Publications by authors named "Wenfei Sun"

19 Publications

  • Page 1 of 1

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.

Cell Metab 2021 Mar 22;33(3):547-564.e7. Epub 2020 Dec 22.

Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address:

In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.
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http://dx.doi.org/10.1016/j.cmet.2020.12.001DOI Listing
March 2021

snRNA-seq reveals a subpopulation of adipocytes that regulates thermogenesis.

Nature 2020 11 28;587(7832):98-102. Epub 2020 Oct 28.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Adipose tissue is usually classified on the basis of its function as white, brown or beige (brite). It is an important regulator of systemic metabolism, as shown by the fact that dysfunctional adipose tissue in obesity leads to a variety of secondary metabolic complications. In addition, adipose tissue functions as a signalling hub that regulates systemic metabolism through paracrine and endocrine signals. Here we use single-nucleus RNA-sequencing (snRNA-seq) analysis in mice and humans to characterize adipocyte heterogeneity. We identify a rare subpopulation of adipocytes in mice that increases in abundance at higher temperatures, and we show that this subpopulation regulates the activity of neighbouring adipocytes through acetate-mediated modulation of their thermogenic capacity. Human adipose tissue contains higher numbers of cells of this subpopulation, which could explain the lower thermogenic activity of human compared to mouse adipose tissue and suggests that targeting this pathway could be used to restore thermogenic activity.
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http://dx.doi.org/10.1038/s41586-020-2856-xDOI Listing
November 2020

Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice.

Nat Metab 2019 08 19;1(8):830-843. Epub 2019 Aug 19.

Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.

Human and rodent brown adipose tissues (BAT) appear morphologically and molecularly different. Here we compare human BAT with both classical brown and brite/beige adipose tissues of 'physiologically humanized' mice: middle-aged mice living under conditions approaching human thermal and nutritional conditions, that is, prolonged exposure to thermoneutral temperature (approximately 30 °C) and to an energy-rich (high-fat, high-sugar) diet. We find that the morphological, cellular and molecular characteristics (both marker and adipose-selective gene expression) of classical brown fat, but not of brite/beige fat, of these physiologically humanized mice are notably similar to human BAT. We also demonstrate, both in silico and experimentally, that in physiologically humanized mice only classical BAT possesses a high thermogenic potential. These observations suggest that classical rodent BAT is the tissue of choice for translational studies aimed at recruiting human BAT to counteract the development of obesity and its comorbidities.
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http://dx.doi.org/10.1038/s42255-019-0101-4DOI Listing
August 2019

ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation.

Front Endocrinol (Lausanne) 2020 12;11:387. Epub 2020 Jun 12.

Institute of Food, Nutrition and Health, Department of Health Sciences and Technology (D-HEST), ETH Zürich, Zurich, Switzerland.

When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/beige adipocytes and . These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/beige adipocyte formation.
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http://dx.doi.org/10.3389/fendo.2020.00387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304443PMC
June 2020

A Genetic Model to Study the Contribution of Brown and Brite Adipocytes to Metabolism.

Cell Rep 2020 03;30(10):3424-3433.e4

Institute of Food Nutrition and Health and Department of Health Sciences and Technology, Eidgenössische Technische Hochschule Zürich (ETH), 8603 Schwerzenbach, Switzerland. Electronic address:

UCP1-dependent thermogenesis is studied to define new strategies to ameliorate obesity and type 2 diabetes; however, animal models are mostly limited to germline mutations of UCP1, which can effect adaptive changes in UCP1-independent pathways. We develop an inducible mouse model for the sequential ablation of UCP1 brown and brite/beige adipocytes in adult mice. We demonstrate that activated brown adipocytes can increase systemic energy expenditure (EE) by 30%, while the contribution of brite/beige UCP1 cells is <5%. Notably, UCP1 adipocytes do not contribute to circulating FGF21 levels, either at room temperature or after cold exposure. We demonstrate that the FGF21-mediated effects on EE and glucose homeostasis are partially dependent on the presence of UCP1 cells, while the effect on weight loss is not. In conclusion, acute UCP1 cell deletion may be a useful model to study the impact of brown and brite/beige adipocytes on metabolism.
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http://dx.doi.org/10.1016/j.celrep.2020.02.055DOI Listing
March 2020

Antioxidants protect against diabetes by improving glucose homeostasis in mouse models of inducible insulin resistance and obesity.

Diabetologia 2019 11 15;62(11):2094-2105. Epub 2019 Jul 15.

Laboratory of Translational Nutrition Biology, Institute of Food, Nutrition and Health, Swiss Federal Institute of Technology, ETH Zürich, CH-8603, Schwerzenbach, Switzerland.

Aims/hypothesis: In the context of diabetes, the health benefit of antioxidant treatment has been widely debated. In this study, we investigated the effect of antioxidant treatment during the development of insulin resistance and hyperphagia in obesity and partial lipodystrophy.

Methods: We studied the role of antioxidants in the regulation of insulin resistance using the tamoxifen-inducible fat-specific insulin receptor knockout (iFIRKO) mouse model, which allowed us to analyse the antioxidant's effect in a time-resolved manner. In addition, leptin-deficient ob/ob mice were used as a hyperphagic, chronically obese and diabetic mouse model to validate the beneficial effect of antioxidants on metabolism.

Results: Acute induction of insulin receptor knockout in adipocytes changed the substrate preference to fat before induction of a diabetic phenotype including hyperinsulinaemia and hyperglycaemia. In healthy chow-fed animals as well as in morbidly obese mice, this diabetic phase could be reversed within a few weeks. Furthermore, after the induction of insulin receptor knockout in mature adipocytes, iFIRKO mice were protected from subsequent obesity development through high-fat diet feeding. By genetic tracing we show that the persistent fat mass loss in mice after insulin receptor knockout in adipocytes is not caused by the depletion of adipocytes. Treatment of iFIRKO mice with antioxidants postponed and reduced hyperglycaemia by increasing insulin sensitivity. In ob/ob mice, antioxidants rescued both hyperglycaemia and hyperphagia.

Conclusions/interpretation: We conclude that fat mass reduction through insulin resistance in adipocytes is not reversible. Furthermore, it seems unlikely that adipocytes undergo apoptosis during the process of extreme lipolysis, as a consequence of insulin resistance. Antioxidants have a beneficial health effect not only during the acute phase of diabetes development, but also in a temporary fashion once chronic obesity and diabetes have been established.
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http://dx.doi.org/10.1007/s00125-019-4937-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805816PMC
November 2019

Environmental and Nutritional Effects Regulating Adipose Tissue Function and Metabolism Across Generations.

Adv Sci (Weinh) 2019 Jun 16;6(11):1900275. Epub 2019 Apr 16.

Department of Health Science and Technologies ETH Zürich Schorenstrasse 16 Schwerzenbach CH-8603 Switzerland.

The unabated rise in obesity prevalence during the last 40 years has spurred substantial interest in understanding the reasons for this epidemic. Studies in mice and humans have demonstrated that obesity is a highly heritable disease; however genetic variations within specific populations have so far not been able to explain this phenomenon to its full extent. Recent work has demonstrated that environmental cues can be sensed by an organism to elicit lasting changes, which in turn can affect systemic energy metabolism by different epigenetic mechanisms such as changes in small noncoding RNA expression, DNA methylation patterns, as well as histone modifications. These changes can directly modulate cellular function in response to environmental cues, however research during the last decade has demonstrated that some of these modifications might be transmitted to subsequent generations, thus modulating energy metabolism of the progeny in an inter- as well as transgenerational manner. In this context, adipose tissue has become a focus of research due to its plasticity, which allows the formation of energy storing (white) as well as energy wasting (brown/brite/beige) cells within the same depot. In this Review, the effects of environmental induced obesity with a particular focus on adipose tissue are discussed.
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http://dx.doi.org/10.1002/advs.201900275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548959PMC
June 2019

Maternal overnutrition programs hedonic and metabolic phenotypes across generations through sperm tsRNAs.

Proc Natl Acad Sci U S A 2019 05 6;116(21):10547-10556. Epub 2019 May 6.

Laboratory of Translational Nutrition Biology, Department of Health Sciences and Technology, ETH Zurich, 8603 Schwerzenbach, Switzerland;

There is a growing body of evidence linking maternal overnutrition to obesity and psychopathology that can be conserved across multiple generations. Recently, we demonstrated in a maternal high-fat diet (HFD; MHFD) mouse model that MHFD induced enhanced hedonic behaviors and obesogenic phenotypes that were conserved across three generations via the paternal lineage, which was independent of sperm methylome changes. Here, we show that sperm tRNA-derived small RNAs (tsRNAs) partly contribute to the transmission of such phenotypes. We observe increased expression of sperm tsRNAs in the F1 male offspring born to HFD-exposed dams. Microinjection of sperm tsRNAs from the F1-HFD male into normal zygotes reproduces obesogenic phenotypes and addictive-like behaviors, such as increased preference of palatable foods and enhanced sensitivity to drugs of abuse in the resultant offspring. The expression of several of the differentially expressed sperm tsRNAs predicted targets such as and GRIN3A, which have been implicated in addiction pathology, are altered in the mesolimbic reward brain regions of the F1-HFD father and the resultant HFD-tsRNA offspring. Together, our findings demonstrate that sperm tsRNA is a potential vector that contributes to the transmission of MHFD-induced addictive-like behaviors and obesogenic phenotypes across generations, thereby emphasizing its role in diverse pathological outcomes.
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http://dx.doi.org/10.1073/pnas.1820810116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534971PMC
May 2019

Fat cells with a sweet tooth.

Nature 2019 01;565(7738):167-168

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http://dx.doi.org/10.1038/d41586-018-07739-6DOI Listing
January 2019

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.

Cell Metab 2019 04 20;29(4):901-916.e8. Epub 2018 Dec 20.

Institute of Food, Nutrition, and Health, ETH Zürich, Schorenstrasse 16, Schwerzenbach 8603, Switzerland. Electronic address:

Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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http://dx.doi.org/10.1016/j.cmet.2018.11.017DOI Listing
April 2019

BATLAS: Deconvoluting Brown Adipose Tissue.

Cell Rep 2018 10;25(3):784-797.e4

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland. Electronic address:

Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
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http://dx.doi.org/10.1016/j.celrep.2018.09.044DOI Listing
October 2018

Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 Nov;24(11):1777

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

In the version of this article originally published, the bars in the mean temperature graph in Fig. 1a were incorrectly aligned. The left-most bar should have been aligned with the Apr label on the projected month of conception axis. The error has been corrected in the print, PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0163-yDOI Listing
November 2018

Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 Nov;24(11):1776

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

In the version of this article originally published, the months on the axis labeled projected month of conception in Fig. 1a were out of order. April and March should have been the first and last months listed, respectively. The error has been corrected in the print, PDF and HTML versions of this article.
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http://dx.doi.org/10.1038/s41591-018-0162-zDOI Listing
November 2018

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Nat Med 2018 09 9;24(9):1372-1383. Epub 2018 Jul 9.

Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.
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http://dx.doi.org/10.1038/s41591-018-0102-yDOI Listing
September 2018

A stromal cell population that inhibits adipogenesis in mammalian fat depots.

Nature 2018 07 20;559(7712):103-108. Epub 2018 Jun 20.

Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL) and Swiss Institute of Bioinformatics, Lausanne, Switzerland.

Adipocyte development and differentiation have an important role in the aetiology of obesity and its co-morbidities. Although multiple studies have investigated the adipogenic stem and precursor cells that give rise to mature adipocytes, our understanding of their in vivo origin and properties is incomplete. This is partially due to the highly heterogeneous and unstructured nature of adipose tissue depots, which has proven difficult to molecularly dissect using classical approaches such as fluorescence-activated cell sorting and Cre-lox lines based on candidate marker genes. Here, using the resolving power of single-cell transcriptomics in a mouse model, we reveal distinct subpopulations of adipose stem and precursor cells in the stromal vascular fraction of subcutaneous adipose tissue. We identify one of these subpopulations as CD142 adipogenesis-regulatory cells, which can suppress adipocyte formation in vivo and in vitro in a paracrine manner. We show that adipogenesis-regulatory cells are refractory to adipogenesis and that they are functionally conserved in humans. Our findings point to a potentially critical role for adipogenesis-regulatory cells in modulating adipose tissue plasticity, which is linked to metabolic control, differential insulin sensitivity and type 2 diabetes.
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http://dx.doi.org/10.1038/s41586-018-0226-8DOI Listing
July 2018

Peroxisome Proliferator Activated Receptor Gamma Controls Mature Brown Adipocyte Inducibility through Glycerol Kinase.

Cell Rep 2018 01;22(3):760-773

Institute of Food, Nutrition and Health, ETH Zurich, Schorenstrasse 16, 8603 Schwerzenbach, Switzerland. Electronic address:

Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
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http://dx.doi.org/10.1016/j.celrep.2017.12.067DOI Listing
January 2018

Bmp4 Promotes a Brown to White-like Adipocyte Shift.

Cell Rep 2016 08 11;16(8):2243-2258. Epub 2016 Aug 11.

Swiss Federal Institute of Technology, Department of Health Science, Institute of Food Nutrition and Health, Laboratory of Translational Nutrition Biology, Schwerzenbach 8603, Switzerland. Electronic address:

While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. This effect is mediated by Smad signaling and might be in part due to suppression of lipolysis, via regulation of hormone sensitive lipase expression linked to reduced Ppar activity. Given that we observed a strong correlation between BMP4 levels and adipocyte size, as well as insulin sensitivity in humans, we propose that Bmp4 is an important factor in the context of obesity and type 2 diabetes.
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http://dx.doi.org/10.1016/j.celrep.2016.07.048DOI Listing
August 2016

DIETARY RATIOS OF N-6/N-3 POLYUNSATURATED FATTY ACIDS DURING MATERNAL PREGNANCY AFFECT HIPPOCAMPAL NEUROGENESIS AND APOPTOSIS IN MOUSE OFFSPRING.

Nutr Hosp 2015 Sep 1;32(3):1170-9. Epub 2015 Sep 1.

Nutrition Research Unit, Beijing Pediatric Research Institute, Beijing Children's Hospital, Capital Medical University, Beijing (China)..

Objective: although n-3 polyunsaturated fatty acids (PUFAs) play crucial roles in brain development and function, neither the optimal level of n-3 PUFAs nor the optimal ratio of n-6/n-3 PUFAs in the maternal diet are well defined. In this study, we investigated the effects of dietary n-6/n-3 PUFA ratios during pregnancy on neurogenesis and apoptosis in the brains of mouse offspring. Metods: female C57BL/6J mice were fed one of three diets with high, medium and low ratios of n-6/n-3 PUFAs (15.7:1, 6.3:1, 1.6:1), as well as a high fish oil diet with a n-6/n-3 ratio of 1:5.7; an n-3 PUFA-deficient diet served as control. The feeding regimens began two months before mouse conception and continued for the duration of the pregnancy. The neurogenesis and apoptosis of hippocampal CA3 area in the offspring were detected.

Results: compared to the n-3 PUFA-deficient diet, n-3 PUFA-containing diets, particularly those with n-6/n-3 PUFA ratios of 6.3:1 and 1.6:1, significantly increased both phosphorylation of histone H3 at ser 10 (p-H3ser10) and calretinin-positive cells in hippocampus CA3 of the offspring. Furthermore, increased expression of Bcl2 protein, decreased expression of Bax protein, and reduced caspase 3 activity and numbers of TUNEL apoptotic cells were found in the three diets with high, medium and low n-6/n-3 PUFA ratios. However, there were no differences in any of these parameters between the high fish oil diet group and the n-3 PUFA-deficient diet group.

Conclusions: these data suggest that a higher intake of n-3 PUFAs with a lower ratio of n-6/n-3 PUFAs of between about 6:1 to 1:1, supplied to mothers during pregnancy, may benefit brain neurogenesis and apoptosis in offspring. However, excessive maternal intake of n-3 PUFAs may exert a negative influence on brain development in the offspring.
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http://dx.doi.org/10.3305/nh.2015.32.3.9259DOI Listing
September 2015