association studies was conducted in Europeans and African Americans, totaling 10,103 individuals from three population-based cohorts, Sweden (n = 3,843), Germany (n = 3,342), and the United States (n = 2,918), followed by replication look-up in the UK Biobank (n = 387,945). A genome-wide association study based on Immunochip data consisting of 141,000 single nucleotide polymorphisms (SNPs) was conducted in males and females in each cohort, respectively. The association test was based on logistic regression using the additive model in LS and non-LS independently. Additionally, gene-based analysis, expression quantitative trait loci (eQTL) assessments, and enrichment analysis were performed to discover functionally relevant mechanisms related to biological sex. Results: In LS sarcoidosis, we identified various sex-dependent genetic variations (798 SNPs in males and 703 SNPs in females). Genetic findings in sex groups were explicitly located in the extended major histocompatibility complex. In non-LS, we detected 16 SNPs in males and 38 in females, primarily localized to the MHC class II region. Additionally, the ANXA11 gene, a well-documented locus in sarcoidosis, was associated exclusively with non-LS males. Gene-based, eQTL assessment and enrichment analyses revealed distinct sex-dependent genomic loci and gene expression variation in the sex groups. Conclusions: Our findings provide new evidence of the existence of sex-dependent genetic variations underlying sarcoidosis genetic architecture. These findings suggest a sex bias in molecular mechanisms of sarcoidosis.

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