Paternal obesity induces changes in sperm chromatin accessibility and has a mild effect on offspring metabolic health.

The increasing global burden of metabolic disorders including obesity and diabetes necessitates a comprehensive understanding of their etiology, which not only encompasses genetic and environmental factors but also parental influence. Recent evidence has unveiled paternal obesity as a contributing factor to offspring's metabolic health via sperm epigenetic modifications. In this study, we investigated the impact of a Western diet-induced obesity in C57BL/6 male mice on sperm chromatin accessibility and the subsequent metabolic health of their progeny. Utilizing Assay for Transposase-Accessible Chromatin with sequencing, we discovered 450 regions with differential accessibility in sperm from obese fathers, implicating key developmental and metabolic pathways. Contrary to expectations, these epigenetic alterations in sperm were not predictive of long-term metabolic disorders in offspring, who exhibited only mild transient metabolic changes early in life. Both male and female F1 progeny showed no enduring predisposition to obesity or diabetes. These results underscore the biological resilience of offspring to paternal epigenetic inheritance, suggesting a complex interplay between inherited epigenetic modifications and the offspring's own developmental compensatory mechanisms. This study calls for further research into the biological processes that confer this resilience, which could inform interventional strategies to combat the heritability of metabolic diseases.

Screening type 2 Diabetes mellitus among Indians using inflammatory biomarkers.

Diabetes is a metabolic disorder associated with chronic inflammation; pre-diabetes phase promotes to inflammatory mechanism then finally progress to diabetes and its associated complications. Therefore, it is of interest to investigate the changes in inflammatory biomarkers Evidence that inflammatory markers play a role in the development as well as severity of Type 2 diabetes mellitus (T2DM). This study has been designed to decipher the involvement of Tumor Necrosis Factor (TNFα), Interleukin-6 (IL-6), Nesfatin-1 and Blood sugar in the etiopathogenesis of T2DM. This retrospective observational study analyzed patient records from our hospital, focusing on those with diabetes or pre-diabetes. Glycosylated hemoglobin, inflammatory biomarkers, Fasting Blood Glucose, and Post-Prandial Blood Glucose were assessed. SPSS 28 facilitated statistical analysis; utilizing Bivariate Correlation assessed the relationship between inflammatory biomarkers and diabetes status (glycosylated hemoglobin). In the pre-diabetic vs. diabetic groups, significant differences exist in IL-6 (p=0.0344), TNF-α (p=0.041), Nesfatin-1 (p=0.0485), fasting blood glucose (p=0.036), and 2h post-prandial blood glucose (p=0.048). IL6 (AUC=0.729, p<0.001), TNF (AUC=0.761, p<0.001), and Nesfatin1 (AUC=0.892, p<0.001) show moderate discriminative power. PP (AUC=0.992, p<0.001) and hbA1c (AUC=0.993, p<0.001) exhibit excellent discriminatory ability. Correlations: IL6 with TNF (r=0.672, p<0.001) and Nesfatin1 (r=0.542, p<0.001); TNF with Nesfatin1 (r=0.591, p<0.001), hbA1c (r=0.683, p<0.001), and PP (r=0.367, p<0.001); Nesfatin1 with PP (r=0.594, p<0.001) and hbA1c (r=0.800, p<0.001). Age has a negative correlation with hbA1c (r=-0.119, p=0.086). Thus, data shows a significant association between inflammatory markers, blood glucose levels, and the progression from pre-diabetes to diabetes.

Rebalancing the Gut: Glucagon-Like Peptide-1 Agonists as a Strategy for Obesity and Metabolic Health.

Obesity significantly impacts gut microbial composition, exacerbating metabolic dysfunction and weight gain. Traditional treatment methods often fall short, underscoring the need for innovative approaches. Glucagon-like peptide-1 (GLP-1) agonists have emerged as promising agents in obesity management, demonstrating significant potential in modulating gut microbiota. These agents promote beneficial bacterial populations, such as Bacteroides, Lactobacillus, and Bifidobacterium, while reducing harmful species like Enterobacteriaceae. By influencing gut microbiota composition, GLP-1 agonists enhance gut barrier integrity, reducing permeability and systemic inflammation, which are hallmarks of metabolic dysfunction in obesity. Additionally, GLP-1 agonists improve metabolic functions by increasing the production of short-chain fatty acids like butyrate, propionate, and acetate, which serve as energy sources for colonocytes, modulate immune responses, and enhance the production of gut hormones that regulate appetite and glucose homeostasis. By increasing microbial diversity, GLP-1 agonists create a more resilient gut microbiome capable of resisting pathogenic invasions and maintaining metabolic balance. Thus, by shifting the gut microbiota toward a healthier profile, GLP-1 agonists help disrupt the vicious cycle of obesity-induced gut dysbiosis and inflammation. This review highlights the intricate relationship between obesity, gut microbiota, and GLP-1 agonists, providing valuable insights into their combined role in effective obesity treatment and metabolic health enhancement.

Associations of Obstructive Sleep Apnea Risk with Obesity, Body Composition and Metabolic Abnormalities in School-Aged Children and Adolescents.

The objective of this study is to explore the associations between obesity, body composition, and the self-reported risk of obstructive sleep apnea (OSA) and to examine whether the risk of OSA is related to metabolic abnormalities in children and adolescents aged 6-17 years. Utilizing data from the 2022 to 2023 Beijing Children and Adolescents Health Cohort baseline survey, 5000 school-aged participants were analyzed. OSA risk was assessed via the Pediatric Sleep Questionnaire, with anthropometric and body composition measurements taken. Metabolic markers included blood pressure, lipid levels, blood glucose, and uric acid. Associations were analyzed using logistic regression and generalized linear models. Results showed that 88.6% were low-risk and 11.4% were high-risk for OSA. Overweight (aOR 1.53, 95% CI 1.22-1.92), obesity (aOR 1.94, 95% CI 1.57-2.40), and abdominal obesity (aOR 1.59, 95% CI 1.31-1.93) significantly increased OSA risk. High fat mass was a critical factor, while muscle mass was not, especially in those who were overweight and obese. Associations of OSA risk with metabolic abnormalities were non-significant after adjusting for BMI. Our research highlights the significant associations of obesity and body composition with OSA risk, with child BMI influencing the relationship between OSA and metabolic abnormalities. Future research should explore causative relationships and the enduring impacts of OSA on metabolic health in children.

Social Risk Profile and Cardiovascular-Kidney-Metabolic Syndrome in US Adults.

BACKGROUND: Poor cardiovascular-kidney-metabolic (CKM) health is associated with premature mortality and excess morbidity in the United States. Adverse social conditions have a prominent impact on cardiometabolic diseases during the life course. We aim to examine the association between social risk profile (SRP) and CKM multimorbidity among US adults. METHODS AND RESULTS: We used data from the National Health and Nutrition Examination Survey from 1999 to 2018. The definition of CKM syndrome is the coexistence of subclinical or clinical cardiovascular disease, chronic kidney disease, and metabolic disorders. We classified participants by 4 CKM stages according to the different clinical severity of different forms of CKM syndrome. We calculated the summed number of positive SRP measures, including employed, high-income level, food secure, high education attainment, private insurance, owning a house, and married, as SRP scores and classified them into 4 levels by quartiles: low (0-2), lower-middle (3-4), upper-middle (5-6), and high (7-8). A total of 18 373 US adults, aged 20 to 79 years, were included in our analyses. There were 2567 (9.4%) participants with low SRP score level. Most individual SRP measures and a combined SRP score were associated with CKM stages. Compared with high SRP score level, low SRP level was associated with higher odds of having CKM stage 1 (odds ratio [OR], 1.34 [95% CI, 1.06-1.70]), CKM stage 2 (OR, 2.03 [95% CI, 1.59-2.58]), CKM stage 3 (OR, 5.28 [95% CI, 3.29-8.47]), and CKM stage 4 (OR, 5.97 [95% CI, 4.20-8.49]). CONCLUSIONS: Cumulative social disadvantage, denoted by higher SRP burden, was associated with higher odds of CKM multimorbidity, independent of demographic and lifestyle factors.

Inulin: a multifaceted ingredient in pharmaceutical sciences.

Inulin, a naturally occurring polysaccharide derived from plants such as chicory root, has emerged as a significant ingredient in pharmaceutical sciences due to its diverse therapeutic and functional properties. This review explores the multifaceted applications of inulin, focusing on its chemical structure, sources, and mechanisms of action. Inulin's role as a prebiotic is highlighted, with particular emphasis on its ability to modulate gut microbiota, enhance gut health, and improve metabolic processes. The review also delves into the therapeutic applications of inulin, including its potential in managing metabolic health issues such as diabetes and lipid metabolism, as well as its immune-modulating properties and benefits in gastrointestinal health. Furthermore, the article examines the incorporation of inulin in drug formulation and delivery systems, discussing its use as a stabilizing agent and its impact on enhancing drug bioavailability. Innovative inulin-based delivery systems, such as nanoparticles and hydrogels, are explored for their potential in controlled release formulations. The efficacy of inulin is supported by a review of clinical studies, underscoring its benefits in managing conditions like diabetes, cardiovascular health, and gastrointestinal disorders. Safety profiles, regulatory aspects, and potential side effects are also addressed. This comprehensive review concludes with insights into future research directions and the challenges associated with the application of inulin in pharmaceutical sciences.

Analyzing urinary hippuric acid as a metabolic health biomarker through a supramolecular architecture.

The prevalence of metabolic disorders has been found to increase concomitantly with alternations in habitual diet and lifestyle, indicating the importance of metabolic health monitoring for early warning of high-risk status and suggesting effective intervention strategies. Hippuric acid (HA), as one of the most abundant metabolites from the gut microbiota, holds potential as a regulator of metabolic health. Accordingly, it is imperative to establish an efficient, sensitive, and affordable method for large-scale population monitoring, revealing the association between HA level and metabolic disorders. Upon systematic screening of macrocycle•dye reporter pair, a supramolecular architecture (guanidinomethyl-modified calix[5]arene, GMC5A) was employed to sense urinary HA by employing fluorescein (Fl), whose complexation behavior was demonstrated by theoretical calculations, accomplishing quantification of HA in urine from 249 volunteers in the range of 0.10 mM and 10.93 mM. Excitedly, by restricted cubic spline, urinary HA concentration was found to have a significantly negative correlation with the risk of metabolic disorders when it exceeded 0.76 mM, suggesting the importance of dietary habits, especially the consumption of fruits, coffee, and tea, which was unveiled from a simple questionnaire survey. In this study, we accomplished a high throughput and sensitive detection of urinary HA based on supramolecular sensing with the GMC5A•Fl reporter pair, which sheds light on the rapid quantification of urinary HA as an indicator of metabolic health status and early intervention by balancing the daily diet.

Longitudinal Analysis of Diabetes Mellitus Risk: Smoking Status and Smoking Cessation.

Background/Objectives: Smoking cessation is acknowledged for its health benefits. However, it paradoxically increases diabetes mellitus (DM) risk shortly after quitting due to weight gain. This research aimed to investigate how smoking status could affect the development of DM, focusing on how the risk of acquiring diabetes changed over time after quitting smoking, independent of variables such as weight gain. Methods: The data of 386,558 participants of the Kangbuk Samsung Health Study, excluding those with pre-existing DM, were examined. Smoking status and its long-term effects on DM risk were assessed using multivariate Cox proportional hazards models. Lifestyle factors, including weight change, physical activity levels, and alcohol intake, were adjusted as time-varying covariates throughout the follow-up period. Results: Modified hazard ratios (HRs) indicated no notable disparity in DM risk between individuals who previously smoked and those who had never smoked (HR: 1.04, 95% CI: 0.999-1.08, p-value < 0.001). In contrast, current smokers exhibited a significantly increased DM risk (HR: 1.29, 95% CI: 1.24-1.35, p-value < 0.001). Within the first six years post-cessation, former smokers initially faced a higher DM risk than never smokers (0-2 years, HR: 1.22, 95% CI: 1.15-1.31, p-value < 0.001; 3-5 years, HR: 1.11, 95% CI: 1.04-1.20, p-value < 0.001). After 12 years, they realigned with never smokers (12-46 years, HR: 0.92, 95% CI: 0.86-0.98, p-value = 0.002). Current smokers consistently showed a higher DM risk (0-9 years, HR: 1.29, 95% CI: 1.14-1.46, p-value < 0.001). Adjusting for covariates such as weight change and physical activity did not alter these findings. Conclusions: Our results indicated that former smokers initially experienced an elevated risk of DM relative to never smokers. This increased risk aligned with the risk of never smokers after six years, and the risk continued to improve after 12 years compared to never smokers. This contrasted with current smokers, who maintained a heightened risk of DM, even when adjustments were made for weight change, physical activity, and alcohol intake as time-varying covariates.

Adipose tissue-liver cross-talk: a route to hepatic dysfunction in pregnant women with obesity.

Obesity during pregnancy has been escalating, becoming a huge problem that poses consequences not only for the health of the offspring but also for the maternal well-being. Women's adipose and hepatic tissue metabolism undergoes significant changes during the gestational period. During pregnancy, obesity is a primary instigator of steatosis, increasing the risk of non-alcholic fatty liver disease (NAFLD), now recognized under the updated nomenclature metabolic dysfunction-associated steatotic liver disease (MASLD). Pregnant women with obesity present higher levels of free fatty acids and glucose, reduction in insulin sensitivity, and adipose tissue endocrine dysregulation. Furthermore, obesity-induced modifications in clock genes and lipid-associated gene expression within adipose tissue disrupt crucial metabolic adaptations, potentially culminating in adipose tissue dysfunction. Thus, the liver experiences increased exposure to free fatty acids through the portal vein. Higher uptake of free fatty acids into the liver disrupts hepatic lipid oxidation while enhances lipogenesis, thereby predisposing to ectopic fat deposition within the liver. This review focuses on the obesity-induced changes during pregnancy in both liver and adipose tissue metabolism, elucidating how the metabolic crosstalk between these two organs can be dysregulated in pregnant women living with obesity.

Associations of metabolic changes and polygenic risk scores with cardiovascular outcomes and all-cause mortality across BMI categories: a prospective cohort study.

BACKGROUND: Associations between metabolic status and metabolic changes with the risk of cardiovascular outcomes have been reported. However, the role of genetic susceptibility underlying these associations remains unexplored. We aimed to examine how metabolic status, metabolic transitions, and genetic susceptibility collectively impact cardiovascular outcomes and all-cause mortality across diverse body mass index (BMI) categories. METHODS: In our analysis of the UK Biobank, we included a total of 481,576 participants (mean age: 56.55; male: 45.9%) at baseline. Metabolically healthy (MH) status was defined by the presence of < 3 abnormal components (waist circumstance, blood pressure, blood glucose, triglycerides, and high-density lipoprotein cholesterol). Normal weight, overweight, and obesity were defined as 18.5 ≤ BMI < 25 kg/m2, 25 ≤ BMI < 30 kg/m2, and BMI ≥ 30 kg/m2, respectively. Genetic predisposition was estimated using the polygenic risk score (PRS). Cox regressions were performed to evaluate the associations of metabolic status, metabolic transitions, and PRS with cardiovascular outcomes and all-cause mortality across BMI categories. RESULTS: During a median follow-up of 14.38 years, 31,883 (7.3%) all-cause deaths, 8133 (1.8%) cardiovascular disease (CVD) deaths, and 67,260 (14.8%) CVD cases were documented. Among those with a high PRS, individuals classified as metabolically healthy overweight had the lowest risk of all-cause mortality (hazard ratios [HR] 0.70; 95% confidence interval [CI] 0.65, 0.76) and CVD mortality (HR 0.57; 95% CI 0.50, 0.64) compared to those who were metabolically unhealthy obesity, with the beneficial associations appearing to be greater in the moderate and low PRS groups. Individuals who were metabolically healthy normal weight had the lowest risk of CVD morbidity (HR 0.54; 95% CI 0.51, 0.57). Furthermore, the inverse associations of metabolic status and PRS with cardiovascular outcomes and all-cause mortality across BMI categories were more pronounced among individuals younger than 65 years (Pinteraction < 0.05). Additionally, the combined protective effects of metabolic transitions and PRS on these outcomes among BMI categories were observed. CONCLUSIONS: MH status and a low PRS are associated with a lower risk of adverse cardiovascular outcomes and all-cause mortality across all BMI categories. This protective effect is particularly pronounced in individuals younger than 65 years. Further research is required to confirm these findings in diverse populations and to investigate the underlying mechanisms involved.

Metabolic health and genetic predisposition in inflammatory bowel disease: Insights from a prospective cohort study.

BACKGROUND: Metabolic disorders exhibit strong inflammatory underpinnings and vice versa. This study aimed to investigate the association between metabolic health status, genetic predisposition, and the risk of inflammatory bowel disease (IBD), and to explore the potential benefits of maintaining ideal metabolic status for individuals with a predetermined genetic risk of IBD. METHOD: This population-based prospective study included 385,820 unrelated European descent participants from the UK Biobank. Using multivariable Cox regression, we assessed the relationship of metabolic phenotypes with risk of IBD and its subtypes. We also developed a polygenic risk score to examine how metabolic health status interacted with genetic risk in relation to IBD risk. RESULTS: During the follow-up period of 4,328,895 person-years, 2,044 newly-diagnosed IBD cases were identified. Higher genetic risk and an increasing number of abnormal metabolic phenotypes were associated with elevated IBD risk (p-trend <0.001). Individuals with high genetic risk and poor metabolic health had a significantly higher risk of IBD (HR=4.56, 95 % CI=3.27-6.36) compared to those with low genetic risk and ideal metabolic health. These results remained consistent for IBD subtypes. Maintaining ideal metabolic status reduced IBD risk within each genetic risk category and jointly decreased subsequent risk by 40 % in high genetic risk individuals. CONCLUSION: Our study reveals a combined impact of poor metabolic health and genetic risk on IBD incidence. Those with low genetic risk and optimal metabolic health exhibit the lowest IBD risk, offering insights into potential management strategies for individuals at predefined genetic risk.

The impact of medium-chain triglycerides on weight loss and metabolic health in individuals with overweight or obesity: A systematic review and meta-analysis.

BACKGROUNDS: The efficacy of medium-chain triglycerides (MCTs) for weight management and mitigating metabolic disorders among individuals with overweight and obesity remains a topic of ongoing discussion. Notably, there is a gap in the distinction between pure MCTs and medium-long-chain triglycerides (MLCTs). METHODS: This meta-analysis investigates the efficacy of MCTs on weight loss and glucolipid metabolism in these populations, explicitly evaluating the differential effects of pure MCTs and MLCTs. We performed a random-effects meta-analysis on relevant studies examining weight loss and glucolipid parameters, incorporating a subgroup analysis conducted based on intervention types, pure MCTs versus MLCTs. RESULTS: Our findings revealed diets enriched with MCTs are more effective in achieving weight reduction (WMD: -1.53%; 95% CI: -2.44, -0.63; p < 0.01), particularly those containing pure MCTs (WMD: -1.62%; 95% CI: -2.78, -0.46; p < 0.01), compared to long-chain fatty acids (LCTs) enriched diets. However, our subgroup analysis indicates that an MLCTs-enriched diet did not significantly reduce weight loss. Additionally, MCTs-enriched diets were associated with significant reductions in blood triglyceride levels and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores, compared to LCTs-enriched diets. CONCLUSIONS: Hence, the authors recommend incorporating pure MCTs in dietary interventions for individuals with overweight and obesity, particularly those with comorbidities such as dyslipidemia and impaired glucose metabolism.

Exploring Multifactorial Relationships: Assessing the Correlation Between Cardiovascular Health Indicators and Metabolic Markers.

BACKGROUND: The significant global health burden associated with cardiometabolic diseases necessitates a better understanding of the complex interrelationships between metabolic markers and cardiovascular health indicators. Crucial indicators of cardiovascular and metabolic health include metabolic markers such as uric acid and gamma-glutamyl transferase (GGT), as well as blood pressure (BP), triglycerides, total cholesterol, high-density lipoprotein (HDL), and fasting blood glucose. OBJECTIVE: This study aims to investigate the multifactorial relationships among several parameters such as age, BP, lipid profile, body mass index (BMI), fasting blood glucose levels, and specific metabolic enzymes. METHODS: A willing participant who visited the outpatient clinic and was in good health but did not have a history of cardiovascular disease was enrolled in the study. The collected data were subjected to a cross-sectional analysis. Various biochemical and health parameters such as height, weight, BMI, uric acid, triglycerides, HDL, BP, gender, age, and fasting blood glucose were analyzed, and a Pearson correlation coefficient analysis was performed to evaluate the correlations between these variables. RESULTS: Among the 50 study participants, significant Pearson correlations were observed between metabolic health markers such as BP (systolic and diastolic), fasting blood sugar, total cholesterol, triglycerides, HDL, and BMI. Additionally, a positive correlation was found between these metabolic parameters, including the levels of uric acid and liver enzyme GGT. CONCLUSION: This study illustrates the intricate relationships among lipid profiles, liver enzymes, BP, and other metabolic health markers in the general population. Understanding these associations can help create focused interventions and individualized care plans for metabolic and cardiovascular disorders. Our findings address the complexity of cardiometabolic health and its management by identifying multifactorial risk factors linked to metabolic disorders and cardiovascular diseases.

Eating Patterns, Chronotypes, and Their Relationship with Metabolic Health in the Early Postpartum Period in Women after Gestational Diabetes Mellitus.

Observational studies have shown a relationship between eating patterns and chronotypes with metabolic health in the general population and in healthy pregnancies. Data are lacking in the postpartum period, which is characterized by an externally driven misalignment of sleep and food intake. We investigated the associations between eating patterns, chronotypes, and metabolic health in the early postpartum period in women who had gestational diabetes mellitus (GDM). We prospectively included 313 women who completed their 6-8 weeks postpartum visit between January 2021 and March 2023 at the Lausanne University Hospital. Women filled questionnaires on the timing of food intake, sleep (a shortened Pittsburgh Sleep Quality Questionnaire), and the chronotype (the Morningness-Eveningness Questionnaire) and underwent HbA1c and fasting plasma glucose measurements. After adjustments for weight, sleep quality, or breastfeeding, the later timing of the first and last food intake were associated with higher fasting plasma glucose and HbA1c levels 6-8 weeks postpartum (all p ≤ 0.046). A higher number of breakfasts per week and longer eating durations were associated with lower fasting plasma glucose levels (all p ≤ 0.028). The chronotype was not associated with metabolic health outcomes. Eating patterns, but not the chronotype, were associated with worsened metabolic health in the early postpartum period in women with previous GDM.

Positive Effects of Physical Activity on Insulin Signaling.

Physical activity is integral to metabolic health, particularly in addressing insulin resistance and related disorders such as type 2 diabetes mellitus (T2DM). Studies consistently demonstrate a strong association between physical activity levels and insulin sensitivity. Regular exercise interventions were shown to significantly improve glycemic control, highlighting exercise as a recommended therapeutic strategy for reducing insulin resistance. Physical inactivity is closely linked to islet cell insufficiency, exacerbating insulin resistance through various pathways including ER stress, mitochondrial dysfunction, oxidative stress, and inflammation. Conversely, physical training and exercise preserve and restore islet function, enhancing peripheral insulin sensitivity. Exercise interventions stimulate ß-cell proliferation through increased circulating levels of growth factors, further emphasizing its role in maintaining pancreatic health and glucose metabolism. Furthermore, sedentary lifestyles contribute to elevated oxidative stress levels and ceramide production, impairing insulin signaling and glucose metabolism. Regular exercise induces anti-inflammatory responses, enhances antioxidant defenses, and promotes mitochondrial function, thereby improving insulin sensitivity and metabolic efficiency. Encouraging individuals to adopt active lifestyles and engage in regular exercise is crucial for preventing and managing insulin resistance and related metabolic disorders, ultimately promoting overall health and well-being.

Sub-Optimal Paternal Diet at the Time of Mating Disrupts Maternal Adaptations to Pregnancy in the Late Gestation Mouse.

Pregnancy represents a stage during which maternal physiology and homeostatic regulation undergo dramatic change and adaptation. The fundamental purpose of these adaptations is to ensure the survival of her offspring through adequate nutrient provision and an environment that is tolerant to the semi-allogenic foetus. While poor maternal diet during pregnancy is associated with perturbed maternal adaptations during pregnancy, the influence of paternal diet on maternal well-being is less clearly defined. We fed C57BL/6 male mice either a control (CD), low protein diet (LPD), a high fat/sugar Western diet (WD) or the LPD or WD supplemented with methyl donors (MD-LPD and MD-WD, respectively) for a minimum of 8 weeks prior to mating with C57BL/6 females. Mated females were culled at day 17 of gestation for the analysis of maternal metabolic, gut, cardiac and bone health. Paternal diet had minimal influences on maternal serum and hepatic metabolite levels or gut microbiota diversity. However, analysis of the maternal hepatic transcriptome revealed distinct profiles of differential gene expression in response to the diet of the father. Paternal LPD and MD-LPD resulted in differential expression of genes associated with lipid metabolism, transcription, ubiquitin conjugation and immunity in dams, while paternal WD and MD-WD modified the expression of genes associated with ubiquitin conjugation and cardiac morphology. Finally, we observed changes in maternal femur length, volume of trabecular bone, trabecular connectivity, volume of the cortical medullar cavity and thickness of the cortical bone in response to the father's diets. Our current study demonstrates that poor paternal diet at the time of mating can influence the patterns of maternal metabolism and gestation-associated adaptations to her physiology.

Systems genetics of metabolic health in the BXD mouse genetic reference population.

Susceptibility to metabolic syndrome (MetS) is dependent on genetics, environment, and gene-by-environment interactions, rendering the study of underlying mechanisms challenging. The majority of experiments in model organisms do not incorporate genetic variation and lack specific evaluation criteria for MetS. Here, we derived a continuous metric, the metabolic health score (MHS), based on standard clinical parameters and defined its molecular signatures in the liver and circulation. In human UK Biobank, the MHS associated with MetS status and was predictive of future disease incidence, even in individuals without MetS. Using quantitative trait locus analyses in mice, we found two MHS-associated genetic loci and replicated them in unrelated mouse populations. Through a prioritization scheme in mice and human genetic data, we identified TNKS and MCPH1 as candidates mediating differences in the MHS. Our findings provide insights into the molecular mechanisms sustaining metabolic health across species and uncover likely regulators. A record of this paper's transparent peer review process is included in the supplemental information.

Dietary isoleucine content defines the metabolic and molecular response to a Western diet.

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

Development and validation of a plasmalogen score as an independent modifiable marker of metabolic health: population based observational studies and a placebo-controlled cross-over study.

BACKGROUND: Decreased levels of circulating ethanolamine plasmalogens [PE(P)], and a concurrent increase in phosphatidylethanolamine (PE) are consistently reported in various cardiometabolic conditions. Here we devised, a plasmalogen score (Pls Score) that mirrors a metabolic signal that encompasses the levels of PE(P) and PE and captures the natural variation in circulating plasmalogens and perturbations in their metabolism associated with disease, diet, and lifestyle. METHODS: We utilised, plasma lipidomes from the Australian Obesity, Diabetes and Lifestyle study (AusDiab; n = 10,339, 55% women) a nationwide cohort, to devise the Pls Score and validated this in the Busselton Health Study (BHS; n = 4,492, 56% women, serum lipidome) and in a placebo-controlled crossover trial involving Shark Liver Oil (SLO) supplementation (n = 10, 100% men). We examined the association of the Pls Score with cardiometabolic risk factors, type 2 diabetes mellitus (T2DM), cardiovascular disease and all-cause mortality (over 17 years). FINDINGS: In a model, adjusted for age, sex and BMI, individuals in the top quintile of the Pls Score (Q5) relative to Q1 had an OR of 0.31 (95% CI 0.21-0.43), 0.39 (95% CI 0.25-0.61) and 0.42 (95% CI 0.30-0.57) for prevalent T2DM, incident T2DM and prevalent cardiovascular disease respectively, and a 34% lower mortality risk (HR = 0.66; 95% CI 0.56-0.78). Significant associations between diet and lifestyle habits and Pls Score exist and these were validated through dietary supplementation of SLO that resulted in a marked change in the Pls Score. INTERPRETATION: The Pls Score as a measure that captures the natural variation in circulating plasmalogens, was not only inversely related to cardiometabolic risk and all-cause mortality but also associate with diet and lifestyle. Our results support the potential utility of the Pls Score as a biomarker for metabolic health and its responsiveness to dietary interventions. Further research is warranted to explore the underlying mechanisms and optimise the practical implementation of the Pls Score in clinical and population settings. FUNDING: National Health and Medical Research Council (NHMRC grant 233200), National Health and Medical Research Council of Australia (Project grant APP1101320), Health Promotion Foundation of Western Australia, and National Health and Medical Research Council of Australia Senior Research Fellowship (#1042095).