Single-cell transcriptomics reveals the long-term high-fat diet impairs male reproduction by disrupting spermatogenesis in pubertal mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE318121 | GEO | 2026/03/31
REPOSITORIES: GEO
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Project description:Recent studies have documented the profound impact of pre-pubertal nutrition on reproductive performance in bulls. Previously, a high plane of nutrition during calfhood (2-30 wk) in beef and dairy bulls hastened puberty explained by an increase in the level of reproductive hormones (LH, testosterone and IGF-I) pre-pubertally, compared to bulls fed less than recommended amounts of energy and protein with no apparent effect on sperm function evaluated by traditional techniques. In addition, upregulated steroid biosynthesis and Sertoli cell maturation was identified in the testicular tissue of high diet bulls at 16 and 24 weeks, respectively. The objective of this study was to evaluate the post- pubertal testes for responses to high (20.0% CP, 67.9% TDN), medium (17.0% CP, 66.0% TDN) and low (12.2% CP, 62.9% TDN) diets fed from 2-30 wk of life. Based on RNA sequencing data, 497 genes were differentially expressed in high vs low diet and 2961 genes in high vs medium diet (P<0.1). According to KEGG analysis, oxidative phosphorylation and ribosome pathways were upregulated in the high diet group (vs medium and low) with majority of the upregulated genes encoding for essential subunits of complex I, III, IV and V of OXYPHOS pathway. In addition, mitochondrial translation, mitotic nuclear division and cell division were enriched in the high vs medium diet group. Supporting the above, the percentage of sperm exhibiting loss of mitochondrial function was lower in the high diet compared to the medium diet (P<0.1). Thus, enhanced early life nutrition upregulated mitochondrial function in both the testes and sperm of post-pubertal Holstein bulls.
2020-01-01 | GSE137690 | GEO
Project description:<p>BACKGROUND: Large-scale farms struggle to effectively address summer heat stress (HS) in dairy goats, which impairs spermatogenesis and reduces reproductive performance by compromising gut and reproductive organ health in male animals. Although Clostridium butyricum (CB) and Enterococcus faecium (EF) have been used to alleviate gut dysbiosis, their protective effects and mechanisms against HS-induced spermatogenic dysfunction in dairy goats remain unclear. This study aims to evaluate the efficacy of CB and EF in mitigating HS-induced spermatogenic disorders in male dairy goats and elucidate the underlying mechanisms.</p><p>RESULTS: HS leads to a significant decline in sperm quality. CB and EF ameliorate HS-induced sperm quality deterioration by reducing pro-inflammatory factors and oxidative stress levels in blood, while modulating the disrupted reproductive hormone levels caused by heat stress. 16S rRNA-based microbiota analysis revealed that CB and EF treatment shifted the gut microbiota of HS-treated male dairy goats toward a composition resembling that of the NC. To investigate whether the protective effects of these probiotics on sperm quality are mediated through gut microbiota modulation, we transplanted fecal microbiota from HS-treated dairy goats (with or without probiotic intervention) into antibiotic-induced microbiome-depleted (AIMD) mice, followed by heat stress exposure. We observed severe testicular damage and spermatogenic impairment in mice receiving HS group microbiota, whereas these pathological manifestations were significantly alleviated in mice receiving microbiota from probiotic-treated HS goats, indicating that CB and EF mitigate HS-induced spermatogenic damage in a microbiota-dependent manner. Furthermore, non-targeted metabolomics sequencing identified significant reductions in arginine (Arg) and pantothenic acid (PaA) levels in both HS-treated goats and HS microbiota-transplanted mice, metabolites that showed correlation with sperm quality parameters. Subsequent studies demonstrated that supplementation with Arg and PaA effectively attenuated the elevation of pro-inflammatory factors and oxidative stress in mouse blood, restored intercellular junctions, and ultimately ameliorated spermatogenic disorders.</p><p>CONCLUSION: This study demonstrates that CB and EF alleviate HS-induced sperm quality decline in dairy goats by modulating the gut microbiota to increase blood levels of Arg and PaA. These findings highlight novel therapeutic avenues for preventing HS-induced spermatogenic disorders in dairy goats and provide fresh insights into the application of probiotics to mitigate heat stress-associated impairments in sperm production.</p>
2025-07-31 | MTBLS12573 | MetaboLights
Project description:Pre-pubertal Holstein bull calves fed a higher plane of nutrition had larger testes, earlier puberty, higher serum LH, testosterone and greater sperm production potential than those fed a restricted diet. In addition, pre-pubertal calves fed a high-nutrition diet had higher IGF-I and more proliferating and differentiating Sertoli cells much earlier in life, compared to those fed normal or low-nutrition diets. The objective was to determine changes in mRNA expression of genes in the testes of bulls fed either a high or low pre-pubertal diet. Holstein bull calves maintained on either a high (20% crude protein (CP) and 71.6% Total Digestible Nutrients (TDN)) or low (12% CP and 64.4% TDN) diet from 2 wk of age, were castrated at 8, 16, 24 and 32 wk and testicular mRNA extracted and sequenced. Differential expression of genes mainly occurred at 16 and 24 wk, with minor changes detected at 32 wk. At 16 wks, functional analysis of DE mRNA with DAVID revealed the common biological processes enriched to be "cholesterol" and "fatty acid biosynthesis" with majority of the genes including HMGCR, HMGCS1, HSD17 being upregulated in high-diet bulls (P<0.05). Major pathways enriched at 16 wks were "cholesterol biosynthesis", "steroid metabolism" and "activation of gene expression by Sterol regulatory element-binding protein (SREBP)" (P<0.05). Mature Sertoli cell marker Connexin 43, was upregulated at 16 wk, whereas an immature Sertoli cell marker, AMH was downregulated at 24 wk, in the high-diet group. Network analysis using IPA, revealed an indirect interaction between insulin family receptor and most upregulated cholesterol biosynthesis genes, implying regulation of testicular function. Thus, enhanced pre-pubertal nutrition in Holstein bulls enhanced testicular cholesterol/steroid biosynthesis and Sertoli cell maturation to promote early reproductive development.
2019-05-15 | GSE125082 | GEO
Project description:Obesity induces spermatogenic disorders in male mice by affecting pituitary gonadotropin levels. Here, using diet-induced obese (DIO) mice, we found that IP3R1 and 9 ZDHHC family members are highly expressed in pituitary gonadotrophs. Mechanistically, we demonstrated that protein palmitoylation and mitochondria-associated endoplasmic reticulum membrane (MAM) are essential for preventing pituitary endocrine defects and spermatogenic disorders in obesity. Overall design: Collect pituitary tissues from normal diet (ND) and high-fat diet (HFD) male mice.
2025-12-10 | GSE310493 | GEO
Project description:The analyses show that consumption of a high-fat diet, compared to a standard control diet, alters hepatic transcriptome in pubertal mice.
2023-01-20 | GSE218932 | GEO
Project description:Age-related and/or high caloric intake driven changes in visceral adipose tissue contribute to the development of diabetes and cardiovascular disease. The lack of reliable, high-throughput methods to analyze the adipose tissue protein composition has limited our understanding of the protein networks responsible for metabolic regulation of various adipose depots. We have developed a proteomic approach using multiple-dimension liquid chromatography tandem mass spectrometry and multiplexed TMT labeling to analyze protein composition of epididymal adipose tissues isolated from mice fed either low or high fat diet for a short (8 weeks) or a long (18 weeks) term, and from mice that aged (26 weeks old) on low vs. high fat diets. Advancing age and high-fat diet feeding led to graded deterioration, with long-term high fat diet exposure being the worst of all measures of peripheral metabolic health such as body weight, adiposity, plasma fasting glucose, insulin, triglycerides, total cholesterol levels, and glucose and insulin tolerance tests. Epididymal adipose depot proteomic analysis identified >3300 proteins per sample. In response to short-term high fat diet, 43 proteins representing lipid metabolism (e.g., AACS, ACOX1, ACLY) and red-ox pathways (e.g., CPD2, CYP2E, SOD3) were significantly altered (FDR < 10%). Long-term high fat diet significantly altered 55 proteins associated with immune response (e.g., IGTB2, IFIT3, LGALS1) and rennin angiotensin system (e.g. ENPEP, CMA1, CPA3, ANPEP). Age-related changes on low fat diet significantly altered only 18 proteins representing mainly urea cycle (e.g., OTC, ARG1, CPS1), and amino acid biosynthesis (e.g., GMT, AKR1C6). Surprisingly, high fat diet driven age-related changes culminated with alterations in 155 proteins involving primarily the urea cycle (e.g., ARG1, CPS1), immune response/complement activation (e.g., C3, C4b, C8, C9, CFB, CFH, FGA), extracellular remodeling (e.g., EFEMP1, FBN1, FBN2, LTBP4, FERMT2, ECM1, EMILIN2, ITIH3) and apoptosis (e.g., YAP1, HIP1, NDRG1, PRKCD, MUL1) pathways. Our unbiased mass spectrometry method, tailored to adipose tissue, identified both age-related and high fat diet specific proteomic signatures. In addition to well-described immune and extracellular remodeling response to high fat feeding, we have uncovered the pronounced involvement of arginine metabolism in response to advancing age, and branched chain amino acid metabolism in early response to high fat feeding. We were able to uncouple age-related metabolic responses from those associated with caloric intake, a task otherwise difficult to achieve.
2017-03-27 | PXD005953 | Pride
Project description:Age-related and/or high caloric intake driven changes in visceral adipose tissue contribute to the development of diabetes and cardiovascular disease. The lack of reliable, high-throughput methods to analyze the adipose tissue protein composition has limited our understanding of the protein networks responsible for metabolic regulation of various adipose depots. We have developed a proteomic approach using multiple-dimension liquid chromatography tandem mass spectrometry and multiplexed TMT labeling to analyze protein composition of epididymal adipose tissues isolated from mice fed either low or high fat diet for a short (8 weeks) or a long (18 weeks) term, and from mice that aged (26 weeks old) on low vs. high fat diets. Advancing age and high-fat diet feeding led to graded deterioration, with long-term high fat diet exposure being the worst of all measures of peripheral metabolic health such as body weight, adiposity, plasma fasting glucose, insulin, triglycerides, total cholesterol levels, and glucose and insulin tolerance tests. Epididymal adipose depot proteomic analysis identified >3300 proteins per sample. In response to short-term high fat diet, 43 proteins representing lipid metabolism (e.g., AACS, ACOX1, ACLY) and red-ox pathways (e.g., CPD2, CYP2E, SOD3) were significantly altered (FDR < 10%). Long-term high fat diet significantly altered 55 proteins associated with immune response (e.g., IGTB2, IFIT3, LGALS1) and rennin angiotensin system (e.g. ENPEP, CMA1, CPA3, ANPEP). Age-related changes on low fat diet significantly altered only 18 proteins representing mainly urea cycle (e.g., OTC, ARG1, CPS1), and amino acid biosynthesis (e.g., GMT, AKR1C6). Surprisingly, high fat diet driven age-related changes culminated with alterations in 155 proteins involving primarily the urea cycle (e.g., ARG1, CPS1), immune response/complement activation (e.g., C3, C4b, C8, C9, CFB, CFH, FGA), extracellular remodeling (e.g., EFEMP1, FBN1, FBN2, LTBP4, FERMT2, ECM1, EMILIN2, ITIH3) and apoptosis (e.g., YAP1, HIP1, NDRG1, PRKCD, MUL1) pathways. Our unbiased mass spectrometry method, tailored to adipose tissue, identified both age-related and high fat diet specific proteomic signatures. In addition to well-described immune and extracellular remodeling response to high fat feeding, we have uncovered the pronounced involvement of arginine metabolism in response to advancing age, and branched chain amino acid metabolism in early response to high fat feeding. We were able to uncouple age-related metabolic responses from those associated with caloric intake, a task otherwise difficult to achieve.
2018-07-03 | MSV000082569 | MassIVE
Project description:To investigate the mechanism by which paternal exposure to high-fat diet (HFD) exacerbates environmental stress-impaired testicular germ cell development in offspring, testicular RNA sequencing was performed in H+Cd (the offspring were treated with Cd after paternal exposure to one-generational HFD) and H+H+Cd (the offspring were treated with Cd after paternal exposure to bi-generational HFD) groups. Compared with HFD1D group and HFD2D group, 229 mRNAs were upregulated and 268 mRNAs were downregulated, screened for a 1.2-fold change and adjusted with P < 0.05. GO analysis revealed that downregulated mRNAs were related to multiple biological processes, including the "retinol metabolic process," the "reproductive process," and the "spermatogenesis".
2023-12-22 | GSE241413 | GEO
Project description:We previously reported that a low versus high glycemic index (GI) diet on a high fat (30% kcal fat) background (LGI and HGI, respectively) significantly retarded adverse health effects in C57BL/6J male mice. The LGI diet enhanced whole body insulin sensitivity and repressed high fat diet-induced body and adipose tissue weight gain, resulting in reduced serum leptin and resistin levels (Faseb J 2009; 23: 1092-1101). How white adipose tissue (WAT) is effected is examined in the present study. We characterized the molecular mechanisms underlying the GI-mediated effects in WAT using whole genome transcriptomics technology. We show that a LGI vs. HGI diet mainly exerts its beneficial effects on substrate metabolism, especially insulin signaling of fatty acid metabolism. In addition, cell adhesion and cytoskeleton remodeling showed reduced expression in line with lower WAT mass, but it might also be due to altered insulin sensitivity. An important transcription factor showing enhanced expression is PPARgamma. Furthermore, serum levels of triglycerides, total cholesterol, HDL- and LDL-cholesterol were significantly reduced by a LGI vs. HGI diet, and muscle insulin sensitivity was significantly increased as analyzed by PKB/Akt phosphorylation. Cumulatively, even though these mice were fed a high fat diet, the low versus high GI induced significantly favorable changes in metabolism in WAT. These effects suggest a partial overlap with pharmacological approaches by thiazolidinediones (TZDs) to treat insulin resistance and statins and plantsterols/stanols for hypercholesterolemia. It is therefore tempting to speculate that such a dietary approach might beneficially support pharmacological treatment of insulin resistance or hypercholesterolemia in humans. We analyzed 19 epididymal whie adipose tissue (epiWAT) samples from a 13 week High fat diet, Low glycemic index dietary group (LGI, n=9) versus a High fat diet, High glycemic index dietary group (HGI, n=10) after 13 weeks of feeding wildtype C57BL/6J male adult mice. Of the 19 arrays, we excluded 2 arrays for downstream analysis based on quality control (total final set contains 8 LGI and 9 HGI samples).
2011-09-12 | E-GEOD-26930 | biostudies-arrayexpress
Project description:Obesity is a known risk factor for breast cancer. To identify genes and underlying pathways in human triple-negative breast cancer cells affected by interaction with adipose tissue, MDA-MB-231 breast cancer cells were cultivated in a co-culture system with or without adipose tissue explants from mice for the purpose of a microarray gene expression analysis. Co-culture of MDA-MB-231 breast cancer cells was performed with adipose tissue explants obtained from C57BL/6J mice that were fed a high-fat diet (HFD, 58%Kcal from fat) or normal chow diet (NC; 11%Kcal from fat) ad libitum for 16 weeks. For co-cultivation analyses of breast cancer cells and adipose tissue explants, we set up a two-dimensional transwell system, which enables intercellular communication through soluble factors secreted into the medium but inhibits intermixture of the different cell types. Following 72 hours of co-culture with or without adipose tissue, total RNA was isolated from the breast cancer cells and subjected to microarray gene expression analyses.
2020-08-17 | E-MTAB-9485 | biostudies-arrayexpress