2025
Effect of ultra-processed food consumption on male reproductive and metabolic health
Preston JM, Iversen J, Hufnagel A, Hjort L, Taylor J, Sanchez C, George V, Hansen AN, Ängquist L, Hermann S, Craig JM, Torekov S, Lindh C, Hougaard KS, Nóbrega MA, Simpson SJ, Barrès R. Cell Metab. 2025 Aug 22:S1550-4131(25)00360-2. doi: 10.1016/j.cmet.2025.08.004
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00360-2
Highlights
- Compared with an unprocessed diet, UPF impaired cardiometabolic and reproductive health
- The deleterious effects of a UPF diet were independent of total caloric intake
- A UPF diet altered the balance of several hormones, including GDF-15 and FSH
- A UPF diet was associated with higher serum concentration of the phthalate cxMINP
Consumption of ultra-processed food is associated with increased caloric intake and impaired health. Here, we conducted a nutrition trial (NCT05368194) with controlled, 2 × 2 crossover design and tested whether ultra-processed food impairs reproductive and metabolic fitness, with further aggravation by excess caloric intake. Comparing the response from an unprocessed to ultra-processed diet identified increased body weight and low-density lipoprotein (LDL):high-density lipoprotein (HDL) ratio, independent of caloric load. Several hormones involved in energy metabolism and spermatogenesis were affected, including decreased levels of growth/differentiation factor 15 and follicle-stimulating hormone. Sperm quality trended toward impairment, with a decrease in total motility. Differential accumulation of pollutants between the discordant diets were detected, such as decreased plasma lithium and a trend for increased levels of the phthalate mono(4-methyl-7-carboxyheptyl)phthalate (cxMINP) in serum, following the ultra-processed diet. Alteration in caloric load alone had distinct effects on the measured outcomes. This study provides evidence that consumption of ultra-processed food is detrimental for cardiometabolic and reproductive outcomes, regardless of excessive caloric intake.
2024
Extracellular vesicles – small messengers with a wide range of applications?
Hufnagel A, Barrès R. Dan Med J 2024 Jul; 71(8)
https://ugeskriftet.dk/dmj/extracellular-vesicles-small-messengers-wide-range-applications
Extracellular vesicles (EVs) are small membranous vesicles secreted by many different cell types that have emerged as potentially important mediators of organ crosstalk. EVs are of research interest in health and disease and as biomarkers and therapeutic agents in various fields, including metabolism, reproduction, cancer, and others. Despite promising data and a growing understanding of their role, challenges and limitations of EV research remain, leaving room for optimisation regarding methods for pure isolations of EVs and translation into clinical practice.
Paternal dietary macronutrient balance and energy intake drive metabolic and behavioral differences among offspring
Crean AJ, Senior AM, Freire T, Clark TD, Mackay F, Austin G, Pulpitel TJ, Nobrega MA, Barrès R, Simpson SJ., Nat Commun 2024 Apr; 15(1): 2982.
https://www.nature.com/articles/s41467-024-46782-y/figures/1
Paternal diet can influence the phenotype of the next generation, yet, the dietary components inducing specific responses in the offspring are not identified. Here, we use the Nutritional Geometry Framework to determine the effects of pre-conception paternal dietary macronutrient balance on offspring metabolic and behavioral traits in mice. Ten isocaloric diets varying in the relative proportion of protein, fats, and carbohydrates are fed to male mice prior to mating. Dams and offspring are fed standard chow and never exposed to treatment diets. Body fat in female offspring is positively associated with the paternal consumption of fat, while in male offspring, an anxiety-like phenotype is associated to paternal diets low in protein and high in carbohydrates. Our study uncovers that the nature and the magnitude of paternal effects are driven by interactions between macronutrient balance and energy intake and are not solely the result of over- or undernutrition.
Dietary macronutrient composition impacts gene regulation in adipose tissue
Farris KM, Senior AM, Sobreira DR, Mitchell RM, Weber ZT, Ingerslev LR, Barrès R, Simpson SJ, Crean AJ, Nobrega MA, Commun Biol 2024 Feb; 7(1): 194.
https://www.nature.com/articles/s42003-024-05876-5
Diet is a key lifestyle component that influences metabolic health through several factors, including total energy intake and macronutrient composition. While the impact of caloric intake on gene expression and physiological phenomena in various tissues is well described, the influence of dietary macronutrient composition on these parameters is less well studied. Here, we use the Nutritional Geometry framework to investigate the role of macronutrient composition on metabolic function and gene regulation in adipose tissue. Using ten isocaloric diets that vary systematically in their proportion of energy from fat, protein, and carbohydrates, we find that gene expression and splicing are highly responsive to macronutrient composition, with distinct sets of genes regulated by different macronutrient interactions. Specifically, the expression of many genes associated with Bardet-Biedl syndrome is responsive to dietary fat content. Splicing and expression changes occur in largely separate gene sets, highlighting distinct mechanisms by which dietary composition influences the transcriptome and emphasizing the importance of considering splicing changes to more fully capture the gene regulation response to environmental changes such as diet. Our study provides insight into the gene regulation plasticity of adipose tissue in response to macronutrient composition, beyond the already well-characterized response to caloric intake.
2023
Dietary macronutrient composition impacts gene regulatioSplicing across adipocyte differentiation is highly dynamic and impacted by metabolic phenotypen in adipose tissue
Nobrega M, Farris K, Andersen E, Donkin I, Versteyhe S, Kristiansen VB, Simpson S, Barres R, Res Sq 2023 Oct
https://www.researchsquare.com/article/rs-3487148/v1
Adipose tissue dysfunction underlies many of the metabolic complications associated with obesity. A better understanding of the gene regulation differences present in metabolically unhealthy adipose tissue can provide insights into the mechanisms underlying adipose tissue dysfunction. Here, we used RNA-seq data collected from a differentiation time course of lean, obese, and obese with type 2 diabetes (T2D) individuals to characterize the role of alterative splicing in adipocyte differentiation and function. We found that splicing was highly dynamic across adipocyte differentiation in all three cohorts, and that the dynamics of splicing were significantly impacted by metabolic phenotype. We also found that there was very little overlap between genes that were differentially spliced in adipocyte differentiation and those that were differentially expressed, positioning alternative splicing as a largely independent gene regulatory mechanism whose impact would be missed when looking at gene expression changes alone. To assess the impact of alternative splicing across adipocyte differentiation on genetic risk for metabolic diseases, we integrated the differential splicing results generated here with genome-wide association study results for body mass index and T2D, and found that variants associated with T2D were enriched in regions that were differentially spliced in early differentiation. These findings provide insight into the role of alternative splicing in adipocyte differentiation and can serve as a resource to guide future variant-to-function studies.
Male reproductive traits are differentially affected by dietary macronutrient balance but unrelated to adiposity
A. Crean, S. Afrin, H. Niranjan, T. Pulpitel, G. Ahmad, A. Senior, T. Freire, F. Mackay, M. Nobrega, R. Barrès, S. Simpson, T. Pini, Nature Communications, 2023, 14 (1), pp.2566. ⟨10.1038/s41467-023-38314-x⟩.
https://www.nature.com/articles/s41467-023-38314-x
Dietary factors influence male reproductive function in both experimental and epidemiological studies. However, there are currently no specific dietary guidelines for male preconception health. Here, we use the Nutritional Geometry framework to examine the effects of dietary macronutrient balance on reproductive traits in C57BL/6 J male mice. Dietary effects are observed in a range of morphological, testicular and spermatozoa traits, although the relative influence of protein, fat, carbohydrate, and their interactions differ depending on the trait being examined. Interestingly, dietary fat has a positive influence on sperm motility and antioxidant capacity, differing to typical high fat diet studies where calorie content is not controlled for. Moreover, body adiposity is not significantly correlated with any of the reproductive traits measured in this study. These results demonstrate the importance of macronutrient balance and calorie intake on reproductive function and support the need to develop specific, targeted, preconception dietary guidelines for males.