Sex Differences In Response Research Articles

Tissue- and sex-specific small RNAomes reveal sex differences in response to the environment.

RNA interference (RNAi) related pathways are essential for germline development and fertility in metazoa and can contribute to inter- and trans-generational inheritance. In the nematode Caenorhabditis elegans, environmental double-stranded RNA provided by feeding can lead to heritable changes in phenotype and gene expression. Notably, transmission efficiency differs between the male and female germline, yet the underlying mechanisms remain elusive. Here we use high-throughput sequencing of dissected gonads to quantify sex-specific endogenous piRNAs, miRNAs and siRNAs in the C. elegans germline and the somatic gonad. We identify genes with exceptionally high levels of secondary 22G RNAs that are associated with low mRNA expression, a signature compatible with silencing. We further demonstrate that contrary to the hermaphrodite germline, the male germline, but not male soma, is resistant to environmental RNAi triggers provided by feeding, in line with previous work. This sex-difference in silencing efficacy is associated with lower levels of gonadal RNAi amplification products. Moreover, this tissue- and sex-specific RNAi resistance is regulated by the germline, since mutant males with a feminized germline are RNAi sensitive. This study provides important sex- and tissue-specific expression data of miRNA, piRNA and siRNA as well as mechanistic insights into sex-differences of gene regulation in response to environmental cues.

Sex Differences in Pulmonary Responses to Ozone in Mice. Role of the Microbiome.

We have previously reported that the mouse gut microbiome contributes to pulmonary responses to ozone, a common asthma trigger, and that short-chain fatty acids, end products of bacterial fermentation, likely contribute to this role of the microbiome. A growing body of evidence indicates that there are sex-related differences in gut microbiota and these differences can have important functional consequences. The purpose of this study was to determine whether there are sex-related differences in the impact of the gut microbiota on pulmonary responses to ozone. After acute exposure to ozone, male mice developed greater airway hyperresponsiveness than female mice. This difference was abolished after antibiotic ablation of the gut microbiome. Moreover, weanling female pups housed in cages conditioned by adult male mice developed greater ozone-induced airway hyperresponsiveness than weanling female pups raised in cages conditioned by adult females. Finally, ad libitum oral administration via drinking water of the short-chain fatty acid propionate resulted in augmented ozone-induced airway hyperresponsiveness in male, but not female, mice. Overall, these data are consistent with the hypothesis that the microbiome contributes to sex differences in ozone-induced airway hyperresponsiveness, likely as a result of sex differences in the response to short-chain fatty acids.

Sex still matters: has the prevalence of male-only studies of drug effects on rodent behaviour changed during the past decade?

During the past 10 years, for a number of biomedical disciplines, including behavioural pharmacology, there have been appeals to include both sexes in animal studies of processes that are not sex specific. In 2007, a survey of experimental studies of drug or other chemical effects on rodent behaviour, published in five prominent journals over 20 months (February 2005 to September 2006, inclusive), revealed that 85% of these conducted with rats and 78% of these conducted with mice involved males only. This was in spite of the evidence of sex differences in responsiveness to an increasing number of compounds. To see if the situation has improved, the survey was repeated with the same journals for a comparable period namely, February 2016 to September 2017 (inclusive). Even though there have been repeated appeals for biomedical research that is not sex specific to involve both sexes, it was apparent that little has changed since 2005-2006, as 82% of rat and 75% of mouse studies were again conducted with males only. However, there was an increase in studies with mice, which may be owing to a greater interest in genetic factors. The male-only situation could be rectified by appropriate funding agencies and journals that publish behavioural pharmacological research insisting that both sexes must be included in research that is not sex specific along with valid scientific justification for single-sex studies, as now typifies some other disciplines.

Understanding sex differences in response to cardiac resynchronization therapy.

Understanding sex differences in response to cardiac resynchronization therapy.

Sex Differences in Response to TNF-Inhibiting Drugs in Patients With Spondyloarthropathies or Inflammatory Bowel Diseases.

Spondyloarthritis (SpA) and inflammatory bowel diseases (IBD) are chronic inflammatory diseases characterized by an aberrant immune response and inflammation with a key role for TNF in their pathogenesis. Accordingly, TNF-inhibiting therapy (TNFi) has dramatically improved the management of these diseases. However, about 30% of patients discontinue TNFi for lack of response, loss of response, and side effects and/or adverse events. Thus, the possibility to identify in advance those patients who will have a good response to TNFi would be extremely beneficial. The aim of this study was to investigate differences between males and females with either SpA or IBD in response to TNFi molecules, i.e., infliximab (IFX) and adalimumab (ADA), considering the reasons for TNFi withdraw. Data of 594 patients, 349 with IBD (M/F: 194/155) and 245 with SpA (M/F: 123/122), previously unexposed to TNFi, were collected. In the IBD group, the rate of female patients discontinuing ADA was significantly higher than that of male patients (p = 0.03). No difference emerged according to the distribution of reason for discontinuation. Otherwise, a similar discontinuation rate between female and male patients receiving IFX therapy was observed. In the SpA group, the overall discontinuation rate was not different between males and females both for ADA and IFX. However, in patients treated with ADA, males interrupted therapy more frequently than females due to lack of response (p = 0.03). In conclusion, the assessment of sex differences in TNFi response could help physicians personalize the therapeutic approach in a sex-oriented perspective.

Sex Differences in Responses to Emotional and Sexual Infidelity in Dating Relationships

Abstract. This study examined the influence of the type of partner infidelity (sexual vs. emotional) and sex of participant on actual mate abandonment and mate retention behaviors. It was predicted that men would engage in significantly more mate abandonment behaviors after experiencing a physical infidelity and that women would engage in significantly more mate abandonment behaviors after experiencing an emotional infidelity. To test this hypothesis, men and women who had either experienced a sexual or emotional infidelity were recruited and were asked to complete several measures designed to indicate their behavioral responses to the infidelity. The men and women in the study showed the predicted asymmetrical pattern of behavioral choices in response to sexual and emotional infidelity.

Sex differences in response to ketamine as a rapidly acting intervention for treatment resistant depression

BackgroundWhile ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women. MethodsA randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori-planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women. ResultsAnalyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55). ConclusionsResults do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results.

Sex Differences in Graphic Warning Label Ratings by Addictions Clients.

Research on sex differences in responses to cigarette graphic warning labels (GWLs) has been limited despite tobacco-related, health disparities for women. We examined whether women had stronger responses to certain labels than to others, whether this pattern differed from men's, and whether there were overall sex ratings differences. Smokers (N = 881) in 24, addictions treatment programs rated 3 of 9 Food and Drug Administration-developed labels on credibility, message reactance, quit motivation, and negative emotions. Participants rated one label depicting a woman and/or baby, and 2 depicting tobacco-related disease or male images. Women's (n = 432) ratings of labels depicting women/babies versus other labels did not differ from men's (n = 449) ratings. Women had higher ratings than men across all labels combined on credibility (p < .001), quit motivation (p = .007), and negative emotions (p < .001). Individual labels were analyzed for sex differences. Women's ratings were higher on credibility for 3 of 9 labels, and on negative emotions for 7 of 9 labels. Female smokers in addictions treatment had generally stronger responses to GWLs than men, supporting GWL implementation in the United States to help close the sex gap in smoking cessation.

Sex Differences in Subjective and Behavioral Responses to Stressful and Smoking Cues Presented in the Natural Environment of Smokers.

Some evidence suggests that female smokers may show more context-dependent smoking and that males may show more stereotyped smoking (regardless of stress or cue exposure). The goal of this study was to characterize sex differences in response to stressful and smoking cues ecologically presented in daily life and variability in day-to-day smoking behavior. Adult smokers (N = 177) provided ratings of mood and cigarette craving before and after stress and smoking cues were presented four times daily for 14 days via a mobile device. Linear mixed models tested whether (1) female smokers exhibited greater reactivity to stressful cues than male smokers; (2) pre-cue negative affect increased reactivity to smoking cues more in female smokers than male smokers; (3) across both sexes, greater reactivity to stressful and smoking cues correlated with greater quantity of smoking within a day; and (4) female smokers exhibited greater variability in cigarettes per day (CPD) relative to males. Relative to male smokers, female smokers reported greater negative affect, stress, and craving in response to stressful cues, but not smoking cues, after accounting for time since last cigarette and pre-cue responding. No sex differences in CPD or variability in CPD were detected. Days with higher subjective reactivity to cues were not associated with increased smoking, in either males or females. Sex differences were observed in response to stress but not smoking cues in the natural environment of regular cigarette smokers. Further research is necessary to evaluate whether stress reactivity in female smokers is associated with reduced latency to smoke following stress exposure in daily life. This study provides naturalistic evidence that female smokers may not be more reactive to smoking cues than males, but experience heightened stress and craving following stress exposure. There was no evidence to support the hypothesis that amount smoked per day varied more for females, relative to males, as a result of more context-driven smoking for females.

PL - 035 Effects of lactate infusion on the molecular response to resistance exercise in men and women

PL - 035 Effects of lactate infusion on the molecular response to resistance exercise in men and women

Intimate partner violence moderates the association between oxytocin and reactivity to dyadic conflict among couples

Emerging literature indicates individual and contextual differences impact response to oxytocin (OT). Intimate partner violence (IPV) is one chronic stressor that may moderate OT response. To test the hypothesis that IPV moderates the association between OT and reactivity to a dyadic conflict task, data from a larger randomized controlled study was collected from heterosexual couples (N = 60 individuals; 30 couples) at high risk for IPV due to substance misuse. Partners within each dyad completed a 10-minute dyadic conflict task in the laboratory, and then self-administered a single dose of OT (40 IU) or placebo. Forty-five minutes later, participants completed another 10-minute dyadic conflict task. Stress reactivity was measured before and after the second conflict task using neuroendocrine (i.e., salivary cortisol), physiological (i.e., skin conductance), and subjective responses. Couple conflict behaviors were observed during the conflict tasks and assessed using a validated coding system. Among women, physical IPV modulated skin conductance in those administered OT, and OT interacted with physical and psychological IPV to yield less positive subjective and behavioral responses. No main or moderating effects were found for men. Findings support emerging literature on sex differences in response to OT. Future research is needed to effectively translate OT into therapeutic intervention.

Diet-Induced Obesity Elicits Macrophage Infiltration and Reduction in Spine Density in the Hypothalami of Male but Not Female Mice.

Increasing prevalence in obesity has become a significant public concern. C57BL/6J mice are prone to diet-induced obesity (DIO) when fed high-fat diet (HFD), and develop chronic inflammation and metabolic syndrome, making them a good model to analyze mechanisms whereby obesity elicits pathologies. DIO mice demonstrated profound sex differences in response to HFD with respect to inflammation and hypothalamic function. First, we determined that males are prone to DIO, while females are resistant. Ovariectomized females, on the other hand, are susceptible to DIO, implying protection by ovarian hormones. Males, but not females, exhibit changes in hypothalamic neuropeptide expression. Surprisingly, ovariectomized females remain resistant to neuroendocrine changes, showing that ovarian hormones are not necessary for protection. Second, obese mice exhibit sex differences in DIO-induced inflammation. Microglial activation and peripheral macrophage infiltration is seen in the hypothalami of males, while females are protected from the increase in inflammatory cytokines and do not exhibit microglia morphology changes nor monocyte-derived macrophage infiltration, regardless of the presence of ovarian hormones. Strikingly, the anti-inflammatory cytokine IL-10 is increased in the hypothalami of females but not males. Third, this study posits a potential mechanism of obesity-induced impairment of hypothalamic function whereby obese males exhibit reduced levels of synaptic proteins in the hypothalamus and fewer spines in GnRH neurons, located in the areas exhibiting macrophage infiltration. Our studies suggest that inflammation-induced synaptic remodeling is potentially responsible for hypothalamic impairment that may contribute to diminished levels of gonadotropin hormones, testosterone, and sperm numbers, which we observe and corresponds to the observations in obese humans. Taken together, our data implicate neuro-immune mechanisms underlying sex-specific differences in obesity-induced impairment of the hypothalamic function with potential consequences for reproduction and fertility.

Sex-Specific Response of Caenorhabditis elegans to Methylmercury Toxicity.

Methylmercury (MeHg), an abundant environmental pollutant, has long been known to adversely affect neurodevelopment in both animals and humans. Several reports from epidemiological studies, as well as experimental data indicate sex-specific susceptibility to this neurotoxicant; however, the molecular bases of this process are still not clear. In the present study, we used Caenorhabditis elegans (C. elegans), to investigate sex differences in response to MeHg toxicity during development. Worms at different developmental stage (L1, L4, and adult) were treated with MeHg for 1h. Lethality assays revealed that male worms exhibited significantly higher resistance to MeHg than hermaphrodites, when at L4 stage or adults. However, the number of worms with degenerated neurons was unaffected by MeHg, both in males and hermaphrodites. Lower susceptibility of males was not related to changes in mercury (Hg) accumulation, which was analogous for both wild-type (wt) and male-rich him-8 strain. Total glutathione (GSH) levels decreased upon MeHg in him-8, but not in wt. Moreover, the sex-dependent response of the cytoplasmic thioredoxin system was observed-males exhibited significantly higher expression of thioredoxin TRX-1, and thioredoxin reductase TRXR-1 expression was downregulated upon MeHg treatment only in hermaphrodites. These outcomes indicate that the redox status is an important contributor to sex-specific sensitivity to MeHg in C. elegans.

Sex difference in cold perception and shivering onset upon gradual cold exposure

To maintain a thermal balance when experiencing cold, humans reduce heat loss and enhance heat production. A potent and rapid mechanism for heat generation is shivering. Research has shown that women prefer a warmer environment and feel less comfortable than men in the same thermal condition. Using the Blanketrol® III, a temperature management device commonly used to study brown adipose tissue activity, we tested whether the experimental temperature (TE) at which men and women start to shiver differs. Twenty male and 23 female volunteers underwent a cooling protocol, starting at 24 °C and gradually decreasing by 1–2 °C every 5 min until an electromyogram detected the shivering or the temperature reached 9 °C. Women started shivering at a higher TE than men (11.3 ± 1.8 °C for women vs 9.6 ± 1.8 °C for men, P = 0.003). In addition, women felt cool, scored by a visual analogue scale, at a higher TE than men (18.3 ± 3.0 °C for women vs 14.6 ± 2.6 °C for men, P < 0.001). This study demonstrates a sex difference in response to cold exposure: women require shivering as a source of heat production earlier than men. This difference could be important and sex should be considered when using cooling protocols in physiological studies.

Myths and Methodologies: Reducing scientific design ambiguity in studies comparing sexes and/or menstrual cycle phases.

What is the topic of this review? We review methodological considerations for the inclusion of women in sex and menstrual cycle phase comparison studies. What advances does it highlight? Improving the methodological design for studies exploring sex differences, menstrual cycle phase differences and/or endogenous versus exogenous female sex hormones will help to close the gap in our understanding of the effects of endogenous and exogenous hormones on exercise science and sports medicine outcomes. In recent years, the increase in scientific literature exploring sex differences has been beneficial to both clinicians and allied health science professionals, although female athletes are still significantly under-represented in sport and exercise science research. Women have faced exclusion throughout history though the complexities of sociocultural marginalization and biomedical disinterest in women's health. These complexities have contributed to challenges of studying women and examining sex differences. One underlying complexity to methodological design may be hormonal perturbations of the menstrual cycle. The biphasic responses of oestrogen and progesterone across the menstrual cycle significantly influence physiological responses, which contribute to exercise capacity and adaptation in women. Moreover, oral contraceptives add complexity through the introduction of varying concentrations of circulating exogenous oestrogen and progesterone, which may moderate physiological adaptations to exercise in a different manner to endogenous ovarian hormones. Thus, applied sport and exercise science research focusing on women remains limited, in part, by poor methodological design that does not define reproductive status. By highlighting specific differences between phases with regard to hormone perturbations and the systems that are affected, methodological inconsistencies can be reduced, thereby improving scientific design that will enable focused research on female athletes in sports science and evaluation of sex differences in responses to exercise. The aims of this review are to highlight the differences between endogenous and exogenous hormone profiles across a standard 28-32 day menstrual cycle, with the goal to improve methodological design for studies exploring sex differences, menstrual cycle phase differences and/or endogenous versus exogenous female sex hormones.

Sex differences in response to emotion recognition training after traumatic brain injury

ABSTRACTObjective: To examine sex differences in the effectiveness of a Stories intervention for teaching affect recognition in people with a traumatic brain injury (TBI).Setting: Post-acute rehabilitation facilities.Participants: 203 participants (53 women and 150 men) with moderate to severe TBI were screened. 71 were eligible and randomized to one of three treatment conditions: two affect recognition conditions and an active control (cognition). This paper examines sex differences between the Stories intervention (n = 23, 5 women and 18 men) and the cognitive treatment control (n = 24, 8 women and 16 men).Design: Randomized controlled trial with immediate, 3- and 6-month follow-up post-tests. Interventions were 9 hours of computer-based training with a therapist.Measures: Facial Affect Recognition (DANVA2-AF); Emotional Inference from Stories Test (EIST).Results: A significant treatment effect was observed for the Stories intervention for women, who demonstrated and maintained improved facial affect recognition. In contrast, males in our sample did not benefit from the Stories intervention.Conclusion: This positive finding for the Stories intervention for females contrasts with our conclusions in a previous paper, where an analysis collapsed across sex did not reveal an overall effectiveness of the Stories intervention. This intervention warrants further research and development.

Sex differences in the traumatic stress response: the role of adult gonadal hormones

BackgroundOur previous study revealed that adult female rats respond differently to trauma than adult males, recapitulating sex differences in symptoms of post-traumatic stress disorder (PTSD) exhibited by women and men. Here, we asked two questions: does the female phenotype depend on (1) social housing condition and/or (2) circulating gonadal hormones?MethodsFor the first study, the effects of single prolonged stress (SPS) were compared for females singly or pair-housed. For the second study, adult male and female rats were gonadectomized or sham-gonadectomized 2 weeks prior to exposure to SPS, with half the gonadectomized rats given testosterone. In addition to the typical measures of the trauma response in rats, acoustic startle response (ASR), and the dexamethasone suppression test (DST), we also used two other measures typically used to assess depressive-like responses, social interaction and sucrose preference. Glucocorticoid receptor (GR) expression in the hypothalamus was also examined.ResultsWe now report that the distinct trauma response of female rats is not influenced by social housing condition. Moreover, sex differences in the response to SPS based on ASR and DST, replicated in the current study, are independent of adult gonadal hormones. Regardless of hormonal status, traumatized males show a hyper-responsive phenotype whereas traumatized females do not. Moreover, testosterone treatment in adulthood did not masculinize the response to trauma in females. Notably, both sucrose preference and social interaction tests revealed an effect of trauma in females but not in males, with the effects of SPS on sucrose preference dependent on ovarian hormones. Effects of SPS on GR expression in the hypothalamus also depended on gonadal hormones in females.ConclusionsWe propose that the trauma response for female rats is depressive in nature, recapitulating the female bias in PTSD for internalizing symptoms and major depression in contrast to the externalizing symptoms of males. Presumed core markers of PTSD (enhanced ASR and negative feedback control of corticosterone) are apparently relevant only to males and are independent of adult gonadal hormones. Such sex differences in trauma responding are likely determined earlier in life. We conclude that males and females show fundamentally different responses to trauma that do not simply reflect differences in resilience.

Dietary methoprene supplement promotes early sexual maturation of male Queensland fruit fly Bactrocera tryoni

Sterile insect technique (SIT) is an environmentally benign pest management technique that relies on released sterile male insects mating with, and curtailing reproduction of, wild females. However, for species with high mortality rates and long adult maturation phases, a large proportion of the released insects can die before maturing and so fail to contribute to SIT. To counter this problem, inclusion of yeast hydrolysate in pre-release diets and treatment of pupae or adults with methoprene, a juvenile hormone analogue, have been investigated as means of accelerating development of some fruit flies, including Queensland fruit fly, Bactrocera tryoni (Froggatt) (‘Q-fly’). Methoprene has most often been administered topically in acetone solution, which is toxic, flammable, and impractical for operational settings. As a practical alternative, we incorporated methoprene (0, 0.05, 0.1, and 0.5%) into Q-fly adult diet of sugar only or sugar mixed with yeast hydrolysate for 2 days, and then provided sugar only for the rest of the trial period. Mating performance of males and females was tested from 4 to 30 days of age. Flies provided sugar mixed with yeast hydrolysate had increased mating propensity in comparison with flies that were provided sugar only. At all ages and for both diets, all methoprene doses increased male mating probability. Methoprene treatment did not affect copula latency of males that received yeast hydrolysate, but males that received only sugar mated earlier if they had received 0.05% methoprene. Methoprene treatment of males was also associated with longer copulations, which may affect fertility of females that later remate. Females differed from males in that methoprene treatment did not significantly affect mating probability or latency, but resembled males in that methoprene treatment resulted in longer copulations. Sex differences in response to methoprene may lead to male-biased operational sex ratio when bisex Q-fly strains are used in SIT. Yeast hydrolysate increased longevity of both males and females, but methoprene treatment did not affect longevity. Overall, findings of the present study indicate that Q-fly sexual maturation can be accelerated, and SIT might hence be enhanced, by incorporation of methoprene and yeast hydrolysate in pre-release diet.

What has sex got to do with it? The role of hormones in the transgender brain.

Sex differences and hormonal effects in presumed cisgender individuals have been well-studied and support the concept of a mosaic of both male and female "characteristics" in any given brain. Gonadal steroid increases and fluctuations during peri-puberty and across the reproductive lifespan influence the brain structure and function programmed by testosterone and estradiol exposures in utero. While it is becoming increasingly common for transgender and gender non-binary individuals to block their transition to puberty and/or use gender-affirming hormone therapy (GAHT) to obtain their desired gender phenotype, little is known about the impact of these manipulations on brain structure and function. Using sex differences and the effects of reproductive hormones in cisgender individuals as the backdrop, we summarize here the existing nascent neuroimaging and behavioral literature focusing on potential brain and cognitive differences in transgender individuals at baseline and after GAHT. Research in this area has the potential to inform our understanding of the developmental origins of gender identity and sex difference in response to gonadal steroid manipulations, but care is needed in our research questions and methods to not further stigmatize sex and gender minorities.

Sex Differences in the Response of C57BL/6 Mice to Ketogenic Diets

Since the initial use of ketogenic diets (KD) as adjunctive treatment for epilepsy, these diets are being increasingly used to promote weight loss and to reduce the risk of metabolic sequelae of obesity. Typical KD are very low in carbohydrate and high in fat, promoting hepatic production of ketone bodies. Few studies have evaluated gender differences in response to KD, and many animal studies tend to be performed in male mice. To explore sex differences in response to KD, female and male wild type mice on the C57BL/6J background were fed either a control diet (CD- 7% fat, 47% carb., 19% protein) or KD (75% fat, 3% carb., 8% protein), following weaning. Females on the CD manifested higher levels of circulating β-hydroxybutyrate (β-HB) than males (2.86-fold, p&amp;lt;0.05). Circulating β-HB concentrations increased with KD in males and females (1.30-fold and 5.05-fold, p&amp;lt;10-4 and p&amp;lt;0.01 respectively) with higher concentrations in females. After 8 weeks, females on KD displayed an increase in body weight (1.07-fold KD vs. CD, p&amp;lt;0.05) while body weight declined in males (0.88-fold, p&amp;lt;0.05). Nuclear magnetic resonance analysis revealed elevated lean mass in females (1.07-fold, p&amp;lt;0.05), but a significant reduction in fat mass in males (0.49-fold, p&amp;lt;0.05) relative to sex-matched mice on CD. The female mice on KD developed impaired glucose tolerance with a 1.35-fold increase in glucose tolerance test area under the curve (GTT AUC) relative to females on CD (p&amp;lt;0.001). In contrast, fasting glucose levels were lower in males on KD (131.8 ± 12.5 mg/ dl vs. 169.2 ± 6.3 mg/dl, p&amp;lt;0.05). Despite no significant change in GTT AUC, the male mice on KD displayed elevated blood glucose concentrations 30 minutes after injection relative to males on CD (344.9 ± 18.7 mg/dl vs. 272.0 ± 10.3 mg/dl, p&amp;lt;0.05). However, after 120 minutes, blood glucose levels returned to initial fasting levels. In conclusion, significant sex differences exist in terms of body composition and metabolism in response to ketogenic diets via mechanisms that remain to be elucidated. Disclosure J. Cochran: None. P.V. Taufalele: None. K.D. Lin: None. Y. Zhang: None. E. Abel: None.