u/Meatrition

Abstract
Fatty acids have been linked to attention-deficit/hyperactivity disorder (ADHD), but the biological basis of this association remains unclear. This study examined dietary and plasma fatty acid profiles and fatty acid desaturase-2 (FADS2) in children with ADHD. This cross-sectional study included 85 children with ADHD and 85 controls aged 6–12 years. ADHD symptoms were assessed using the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R: S).

Dietary fatty acid intake was estimated from three non-consecutive 24-hour recalls. Plasma fatty acids were measured by GC-MS. Plasma FADS2 protein levels were quantified by ELISA, and FADS2 mRNA expression was assessed by real-time PCR. Principal component analysis (PCA) was used to derive fatty acid components, followed by structural equation modeling (SEM) to evaluate associations with ADHD symptom severity. 

#Children with ADHD showed a greater relative dietary contribution of omega-6 fatty acids and total PUFAs, higher plasma LA levels and omega-6/omega-3 ratio, and lower plasma MUFAs, GLA, and docosanoic acid than controls.

Plasma FADS2 protein levels were numerically higher but not significantly different, whereas relative FADS2 mRNA expression was lower in the ADHD group. In SEM, greater ADHD symptom severity was associated with a PCA-derived component characterized by higher LA and omega-6/omega-3 ratio together with lower nervonic acid. Children with ADHD differed from controls across multiple dietary, plasma, and FADS2-related fatty acid measures, particularly those related to omega-6 balance. ADHD symptom severity was also associated with a multivariable fatty acid profile

Abstract

Context
Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options.

Objective
This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs.

Data Sources
Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs.

Data Extraction
Two-sample MR technology was used to assess the role of PUFAs in MDs.

Data Analysis
The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders.

Conclusion

High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies

Abstract

Objective: Type 2 diabetes mellitus (T2DM) arises from sustained energy imbalance and macronutrient dysregulation. This study elucidates how distinct dietary sugar-to-lipid ratios modulate T2DM progression and delineates the underlying molecular mechanisms.

Methods: Forty C57BL/6 mice were randomized into a control group (standard diet) and three high-energy cohorts with varying sugar-to-fat ratios (10% fat/70% carbohydrate; 45% fat/35% carbohydrate; 60% fat/20% carbohydrate). Body weight and fasting blood glucose were longitudinally monitored to assess obesity and T2DM onset. Following diagnosis, we analyzed serum metabolic profiles, insulin resistance, organ indices, and histopathology of the liver, pancreas, and white adipose tissue. Integrated proteomic and untargeted metabolomic analyses of liver tissue were employed to decode mechanistic pathways, with key targets validated via molecular assays.

Results: Elevated dietary fat content dose-dependently accelerated obesity and T2DM onset, exacerbating glycolipid dysregulation, insulin resistance, hepatic steatosis, and adipose inflammation. Proteomic profiling revealed that differentially expressed proteins, primarily localized to the mitochondria, endoplasmic reticulum, and plasma membrane, were enriched in lipid, amino acid, and cofactor metabolism. Concurrently, metabolomics identified 4,276 hepatic metabolites with significant enrichment in glycerophospholipid and linoleic acid pathways. Integrated analysis demonstrated that high-fat diets disrupt systemic homeostasis by inducing coordinated perturbations in specific lipid metabolism networks. Validation confirmed that these diets suppressed mitochondrial markers (AMPK, PGC-1α, TFAM, NRF1) while dysregulating lipid regulators (upregulated PPAR-γ, downregulated PPAR-α).

Conclusion: High-fat diets exert more severe metabolic detriment than other macronutrient configurations. This progression is driven by a dual interaction network involving mitochondrial dysfunction and lipid metabolic reprogramming, which collectively dismantle systemic metabolic homeostasis.

Abstract

Between 1920 and 1950, cardiovascular disease (CVD) underwent a profound epidemiological shift, rising from a relatively rare and infrequently diagnosed condition to become the leading cause of death in industrialized nations. This epidemic coincided with a series of changes in the food supply, including the expanded use of refined carbohydrates, industrial seed and vegetable oils, and trans fatty acids. In response, the "Diet-Heart Hypothesis" emerged, dominated by Ancel Keys' lipid theory, which focused scientific and public health attention on saturated fat and cholesterol as the primary causes of CVD. This paradigm profoundly shaped dietary guidelines for decades, yet the sugar industry's documented influence on nutritional research during this period raises questions about how economic interests may have deflected scrutiny from other dietary factors. This review critically examines the evolution of cardiovascular risk assessment, exploring both the historical context of CVD emergence and the contemporary evidence supporting biomarkers that may be better at predicting risk than traditional cholesterol-focused approaches. Significant evidence reveals limitations in the lipid hypothesis, which oversimplified cardiovascular risk by demonizing total and LDL cholesterol. Research now demonstrates that apolipoprotein B and non‑HDL cholesterol more accurately reflect atherogenic lipoprotein burden than LDL cholesterol alone, while the triglyceride‑to‑HDL cholesterol ratio is a useful marker of insulin resistance and metabolic dysfunction. Lipoprotein(a), an independent genetic risk factor, accounts for a substantial proportion of cardiovascular events previously attributed to other causes. Furthermore, inflammatory markers like high-sensitivity C-reactive protein add prognostic value beyond traditional lipid panels. Perhaps most importantly, the historical dominance of saturated fat as a dietary "villain" is challenged by contemporary meta-analyses showing no significant association with CVD, while the roles of refined carbohydrates, industrial trans fats, and excess omega-6 fatty acids, such as those in soybean oil, warrant greater scrutiny. Contemporary cardiovascular risk assessment must move beyond LDL cholesterol-centric approaches to incorporate comprehensive metabolic and inflammatory markers. Apolipoprotein B, lipoprotein(a), triglyceride-to-HDL ratio, and high-sensitivity C-reactive protein provide more nuanced risk stratification, while dietary recommendations should acknowledge that industrial food processing, refined carbohydrates, and specific fatty acid compositions may pose greater cardiovascular threats than naturally occurring saturated fats. This paradigm shift demands updated clinical guidelines that reflect current scientific understanding rather than historical assumptions, potentially revolutionizing both prevention and treatment strategies for CVD.

Keywords: apolipoprotein b (apob), cardiovascular risk assessment, diet-heart hypothesis, lipoprotein(a), refined carbohydrates and metabolic syndrome, saturated fat and cholesterol, trans fatty acids, triglyceride-to-hdl ratio

The mechanism of lipid peroxidation and free radical cascades
The key to the pathology of seed oils lies in their high content of polyunsaturated fatty acids (PUFAs), especially linoleic acid (LA), a type of omega-6 fatty acid. These molecules are highly vulnerable to degradation because their multiple double bonds are chemically unstable [18]. Industrial processing, which uses chemical solvents and refining methods, and the subsequent application of heat during cooking - particularly repeated heating, as often occurs in commercial frying - initiate a process known as lipid peroxidation [35].
This peroxidation process generates highly toxic free radicals and reactive oxygen species (ROS) that induce severe oxidative stress at the cellular and molecular levels. The degradation of these oxidized lipids produces cytotoxic aldehydes, notably malondialdehyde (MDA) and 4-hydroxy-2-nonenal (4-HNE) [36]. It is important to note that much of this evidence derives from in vitro and animal studies, as well as biochemical modeling; direct causal evidence from controlled human clinical trials remains limited and is an active area of ongoing investigation.
These reactive compounds act as "second messengers" of oxidative stress, interacting with various macromolecules, including DNA, proteins, and phospholipids, causing widespread molecular damage [37]. While this mechanistic pathway is biochemically well-characterized and biologically plausible, the extent to which these processes translate into clinically meaningful cardiovascular outcomes in human populations has not yet been definitively established. The available human data, including observational studies and biomarker analyses, are consistent with the proposed mechanism but fall short of confirming direct causation. Distinguishing between mechanistic plausibility and demonstrated causal effect in living populations remains a critical and unresolved challenge in this field, and readers should interpret the foregoing biochemical evidence accordingly.

#Low-carbohydrate diets with higher fiber, monounsaturated fat, protein, and lower omega-6:omega-3 ratios were associated with improved metabolic health.

Abstract

Background:
Metabolic syndrome and related abnormalities, including insulin resistance and hyperinsulinemia, remain critical public health challenges, particularly among women. However, recent nationwide trends and diet-related determinants have not been fully explored.

Methods:
4,426 women aged ≥18 years from the 2013–2023 National Health and Nutrition Examination Survey were included. Metabolic syndrome (MetS) was defined according to NCEP ATP III, WHO, and International Diabetes Federation criteria. Additional outcomes included elevated hemoglobin A1c (HbA1c ≥ 5.7%), hyperinsulinemia (≥10 μU/mL), and IR (HOMA-IR ≥ 2.6). Survey-weighted logistic regression and generalized structural equation modeling were used to examine temporal trends and dietary associations, adjusting for race/ethnicity, menopausal stage, physical activity, and energy intake.

Results:
Overall prevalence of MetS remained around 20%, whereas IR and hyperinsulinemia affected over 40% of women, peaking during 2017–2020. Later menopausal stages were strongly associated with higher odds of MetS, IR, and hyperinsulinemia. Moderate-carbohydrate diets became more common. Low-carbohydrate diets, which remained rare (<2%), were associated with lower odds of elevated HbA1c (odds ratio [OR] = 0.40, 95% confidence interval [CI]: 0.15–1.00) and hyperinsulinemia (OR = 0.35, 95% CI: 0.14–0.87). Higher fiber and monounsaturated fatty acid intakes were inversely associated with MetS and insulin-related markers, whereas greater omega-6 fatty acid intake and higher omega-6:omega-3 ratios were positively associated with insulin resistance. Elevated protein intake was protective among perimenopausal and naturally menopausal women.

Conclusions:
Between 2013 and 2023, U.S. women exhibited persistently high rates of metabolic abnormalities, with risk increasing across menopausal stages. Low-carbohydrate diets with higher fiber, monounsaturated fat, protein, and lower omega-6:omega-3 ratios were associated with improved metabolic health.

Abstract

BACKGROUND:
Systemic thromboxane A2 generation, assessed via measurement of its urinary metabolites, is associated with cardiovascular disease (CVD) risk. Modifiable correlates with thromboxane A2 generation, including potentially nonplatelet sources not readily affected by aspirin, are poorly understood.

METHODS:
We investigated 2655 FHS (Framingham Heart Study) participants with measurements of urinary thromboxane B2metabolites normalized for renal function (TXB2-MGFR). Life’s Essential 8 (LE8) score was constructed from 8 modifiable factors. We additionally examined erythrocyte omega-3 fatty acids and omega-6 fatty acid levels, namely, eicosapentaenoic acid, docosahexaenoic acid, and arachidonic acid. In a subset of participants, objective measurements of vascular stiffness and adiposity were obtained. We related these factors to TXB2-MGFR using linear models, adjusting for age, sex, and aspirin use. We also explored the association of LE8 or omega-3 fatty acids with total CVD or heart failure stratified by TXB2-MGFR.

RESULTS:
Both total LE8 score (P<0.001) and individual LE8 components (P<0.05 for each), including favorable diet, physical activity, blood glucose, blood pressure, and nonsmoking, were associated with lower TXB2-MGFR. Higher omega-3 fatty acids (eicosapentaenoic acid+docosahexaenoic acid) and lower arachidonic acid were associated with lower TXB2-MGFR (P<0.005 for each). Higher TXB2-MGFR was related to greater waist circumference, computed tomography–measured visceral adipose tissue, and hepatic steatosis (P<0.01 for each), and higher large artery vascular stiffness (P<0.001). Findings were generally consistent across aspirin use status. After median follow-up of 12.9 years (371 CVD and 214 heart failure events), individuals with both high TXB2-MGFR and low LE8 displayed an over 5-fold higher risk of heart failure (hazard ratio, 5.07 [95% CI, 3.26–7.89]) and 2.5-fold higher risk of CVD (hazard ratio, 2.74 [95% CI, 2.04–3.68]) compared with participants with low TXB2-MGFR and high LE8.

CONCLUSIONS:
Our findings suggest several modifiable factors that may impact systemic thromboxane A2 generation. Higher systemic thromboxane A2 generation also appears to modulate the association of lifestyle measures (as assessed by LE8 score) with CVD and heart failure.

Abstract
Background: Unhealthy expansion of adipose tissue (AT) due to excessive dietary intake of omega-6 or overnutrition stimulates the overaccumulation of the extracellular matrix (ECM), resulting in AT metabolic dysregulation. Hypertrophic conditions, excessive adipose depots, and hypoxia stimulate the overproduction of collagenous and non-collagenous proteins, which pathophysiologically initiate the pro-fibrotic signaling pathway associated with fibrosis progression, resulting in atherosclerosis and cardiovascular diseases.

Methods: We aimed to investigate adipocyte plasticity in response to a varying ratio of omega-3 (ω3) to omega-6 (ω6) supplementation during the chemically induced adipogenic differentiation of human mesenchymal stem cells. Additionally, changes in lipid accumulation, adipocyte hypertrophy and hyperplasia, active lipid metabolites, and inflammatory cytokine profiles were evaluated. Furthermore, conditioned media from adipocytes treated with different ω3/ω6 ratios were applied to platelets to assess inflammatory responses through prostaglandin and thromboxane measurements.

Results: A 1:3 ratio of ω3/ω6 (20:60 µM) significantly reduced lipid accumulation, promoted brown-like adipocyte morphology, and decreased apoptosis and reactive oxygen species (ROS) generation, as confirmed via FACS analysis. Transcriptional control of adipose tissue expansion was confirmed by the downregulation of LIPIN1 and COL1A1 mRNA expression and p-prostaglandin12-R protein levels in a 1:3 ratio when compared with 1:1, 1:2, 1:4, or 2:6 ratios of ω3/ω6. Notably, a 1:3 ratio of fatty-acid-treated adipocyte-conditioned media-treated platelets significantly reduced platelet activation and aggregation, as evidenced by lower p-thromboxane A2 protein levels.

Conclusions: Supplementation with a 1:3 (20:60 µM) ω3/ω6 ratio favored the development of lean adipocytes, evidenced by the decreased lipid storage achieved by mitochondrial thermogenesis, which attenuated minimal adipocyte expansion and metabolic inflammation.
Keywords: essential fatty acid; adipose tissue; metabolic inflammation; prostaglandin and thromboxane

Abstract

Objective
This study aimed to characterize the gut microbiota composition and predicted metabolic functionality of healthy individuals with long-term adherence to a carnivore diet and to compare those with confounder-matched omnivore controls.

Methods
A cross-sectional analysis was conducted including ten healthy individuals following a carnivore diet for an average of 36 ± 11·9 months and 874 confounder-matched controls. 16S rRNA sequencing was used to assess composition and predicted functionality. Diversity metrics, differential abundance testing and multivariate regression modeling were applied to evaluate the associations.

Results
Carnivore diet adherence was a dominant independent predictor of microbiota composition and predicted functionality. Alpha-diversity metrics did not differ significantly between groups, whereas carnivores exhibited higher Chao1 richness. Several low-abundance phyla, including Synergistetes and Desulfobacterota, were enriched. Functional profiling revealed substantial metabolic differences, with significant differences in over 300 metabolic pathways and 13 functional modules, including those related to amino acid degradation, vitamin B synthesis, energy metabolism, gut barrier integrity and protein fermentation. Modules associated with cytotoxicity, inflammation and constipation were also elevated. Regression analyses confirmed that these taxonomic and functional shifts were primarily attributable to the diet itself.

Conclusions
Long-term carnivore diet adherence leads to distinct taxonomic changes and profound functional alterations of the gut microbiota.

Significance statement
These findings challenge the assumption that dietary fiber is essential for maintaining microbiota diversity, suggesting the potential prebiotic effects of certain nutrients in the animal-based diet, while highlighting potential long-term risks associated with an exclusively animal-based diet.