Sex-Dependent Effects of Cardiometabolic Health and APOE4 on Brain Age: A Longitudinal Cohort Study.

BACKGROUND AND OBJECTIVES: The aging population is growing faster than all other demographic strata. With older age comes a greater risk of health conditions such as obesity and high blood pressure (BP). These cardiometabolic risk factors (CMRs) exhibit prominent sex differences in midlife and aging, yet their influence on brain health in females vs males is largely unexplored. In this study, we investigated sex differences in relationships between BP, body mass index (BMI), and brain age over time and tested for interactions with APOE ε4 genotype (APOE4), a known genetic risk factor of Alzheimer disease. METHODS: The sample included participants from 2 United Kingdom-based longitudinal birth cohorts, the Lothian Birth Cohort (1936) and Insight 46 (1946). Participants with MRI data from at least 1 time point were included to evaluate sex differences in associations between CMRs and brain age. The open-access software package brainageR 2.1 was used to estimate brain age for each participant. Linear mixed-effects models were used to assess the relationships between brain age, BMI, BP, and APOE4 status (i.e., carrier vs noncarrier) in males and females over time. RESULTS: The combined sample comprised 1,120 participants (48% female) with a mean age (SD) of 73 (0.72) years in the Lothian Birth Cohort and 71 (0.68) years in Insight 46 at the time point 1 assessment. Approximately 30% of participants were APOE4 carriers. Higher systolic and diastolic BP was significantly associated with older brain age in females only (ß = 0.43-0.56, p < 0.05). Among males, higher BMI was associated with older brain age across time points and APOE4 groups (ß = 0.72-0.77, p < 0.05). In females, higher BMI was linked to older brain age among APOE4 noncarriers (ß = 0.68-0.99, p < 0.05), whereas higher BMI was linked to younger brain age among carriers, particularly at the last time point (ß = -1.75, p < 0.05). DISCUSSION: This study indicates sex-dependent and time-dependent relationships between CMRs, APOE4 status, and brain age. Our findings highlight the necessity of sex-stratified analyses to elucidate the role of CMRs in individual aging trajectories, providing a basis for developing personalized preventive interventions.

SexAnnoDB, a knowledgebase of sex-specific regulations from multi-omics data of human cancers.

BACKGROUND: Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules. METHODS: In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, as well as sex-biased expression quantitative trait loci, sex-biased expression quantitative trait methylation, sex-biased splicing quantitative trait loci, and the identification of sex-biased cancer therapeutic drug target genes. All findings from these analyses are accessible on SexAnnoDB ( https://ccsm.uth.edu/SexAnnoDB/ ). RESULTS: From these analyses, we defined 126 cancer therapeutic target sex-associated genes. Among them, 9 genes showed sex-biased at both the mRNA and protein levels. Specifically, S100A9 was the target of five drugs, of which calcium has been approved by the FDA for the treatment of colon and rectal cancers. Transcription factor (TF)-gene regulatory network analysis suggested that four TFs in the SARC male group targeted S100A9 and upregulated the expression of S100A9 in these patients. Promoter region methylation status was only associated with S100A9 expression in KIRP female patients. Hypermethylation inhibited S100A9 expression and was responsible for the downregulation of S100A9 in these female patients. CONCLUSIONS: Comprehensive network and association analyses indicated that the sex differences at the transcriptome level were partially the result of corresponding sex-biased epigenetic and genetic molecules. Overall, SexAnnoDB offers a discipline-specific search platform that could potentially assist basic experimental researchers or physicians in developing personalized treatment plans.

Sexual variations at the molecular level have a profound impact on cancer biology and outcomes, influencing drug responses that diverge between men and women exposed to the same drugs. Despite existing databases on sex differences in human tissues, our understanding of the regulations governing sex disparities in cancer is limited, lacking detailed mechanistic studies on sex-biased molecules. This study addresses this gap by conducting a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, specifically focusing on sex-biased effects. The analyses led to the identification of 126 cancer therapeutic target sex-associated genes and shed light on the intricate relationship between sexual differences and cancer. Furthermore, the findings from these analyses are made accessible through SexAnnoDB, providing a specialized search platform. This platform has the potential to assist basic experimental researchers or physicians in developing personalized treatment plans based on a deeper understanding of sex-specific factors in cancer.

Sex chromosome-encoded protein homologs: current progress and open questions.

The complexity of biological sex differences is markedly evident in human physiology and pathology. Although many of these differences can be ascribed to the expression of sex hormones, another contributor to sex differences lies in the sex chromosomes beyond their role in sex determination. Although largely nonhomologous, the human sex chromosomes express seventeen pairs of homologous genes, referred to as the 'X-Y pairs.' The X chromosome-encoded homologs of these Y-encoded proteins are crucial players in several cellular processes, and their dysregulation frequently results in disease development. Many diseases related to these X-encoded homologs present with sex-biased incidence or severity. By contrast, comparatively little is known about the differential functions of the Y-linked homologs. Here, we summarize and discuss the current understanding of five of these X-Y paired proteins, with recent evidence of differential functions and of having a potential link to sex biases in disease, highlighting how amino acid-level sequence differences may differentiate their functions and contribute to sex biases in human disease.

Sex Differences in Dementia, Cognition, and Health in the Cognitive Function and Ageing Studies (CFAS).

Background: There is renewed interest in whether sex differences in dementia risk exist, and what influence social and biological factors have. Objective: To review evidence from the Cognitive Function and Ageing Studies (CFAS), a multi-center population-representative cohort study in the UK; focusing on dementia and cognition, incorporating findings on participants' health and social circumstances. Methods: After identifying all CFAS publications, the results of all sex-stratified primary analyses of CFAS data were narratively reviewed. Results: Of 337 publications, 94 report results by sex (including null findings), which are summarized by theme: dementia epidemiology, cognition, mental health, health expectancy, social context and biological resource (including neuropathology). Conclusions: Where differences are found they most commonly favor men; however, greater mortality in men may confound associations with age-related outcomes. This 'survival bias' may explain findings of greater risk of dementia and faster cognitive decline in women. Age-specific dementia incidence was similar between sexes, although reduced incidence across study generations was more pronounced in men. Mood disorders were more prevalent in women, but adjusting for disability and deprivation attenuated the association. Prominent findings from other cohorts that women have more Alzheimer's disease pathology and greater risk of dementia from the Apolipoprotein E ɛ4 allele were not observed, warranting further investigation. The 'male-female health-survival paradox' is demonstrated whereby women live longer but with more comorbidity and disability. Examining why health expectancies changed differently over two decades for each sex (interacting with deprivation) may inform population interventions to improve cognitive, mental and physical health in later life.

Host-specific effects of a generalist parasite of mosquitoes.

Microsporidians are obligate parasites of many animals, including mosquitoes. Some microsporidians have been proposed as potential agents for the biological control of mosquitoes and the diseases they transmit due to their detrimental impact on larval survival and adult lifespan. To get a more complete picture of their potential use as agents of biological control, we measured the impact of Vavraia culicis on several life-history traits of Aedes aegypti and Anopheles gambiae. We measured the infection dynamics and clearance rate for the two species, and we assessed sexual dimorphism in infection dynamics within each species. Our results show differences in infection dynamics, with Ae. aegypti life-history traits being more affected during its aquatic stage and exhibiting higher clearance of the infection as adults. In contrast, An. gambiae was unable to clear the infection. Additionally, we found evidence of sexual dimorphism in parasite infection in An. gambiae, with males having a higher average parasite load. These findings shed light and improve our knowledge of the infection dynamics of V. culicis, a microsporidian parasite previously recognized as a potential control agent of malaria.

Cellular sex throughout the organism underlies somatic sexual differentiation.

Sex chromosomes underlie the development of male or female sex organs across species. While systemic signals derived from sex organs prominently contribute to sex-linked differences, it is unclear whether the intrinsic presence of sex chromosomes in somatic tissues has a specific function. Here, we use genetic tools to show that cellular sex is crucial for sexual differentiation throughout the body in Drosophila melanogaster. We reveal that every somatic cell converts the intrinsic presence of sex chromosomes into the active production of a sex determinant, a female specific serine- and arginine-rich (SR) splicing factor. This discovery dismisses the mosaic model which posits that only a subset of cells has the potential to sexually differentiate. Using cell-specific sex reversals, we show that this prevalence of cellular sex drives sex differences in organ size and body weight and is essential for fecundity. These findings demonstrate that cellular sex drives differentiation programs at an organismal scale and highlight the importance of cellular sex pathways in sex trait evolution.

Sex Differences in the Etiology of Victimization in Adulthood.

Until relatively recently, the study of victimization has been largely outside the purview of behavioral geneticists and evolutionary psychologists. Recent victimology research, however, has shown that genetic and evolutionary forces are connected to the risk of victimization. The current study expands on these findings by examining whether genetic influences differentially explain victimization in males and females. To do so, we use a sample of sibling pairs drawn from the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 4,244). The analyses revealed no significant quantitative sex differences in the etiology of adult victimization. However, the results of this study do highlight the importance of accounting for genetic factors when studying the etiology of specific types of adult victimization. We conclude by discussing the implications of the current study for future research.

Sex-dependent effects of Setd1a haploinsufficiency on development and adult behaviour.

Loss of function (LoF) mutations affecting the histone methyl transferase SETD1A are implicated in the aetiology of a range of neurodevelopmental disorders including schizophrenia. We examined indices of development and adult behaviour in a mouse model of Setd1a haploinsufficiency, revealing a complex pattern of sex-related differences spanning the pre- and post-natal period. Specifically, male Setd1a+/- mice had smaller placentae at E11.5 and females at E18.5 without any apparent changes in foetal size. In contrast, young male Setd1a+/- mice had lower body weight and showed enhanced growth, leading to equivalent weights by adulthood. Embryonic whole brain RNA-seq analysis revealed expression changes that were significantly enriched for mitochondria-related genes in Setd1a+/ samples. In adulthood, we found enhanced acoustic startle responding in male Setd1a+/- mice which was insentitive to the effects of risperidone, but not haloperidol, both commonly used antipsychotic drugs. We also observed reduced pre-pulse inhibition of acoustic startle, a schizophrenia-relevant phenotype, in both male and female Setd1a+/- mice which could not be rescued by either drug. In the open field and elevated plus maze tests of anxiety, Setd1a haplosufficiency led to more anxiogenic behaviour in both sexes, whereas there were no differences in general motoric ability and memory. Thus, we find evidence for changes in a number of phenotypes which strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia. Furthermore, our data point towards possible underpinning neural and developmental mechanisms that may be subtly different between the sexes.

Decoding the decline: unveiling drivers of sarcopenia.

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI, Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.

Sex- and strain-dependent effects of ageing on sleep and activity patterns in Drosophila.

The fruit fly Drosophila is a major discovery platform in the biology of ageing due to its balance of relatively short lifespan and relatively complex physiology and behaviour. Previous studies have suggested that some important phenotypes of ageing, for instance increasingly fragmented sleep, are shared from humans to Drosophila and can be useful measures of behavioural change with age: these phenotypes therefore hold potential as readouts of healthy ageing for genetic or pharmacological interventions aimed at the underpinning biology of ageing. However, some age-related phenotypes in Drosophila show differing results among studies, leading to questions regarding the source of discrepancies among experiments. In this study, I have tested females and males from three common laboratory strains of Drosophila to determine the extent to which sex and background strain influence age-related behavioural changes in sleep and activity patterns. Surprisingly, I find that some phenotypes-including age-related changes in total activity, total sleep, and sleep fragmentation-depend strongly on sex and strain, to the extent that some phenotypes show opposing age-related changes in different sexes or strains. Conversely, I identify other phenotypes, including age-related decreases in morning and evening anticipation, that are more uniform across sexes and strains. These results reinforce the importance of controlling for background strain in both behavioural and ageing experiments, and they imply that caution should be used when drawing conclusions from studies on a single sex or strain of Drosophila. At the same time, these findings also offer suggestions for behavioural measures that merit further investigation as potentially more consistent phenotypes of ageing.

Sex-dependent changes in AMPAR expression and Na, K-ATPase activity in the cerebellum and hippocampus of α-Klotho-Hypomorphic mice.

Aging is characterized by a functional decline in several physiological systems. α-Klotho-hypomorphic mice (Kl-/-) exhibit accelerated aging and cognitive decline. We evaluated whether male and female α-Klotho-hypomorphic mice show changes in the expression of synaptic proteins, N-methyl-d-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, postsynaptic density protein 95 (PSD-95), synaptophysin and synapsin, and the activity of Na+, K+-ATPase (NaK) isoforms in the cerebellum and hippocampus. In this study, we demonstrated that in the cerebellum, Kl-/- male mice have reduced expression of GluA1 (AMPA) compared to wild-type (Kl+/+) males and Kl-/- females. Also, Kl-/- male and female mice show reduced ɑ2/ɑ3-NaK and Mg2+-ATPase activities in the cerebellum, respectively, and sex-based differences in NaK and Mg2+-ATPase activities in both the regions. Our findings suggest that α-Klotho could influence the expression of AMPAR and the activity of NaK isoforms in the cerebellum in a sex-dependent manner, and these changes may contribute, in part, to cognitive decline.

Sexually dimorphic DNA methylation and gene expression patterns in human first trimester placenta.

BACKGROUND: Fetal sex and placental development impact pregnancy outcomes and fetal-maternal health, but the critical timepoint of placenta establishment in first trimester is understudied in human pregnancies. METHODS: Pregnant subjects were recruited in late first trimester (weeks 10-14) at time of chorionic villus sampling, a prenatal diagnostic test. Leftover placenta tissue was collected and stored until birth outcomes were known, then DNA and RNA were isolated from singleton, normal karyotype pregnancies resulting in live births. DNA methylation was measured with the Illumina Infinium MethylationEPIC BeadChip array (n = 56). Differential methylation analysis compared 25 females versus 31 males using a generalized linear model on 743,461 autosomal probes. Gene expression sex differences were analyzed with RNA-sequencing (n = 74). An integrated analysis was performed using linear regression to correlate gene expression and DNA methylation in 51 overlapping placentas. RESULTS: Methylation analysis identified 151 differentially methylated probes (DMPs) significant at false discovery rate < 0.05, including 89 (59%) hypermethylated in females. Probe cg17612569 (GABPA, ATP5J) was the most significant CpG site, hypermethylated in males. There were 11 differentially methylated regions affected by fetal sex, with transcription factors ZNF300 and ZNF311 most significantly hypermethylated in males and females, respectively. RNA-sequencing identified 152 genes significantly sexually dimorphic at false discovery rate < 0.05. The 151 DMPs were associated with 18 genes with gene downregulation (P < 0.05) in the direction of hypermethylation, including 2 genes significant at false discovery rate < 0.05 (ZNF300 and CUB and Sushi multiple domains 1, CSMD1). Both genes, as well as Family With Sequence Similarity 228 Member A (FAM228A), showed significant correlation between DNA methylation and sexually dimorphic gene expression, though FAM228A DNA methylation was less sexually dimorphic. Comparison with other sex differences studies found that cg17612569 is male-hypermethylated across gestation in placenta and in human blood up to adulthood. CONCLUSIONS: Overall, sex dimorphic differential methylation with associated differential gene expression in the first trimester placenta is small, but there remain significant genes that may be regulated through methylation leading to differences in the first trimester placenta.

Fetal sex and placenta development affect pregnancy outcomes for both the fetus and mother throughout pregnancy, including risk of miscarriages, preterm birth, preeclampsia, and other outcomes. Epigenetics, the "overlay" of regulatory signals on DNA which affects how DNA is read, is not well understood in early pregnancy when critical placenta developments are happening that affect the rest of pregnancy. Here, we use leftover placenta biopsy samples (n = 56) donated by Cedars-Sinai patients with informed consent to learn about first trimester human placenta DNA methylation differences due to fetal sex. Out of the total 743,461 sites analyzed, we identified 151 sites significantly affected by fetal sex after correcting p-values to reduce false positives (false discovery rate < 0.05). We also performed an analysis to look at multiple sites and identified 11 regions across the genome with significant DNA methylation changes due to fetal sex. Furthermore, because DNA methylation is a regulatory mark on DNA which typically dampens gene expression, we also compared the DNA methylation sex differences to placental RNA-sequencing gene expression analysis using the same tissue from a mostly overlapping patient group (n = 74 total sequenced, n = 51 overlap). We identify 18 genes which show both significant DNA methylation differences and gene expression changes. The most significant gene was transcription factor ZNF300 with higher DNA methylation in males and reduced gene expression in males (and thus higher gene expression in females). This study identifies some sex differences that continue until later pregnancy and others that are unique to first trimester.

Maternal immune activation and its multifaceted effects on learning and memory in rodent offspring: A systematic review.

This systematic review explored the impact of maternal immune activation (MIA) on learning and memory behavior in offspring, with a particular focus on sexual dimorphism. We analyzed 20 experimental studies involving rodent models (rats and mice) exposed to either lipopolysaccharide (LPS) or POLY I:C during gestation following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Our findings reveal that most studies report a detrimental impact of MIA on the learning and memory performance of offspring, highlighting the significant role of prenatal environmental factors in neurodevelopment. Furthermore, this review underscores the complex effects of sex, with males often exhibiting more pronounced cognitive impairment compared to females. Notably, a small subset of studies report enhanced cognitive function following MIA, suggesting complex, context-dependent outcomes of prenatal immune challenges. This review also highlights sex differences caused by the effects of MIA in terms of cytokine responses, alterations in gene expression, and differences in microglial responses as factors that contribute to the cognitive outcomes observed.

Mouse sarcopenia model reveals sex- and age-specific differences in phenotypic and molecular characteristics.

Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.

Do Sex and Gender Have Separate Identities?

The largely binary nature of biological sex and its conflation with the socially constructed concept of gender has created much strife in the last few years. The notion of gender identity and its differences and similarities with sex have fostered much scientific and legal confusion and disagreement. Settling the debate can have significant repercussions for science, medicine, legislation, and people's lives. The present review addresses this debate though different levels of analysis (i.e., genetic, anatomical, physiological, behavioral, and sociocultural), and their implications and interactions. We propose a rationale where both perspectives coexist, where diversity is the default, establishing a delimitation to the conflation between sex and gender, while acknowledging their interaction. Whereas sex in humans and other mammals is a biological reality that is largely binary and based on genes, chromosomes, anatomy, and physiology, gender is a sociocultural construct that is often, but not always, concordant with a person' sex, and can span a multitude of expressions.

Sex-related differences in corticospinal excitability outcome measures of the biceps brachii during a submaximal elbow flexor contraction.

The purpose of this study was to investigate the effects of sex, muscle thickness, and subcutaneous fat thickness (SFT) on corticospinal excitability outcome measures of the biceps brachii. Eighteen participants (10 males and 8 females) completed this study. Ultrasound was used to assess biceps brachii muscle thickness and the overlying SFT. Transcranial magnetic stimulation (TMS) was used to determine corticospinal excitability by inducing motor-evoked potentials (MEPs) at eight different TMS intensities from 90% to 160% of active motor threshold (AMT) from the biceps brachii during an isometric contraction of the elbow flexors at 10% of maximum voluntary contraction (MVC). Biceps brachii maximal compound muscle action potential (Mmax) was also recorded prior to and after TMS. Males had higher (p < 0.001) biceps brachii muscle thickness and lower SFT, produced higher levels of MVC force and had, on average, higher (p < 0.001) MEP amplitudes at lower (p < 0.05) percentages of maximal stimulator output than females during the 10% elbow flexion MVC. Multiple linear regression modeling revealed that sex was not associated with any of the neurophysiological parameters examined, while SFT showed a positive association with the stimulation intensity required at AMT (p = 0.035) and a negative association with biceps brachii pre-stimulus electromyography (EMG) activity (p = 0.021). Additionally, there was a small positive association between muscle thickness and biceps brachii pre-stimulus EMG activity (p = 0.049). Overall, this study suggests that some measures of corticospinal excitability may be different between the sexes and influenced by SFT and muscle thickness.

Oxidative stress and galectin-3 levels during skin grafting after hand injury: gender differences.

The study included 40 patients of both genders who underwent skin transplantation after a hand injury. The study aims to evaluate the oxidative stress parameters in patients' blood and serum levels of galectin-3 in order to investigate gender differences pre- and post- skin transplantation. The results of the study suggest a significant increase in superoxide anion radical levels, catalase activity, and reduced glutathione levels in females before skin transplantation. The surgical treatment caused significant increase in superoxide anion radical and hydrogen peroxide levels as prooxidants in males, while superoxide dismutase and catalase activity were also increased 7 days after the procedure. In females, superoxide anion radical and TBARS levels increased after surgical procedure as well as the activity of catalase. Regarding galectin-3 levels, a significant interaction between gender and time was observed (gender×time; p=0.000). Correlation analysis of different oxidative stress markers with gal-3 revealed the existence of a significant negative correlation of superoxide anion radical, catalase, and reduced glutathione with gal-3, but only in female patients. It can be concluded that OS as well as galectin-3 play important roles at least in the first 7 days of the postoperative period.

Sex-Dependent T Cell Dysregulation in Mice with Diet-Induced Obesity.

Obesity is an emerging public health problem. Chronic low-grade inflammation is considered a major promotor of obesity-induced secondary diseases such as cardiovascular and fatty liver disease, type 2 diabetes mellitus, and several cancer entities. Most preliminary studies on obesity-induced immune responses have been conducted in male rodents. Sex-specific differences between men and women in obesity-induced immune dysregulation have not yet been fully outlined but are highly relevant to optimizing prevention strategies for overweight-associated complications. In this study, we fed C57BL/6 female vs. male mice with either standard chow or an obesity-inducing diet (OD). Blood and spleen immune cells were isolated and analyzed by flow cytometry. Lean control mice showed no sex bias in systemic and splenic immune cell composition, whereas the immune responses to obesity were significantly distinct between female and male mice. While immune cell alterations in male OD mice were characterized by a significant reduction in T cells and an increase in myeloid-derived suppressor cells (MDSC), female OD mice displayed preserved T cell numbers. The sex-dependent differences in obesity-induced T cell dysregulation were associated with varying susceptibility to body weight gain and fatty liver disease: Male mice showed significantly more hepatic inflammation and histopathological stigmata of fatty liver in comparison to female OD mice. Our findings indicate that sex impacts susceptibility to obesity-induced T cell dysregulation, which might explain sex-dependent different incidences in the development of obesity-associated secondary diseases. These results provide novel insights into the understanding of obesity-induced chronic inflammation from a sex-specific perspective. Given that most nutrition, exercise, and therapeutic recommendations for the prevention of obesity-associated comorbidities do not differentiate between men and women, the data of this study are clinically relevant and should be taken into consideration in future trials and treatment strategies.