|
1
|
Chaves WF, de Oliveira Costa S, Santos NJ, de Aguiar MS, Elias CF, Torsoni MA, Pinheiro IL, da Silva Aragão R. Maternal high-fat diet exposure impairs LKB1-TGFβ1 inflammatory pathway and increases hypothalamic 5HT receptors gene expression and somatic growth in young rats. Brain Res 2025; 1862:149706. [PMID: 40381902 DOI: 10.1016/j.brainres.2025.149706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 04/26/2025] [Accepted: 05/13/2025] [Indexed: 05/20/2025]
Abstract
The serotonergic system regulates various psychobiological processes, including neurodevelopment, mood, and feeding behavior. Maternal exposure to a high-fat diet (HFD) increases circulating proinflammatory cytokines, impairing the development of the serotonergic system in the offspring's brain. The effects of maternal exposure to HFD on the offspring's feeding behavior, somatic growth, and hypothalamic serotonergic system were investigated. Wistar rat offspring from HFD-fed dams displayed increased body weight, fat mass, and somatic growth but no changes in food intake or feeding behavior. They also showed elevated total cholesterol and reduced serum creatinine. At the molecular level, increased hypothalamic gene expression of Htr1a, Htr2a, and Tgfb1, along with a reduction in the phosphorylation of FoxO1Thr24, cAMP response element-binding protein (CREBSer133), and liver kinase B1 (LKB1Ser428) were observed. No differences in leptin or insulin signaling were found. These results suggest an initial disruption in energy homeostasis mediated by the serotonergic system.
Collapse
Affiliation(s)
- Wenicios Ferreira Chaves
- Graduate Program in Science of Nutrition, Sports and Metabolism, University of Campinas, UNICAMP, Limeira, SP, Brazil
| | - Suleyma de Oliveira Costa
- Laboratory of Metabolic Disease, School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil
| | - Nilton J Santos
- Laboratory of Metabolic Disease, School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil
| | - Melissa Santos de Aguiar
- Laboratory of Metabolic Disease, School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil
| | - Carol Fuzeti Elias
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, United States
| | - Marcio Alberto Torsoni
- Graduate Program in Science of Nutrition, Sports and Metabolism, University of Campinas, UNICAMP, Limeira, SP, Brazil; Laboratory of Metabolic Disease, School of Applied Sciences, University of Campinas, UNICAMP, Limeira, SP, Brazil
| | - Isabeli Lins Pinheiro
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, UFPE, Vitoria de Santo Antao, PE, Brazil
| | - Raquel da Silva Aragão
- Graduate Program in Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, UFPE, Vitoria de Santo Antao, PE, Brazil; Graduate Program in Nutrition, Federal University of Pernambuco, UFPE, Recife, PE, Brazil.
| |
Collapse
|
|
2
|
Geng C, Li X, Dan L, Xie L, Zhou M, Guan K, Chen Q, Xu Y, Ding R, Li J, Zhang Y, Sharifzadeh M, Liu R, Li W, Lu H. Female mice exposed to varying ratios of stearic to palmitic acid in a high-fat diet during gestation and lactation shows differential impairments of beta-cell function. Life Sci 2025; 369:123532. [PMID: 40057226 DOI: 10.1016/j.lfs.2025.123532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 02/19/2025] [Accepted: 03/03/2025] [Indexed: 03/30/2025]
Abstract
AIMS While emerging evidence implicates an abnormal stearic-to-palmitic acid ratio in saturated fats in beta-cell dysfunction, their gestational/lactational impacts remain underexplored. This study evaluates the differential transient and long-lasting effects of high-fat diets with contrasting stearic-to-palmitic acid ratios on maternal beta-cell function. MATERIALS AND METHODS Female mice were fed high-fat diets with high/low stearic-to-palmitic acid ratios during gestation/lactation, followed by a recovery period and subsequent exposure to an obesogenic diet. Beta-cell function was assessed using ex-vivo glucose-stimulated insulin secretion (GSIS) and immunohistochemistry. Islets mRNA profiling was performed using RNA-sequencing. KEY FINDINGS Both high- and low-ratio groups showed impaired GSIS post-lactation. High-ratio-fed dams exhibited pronounced compensatory responses, including increased islet size, number, and elevated Stx1a, Stx4, Pdx1, Mafa expression. Following metabolic re-challenge, high-ratio group demonstrated more severely impaired ex vivo insulin release. No significant differences in islet apoptosis and senescence were observed between the two groups. Transcriptomic profiling, however, revealed distinct mechanistic pathways: the high-ratio diet was likely to disrupt beta-cell organelles ultrastructure, while the low-ratio diet predominantly dysregulated chemokine-mediated immune signaling networks. SIGNIFICANCE Gestational/lactational exposure to high-fat diets with both high and low ratios of stearic-to-palmitic acid exerts pronounced transient impacts on beta-cell function, with the high-ratio diet inducing more severe and persistent detrimental effects. These findings highlight the critical influence and importance of dietary saturated fatty acid composition in maternal metabolic programming and beta-cell vulnerability.
Collapse
Affiliation(s)
- Chenchen Geng
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Xiaohan Li
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Lingfeng Dan
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Liyan Xie
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Min Zhou
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Kaile Guan
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Qi Chen
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Yan Xu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Rong Ding
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Jiaqi Li
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Yue Zhang
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Mohammad Sharifzadeh
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| | - Rui Liu
- Department of Tropical and Liver Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570100, China.
| | - Wenting Li
- Department of Tropical and Liver Diseases, The Second Affiliated Hospital of Hainan Medical University, Haikou 570100, China; Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
| | - Huimin Lu
- Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, Harbin, China.
| |
Collapse
|
|
3
|
Sheng C, Liu B, Chavarro J, Hart JE, Zhang C, Wang M, Sun Q. Maternal macronutrient intake at pregnancy and offspring growth trajectory through childhood: a prospective analysis in the Growing Up Today Study 2 cohort. Am J Clin Nutr 2025; 121:843-852. [PMID: 39900248 PMCID: PMC11968214 DOI: 10.1016/j.ajcnut.2025.01.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 12/20/2024] [Accepted: 01/29/2025] [Indexed: 02/05/2025] Open
Abstract
BACKGROUND Childhood obesity has become a public health challenge globally. Existing studies have indicated a potential link between maternal dietary macronutrient compositions and subsequent weight changes in their offspring during early childhood, although few studies have been conducted through early adulthood. OBJECTIVES We aimed to investigate the relationship between maternal macronutrient intake before or during pregnancy and offspring body weight from late childhood till early adulthood. METHODS We included 5715 children from the Growing Up Today Study 2 (GUTS2) (mean 11.8 y old at baseline in 2004) born to 4731 mothers who participated in the Nurses' Health Study II (NHSII) during 1989-1995. Diet during or before pregnancy was assessed using a validated food frequency questionnaire (FFQ) in 1991 and 1995. Age- and sex-specific body mass index (BMI) were used to define overweight and obesity in childhood and adolescence. Multivariable linear and log-binomial regression models with generalized estimating equations were used to evaluate the associations of interest. RESULTS The mean (SD) maternal macronutrient percent energy intake during pregnancy was 19.3% (3.1) for protein, 51.2% (6.6) for carbohydrates, and 30.8% (5.0) for total fat. For diet during pregnancy, after multivariate adjustment for maternal and offspring risk factors, compared with the lowest quartile, the highest quartile of trans fatty acid consumption was associated with a 0.20 unit (95% confidence interval [CI]: 0.00, 0.40) increase in BMI z-score without a significant linear trend (P-trend = 0.06). A positive association with BMI z-score was also observed for total fat intake (β: 0.21; 95% CI: 0.05, 0.36; P-trend = 0.02) when replacing total carbohydrate, and vice versa (β: -0.24; 95% CI: -0.40, -0.08; P-trend = 0.02 for total carbohydrate intake). For diet before pregnancy, none of the macronutrients were associated with offspring BMI z-score or the risk of overweight or obesity. CONCLUSIONS Higher fat, especially trans fat intake, during pregnancy was positively associated with higher body weight among offspring. Other macronutrients from various food sources were not associated with the offspring weight. Overall, these data suggest that, apart from trans fatty acids, other macronutrient composition of maternal diet may have minimal impact on offspring body weight in this well-nourished population.
Collapse
Affiliation(s)
- Chen Sheng
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Binkai Liu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Jorge Chavarro
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Jaime E Hart
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States; Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
| | - Cuilin Zhang
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States; Global Center for Asian Women's Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Qi Sun
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
| |
Collapse
|
|
4
|
Haidery F, Lambertini L, Tse I, Dodda S, Garcia-Ocaña A, Scott DK, Baumel-Alterzon S. NRF2 deficiency leads to inadequate beta cell adaptation during pregnancy and gestational diabetes. Redox Biol 2025; 81:103566. [PMID: 40054060 PMCID: PMC11930207 DOI: 10.1016/j.redox.2025.103566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Revised: 02/13/2025] [Accepted: 02/24/2025] [Indexed: 03/12/2025] Open
Abstract
The late stages of mammalian pregnancy are accompanied by a mild increase in insulin resistance likely due to enhanced glucose demand of the growing fetus. Therefore, as an adaptive process to maintain euglycemia during pregnancy, maternal β-cell mass expands leading to increased insulin release. Defects in functional β-cell adaptive expansion during pregnancy can lead to gestational diabetes mellitus (GDM). While the exact mechanisms that promote GDM are poorly understood, GDM is associated with inadequate functional β-cell mass expansion and with a systematic increase of oxidative stress. Here, we show that NRF2 levels are upregulated in mouse β-cells at gestational day 15 (GD15). Inducible β-cell-specific Nrf2 deleted (βNrf2KO) mice display reduced β-cell proliferation, increased β-cell oxidative stress and lipid peroxidation, compromised β-cell function, and elevated β-cell death, leading to impaired β-cell mass expansion and dysregulated glucose homeostasis towards the end of pregnancy. Importantly, the gestational hormone 17-β-estradiol (E2) increases NRF2 levels, and downregulation of NRF2 suppresses E2-induced protection of β-cells against oxidative stress, suggesting that E2 exerts its antioxidant effects through activation of NRF2 signaling in β-cells. Collectively, these data highlight the critical role of NRF2 in regulating oxidative stress during the adaptive response of β-cells in pregnancy and identify NRF2 as a potential therapeutic target for GDM treatment.
Collapse
Affiliation(s)
- Fatema Haidery
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Luca Lambertini
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sriya Dodda
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adolfo Garcia-Ocaña
- Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA
| | - Donald K Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Molecular and Cellular Endocrinology, Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope, Duarte, CA, USA.
| |
Collapse
|
|
5
|
Brown AA, Widdowson M, Brandt S, Mohammadzadeh P, Rosenberg JB, Jepsen JRM, Ebdrup BH, Hernández-Lorca M, Bønnelykke K, Chawes B, Stokholm J, Thorsen J, Ibrahimi P, Li X, Sørensen SJ, Rasmussen MA. Associations of the gut microbiome and inflammatory markers with mental health symptoms: a cross-sectional study on Danish adolescents. Sci Rep 2025; 15:10378. [PMID: 40140473 PMCID: PMC11947166 DOI: 10.1038/s41598-025-94687-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/17/2025] [Indexed: 03/28/2025] Open
Abstract
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that often persists into adulthood and is accompanied by comorbid mental health problems. This cross-sectional cohort study analyzed 411 18-year-olds from the Danish COPSAC2000 birth cohort to investigate the relationship between the gut microbiome, fasting and postprandial systemic inflammation, ADHD symptoms, and symptoms of anxiety, stress, and depression. ADHD was assessed using the Adult ADHD Self-Report Scale (ASRS), while depression, stress, and anxiety were evaluated with the Depression, Anxiety, and Stress Scale 21 (DASS-21). Fecal metagenomic data and inflammation levels, measured as glycosylated protein A (GlycA), were analyzed following a standardized meal challenge. In males, higher ADHD symptom scores correlated significantly with increased abundance of a tryptophan biosynthesis pathway (MetaCyc Metabolic Pathways Database) and elevated fasting and postprandial GlycA levels (p < 0.05). While the severity of depression, anxiety, and stress symptoms showed weak associations with GlycA and the gut microbiome, our findings indicate a significant link between ADHD symptoms and postprandial inflammation, warranting further investigation into underlying mechanisms.
Collapse
Affiliation(s)
- Aisha Alayna Brown
- Section of Global Health, Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Michael Widdowson
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
| | - Sarah Brandt
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Parisa Mohammadzadeh
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Julie B Rosenberg
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Jens Richardt Møllegaard Jepsen
- Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark
- Child and Adolescent Mental Health Center, Copenhagen University Hospital-Mental Health Services CPH, Copenhagen, Denmark
| | - Bjørn H Ebdrup
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark
| | - María Hernández-Lorca
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Center for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, University of Copenhagen, Glostrup, Denmark
| | - Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Bo Chawes
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jakob Stokholm
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics, Slagelse Hospital, Slagelse, Denmark
| | - Jonathan Thorsen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Parvaneh Ibrahimi
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark
- Department of Health Technology, Technical University of Denmark, Lyngby, Denmark
| | - Xuanji Li
- Section of Microbiology, School of Life Sciences, University of Zhejiang, Hangzhou, China
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Søren Johannes Sørensen
- Section of Microbiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Morten Arendt Rasmussen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
- Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
6
|
Chen J, Zeng W, Dai D, Tang Y, Dong Y, Zhong Z, Zhou M, Ye J. A systematic analysis and prediction of the disease burden of ischemic heart disease caused by hyperglycemia. J Diabetes Investig 2025. [PMID: 40077954 DOI: 10.1111/jdi.70006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 01/23/2025] [Accepted: 01/29/2025] [Indexed: 03/14/2025] Open
Abstract
OBJECTIVE This study aims to analyze the disease burden of ischemic heart disease (IHD) caused by hyperglycemia and its changing trend, and to construct a visualization platform for disease burden and forecast trends on the Shiny platform. MATERIALS AND METHODS Using data from the 2021 Global Burden of Disease Study, we analyzed deaths and disability-adjusted life years (DALYs) due to IHD triggered by hyperglycemia, with detailed analysis by region, gender, and age. The age-period-cohort model was used to assess the impact of age, cohort, and period on age-standardized disease rates across different Socio-Demographic Index (SDI) regions, and decomposition analysis was employed to disentangle the contributions of population, aging, and epidemiological changes. RESULTS In 2021, approximately 14-15% of IHD's DALYs and deaths were attributed to high fasting plasma glucose (HFPG), with a nonsignificant decrease in the annual average percentage change of DALYs. In middle, low-middle, and low SDI regions, the age-standardized mortality rates caused by HFPG are increasing, particularly among males. In high-middle and high SDI regions, the effects of aging and epidemiological changes surpass population growth, whereas in low SDI regions, population growth is the main factor. By 2050, the global Age-Standardized Mortality Rate of IHD attributed to HFPG is projected to reach 16.96. More data can be accessed by visiting the disease burden visualization platform. CONCLUSION Global HFPG-induced IHD health presents significant imbalances. In low SDI regions with larger populations and more unbalanced healthcare distribution, there is a need to strengthen the construction of medical levels.
Collapse
Affiliation(s)
- Jianxing Chen
- Dongguan Hospital of Guangzhou University of Traditional Chinese Medicine, Dongguan, China
| | | | - Dandan Dai
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yujin Tang
- Eighth Clinical School, Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Yangwen Dong
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zilan Zhong
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Miao Zhou
- Foshan Hospital of Traditional Chinese Medicine, Foshan, China
| | - Jianhong Ye
- Foshan Hospital of Traditional Chinese Medicine, Foshan, China
| |
Collapse
|
|
7
|
Hill DJ, Hill TG. Maternal diet during pregnancy and adaptive changes in the maternal and fetal pancreas have implications for future metabolic health. Front Endocrinol (Lausanne) 2024; 15:1456629. [PMID: 39377073 PMCID: PMC11456468 DOI: 10.3389/fendo.2024.1456629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2024] [Accepted: 08/28/2024] [Indexed: 10/09/2024] Open
Abstract
Fetal and neonatal development is a critical period for the establishment of the future metabolic health and disease risk of an individual. Both maternal undernutrition and overnutrition can result in abnormal fetal organ development resulting in inappropriate birth size, child and adult obesity, and increased risk of Type 2 diabetes and cardiovascular diseases. Inappropriate adaptive changes to the maternal pancreas, placental function, and the development of the fetal pancreas in response to nutritional stress during pregnancy are major contributors to a risk trajectory in the offspring. This interconnected maternal-placental-fetal metabolic axis is driven by endocrine signals in response to the availability of nutritional metabolites and can result in cellular stress and premature aging in fetal tissues and the inappropriate expression of key genes involved in metabolic control as a result of long-lasting epigenetic changes. Such changes result is insufficient pancreatic beta-cell mass and function, reduced insulin sensitivity in target tissues such as liver and white adipose and altered development of hypothalamic satiety centres and in basal glucocorticoid levels. Whilst interventions in the obese mother such as dieting and increased exercise, or treatment with insulin or metformin in mothers who develop gestational diabetes, can improve metabolic control and reduce the risk of a large-for-gestational age infant, their effectiveness in changing the adverse metabolic trajectory in the child is as yet unclear.
Collapse
Affiliation(s)
- David J. Hill
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON, Canada
- Departments of Medicine, Physiology and Pharmacology, Western University, London, ON, Canada
| | - Thomas G. Hill
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
| |
Collapse
|
|
8
|
Eileen L, Peterson M. High-Fat Diets Fed during Pregnancy Cause Changes to Pancreatic Tissue DNA Methylation and Protein Expression in the Offspring: A Multi-Omics Approach. Int J Mol Sci 2024; 25:7317. [PMID: 39000422 PMCID: PMC11242410 DOI: 10.3390/ijms25137317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
Maternal obesity, caused by diets rich in fats and sugars during pregnancy, can predispose offspring to metabolic diseases such as diabetes. We hypothesized that obesity during pregnancy leads to increased DNA methylation and reduced protein expression in factors regulating β-cell function and apoptosis. Female C57BL/6J mice were fed a high-fat diet (HFD; 42% fat content; n = 3) or a control diet (CON; 16% fat content; n = 3) for fourteen weeks before and during pregnancy. Offspring were euthanized at 8 weeks and pancreatic tissue was collected. Isolated DNA was analyzed using whole-genome bisulfite sequencing. Protein expression was quantified using LC-MS. No significant differences in body weight were observed between HFD and control pups (p = 0.10). Whole-genome bisulfite sequencing identified 91,703 and 88,415 differentially methylated regions (DMRs) in CON vs. HFD male and female offspring. A total of 34 and 4 proteins were determined to have changes in expression that correlated with changes in DNA methylation in CON vs. HFD males and females, respectively. The majority of these factors were grouped into the metabolic function category via pathway analyses. This study illustrates the complex relationship between epigenetics, diet, and sex-specific responses, therefore offering insights into potential therapeutic targets and areas for further research.
Collapse
Affiliation(s)
| | - Maria Peterson
- Department of Fisheries, Veterinary, and Animal Science, University of Rhode Island, 45 Upper College Rd., Kingston, RI 02881, USA;
| |
Collapse
|
|
9
|
Heinecke F, Fornes D, Capobianco E, Flores Quiroga JP, Labiano M, Faletti AG, Jawerbaum A, White V. Intestinal alterations and mild glucose homeostasis impairments in the offspring born to overweight rats. Mol Cell Endocrinol 2024; 587:112201. [PMID: 38494045 DOI: 10.1016/j.mce.2024.112201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 03/06/2024] [Accepted: 03/07/2024] [Indexed: 03/19/2024]
Abstract
The gut plays a crucial role in metabolism by regulating the passage of nutrients, water and microbial-derived substances to the portal circulation. Additionally, it produces incretins, such as glucose-insulinotropic releasing peptide (GIP) and glucagon-like derived peptide 1 (GLP1, encoded by gcg gene) in response to nutrient uptake. We aimed to investigate whether offspring from overweight rats develop anomalies in the barrier function and incretin transcription. We observed pro-inflammatory related changes along with a reduction in Claudin-3 levels resulting in increased gut-permeability in fetuses and offspring from overweight rats. Importantly, we found decreased gip mRNA levels in both fetuses and offspring from overweight rats. Differently, gcg mRNA levels were upregulated in fetuses, downregulated in female offspring and unchanged in male offspring from overweight rats. When cultured with high glucose, intestinal explants showed an increase in gip and gcg mRNA levels in control offspring. In contrast, offspring from overweight rats did not exhibit any response in gip mRNA levels. Additionally, while females showed no response, male offspring from overweight rats did exhibit an upregulation in gcg mRNA levels. Furthermore, female and male offspring from overweight rats showed sex-dependent anomalies when orally challenged with a glucose overload, returning to baseline glucose levels after 120 min. These results open new research questions about the role of the adverse maternal metabolic condition in the programming of impairments in glucose homeostasis, enteroendocrine function and gut barrier function in the offspring from overweight mothers and highlight the importance of a perinatal maternal healthy metabolism.
Collapse
Affiliation(s)
- Florencia Heinecke
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Daiana Fornes
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Evangelina Capobianco
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Jeremias Pablo Flores Quiroga
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Marina Labiano
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Alicia G Faletti
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Alicia Jawerbaum
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina
| | - Verónica White
- Centre for Pharmacological and Botanical Studies (CEFYBO-CONICET-UBA), School of Medicine, University of Buenos Aires, Buenos Aires, Argentina.
| |
Collapse
|
|
10
|
Yadav MK, Khan ZA, Wang JH, Ansari A. Impact of Gut–Brain Axis on Hepatobiliary Diseases in Fetal Programming. JOURNAL OF MOLECULAR PATHOLOGY 2024; 5:215-227. [DOI: 10.3390/jmp5020014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025] Open
Abstract
The hepatobiliary system is vital for the biotransformation and disposition of endogenous molecules. Any impairment in the normal functioning of the hepatobiliary system leads to a spectrum of hepatobiliary diseases (HBDs), such as liver cirrhosis, fatty liver, biliary dyskinesia, gallbladder cancer, etc. Especially in pregnancy, HBD may result in increased maternal and fetal morbidity and mortality. Maternal HBD is a burden to the fetus’s growth, complicates fetal development, and risks the mother’s life. In fetal programming, the maternal mechanism is significantly disturbed by multiple factors (especially diet) that influence the development of the fetus and increase the frequency of metabolic diseases later in life. Additionally, maternal under-nutrition or over-nutrition (especially in high-fat, high-carbohydrate, or protein-rich diets) lead to dysregulation in gut hormones (CCK, GLP-1, etc.), microbiota metabolite production (SCFA, LPS, TMA, etc.), neurotransmitters (POMC, NPY, etc.), and hepatobiliary signaling (insulin resistance, TNF-a, SREBPs, etc.), which significantly impact fetal programming. Recently, biotherapeutics have provided a new horizon for treating HBD during fetal programming to save the lives of the mother and fetus. This review focuses on how maternal impaired hepatobiliary metabolic signaling leads to disease transmission to the fetus mediated through the gut–brain axis.
Collapse
Affiliation(s)
- Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda 151401, India
| | - Zeeshan Ahmad Khan
- Department of Physical Therapy, College of Health Medical Science and Engineering, Inje University, Gimhae 50834, Republic of Korea
| | - Jing-Hua Wang
- Department of Korean Medicine, Daejeon University, Daejeon 35235, Republic of Korea
| | - AbuZar Ansari
- Department of Obstetrics and Gynecology, Ewha Womans University Mokdong Hospital, Seoul 07984, Republic of Korea
| |
Collapse
|
|
11
|
Dong C, Wu G, Li H, Qiao Y, Gao S. Type 1 and type 2 diabetes mortality burden: Predictions for 2030 based on Bayesian age-period-cohort analysis of China and global mortality burden from 1990 to 2019. J Diabetes Investig 2024; 15:623-633. [PMID: 38265170 PMCID: PMC11060160 DOI: 10.1111/jdi.14146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 12/07/2023] [Accepted: 12/27/2023] [Indexed: 01/25/2024] Open
Abstract
AIMS This study assessed diabetes (type 1 and type 2) mortality in China and globally from 1990 to 2019, predicting the next decade's trends. MATERIALS AND METHODS Data came from the Global Burden of Disease (GBD) database. The annual percentage change (AAPC) in age-standardized mortality rates (ASMR) for diabetes (type 1 and type 2) during 1990-2019 was calculated. A Bayesian age-period-cohort (BAPC) model predicted diabetes (type 1 and type 2) mortality from 2020 to 2030. RESULTS In China, type 1 diabetes deaths declined from 6,005 to 4,504 cases (AAPC -2.827), while type 2 diabetes deaths rose from 64,084 to 168,388 cases (AAPC -0.763) from 1990 to 2019. Globally, type 1 diabetes deaths increased from 55,417 to 78,236 cases (AAPC 0.223), and type 2 diabetes deaths increased from 606,407 to 1,472,934 cases (AAPC 0.365). Both China and global trends showed declining type 1 diabetes ASMR. However, female type 2 diabetes ASMR in China initially increased and then decreased, while males had a rebound trend. Peak type 1 diabetes deaths were in the 40-44 age group, and type 2 diabetes peaked in those over 70. BAPC predicted declining diabetes (type 1 and type 2) mortality burden in China and globally over the next 10 years. CONCLUSIONS Type 2 diabetes mortality remained high in China and globally despite decreasing type 1 diabetes mortality over 30 years. Predictions suggest a gradual decrease in diabetes mortality over the next decade, highlighting the need for continued focus on type 2 diabetes prevention and treatment.
Collapse
Affiliation(s)
- Chunping Dong
- Department of EndocrinologyShaanxi Provincial People's HospitalXi'an CityChina
| | - Guifu Wu
- Department of EndocrinologyShaanxi Provincial People's HospitalXi'an CityChina
| | - Hui Li
- Department of EndocrinologyShaanxi Provincial People's HospitalXi'an CityChina
| | - Yuan Qiao
- Department of EndocrinologyShaanxi Provincial People's HospitalXi'an CityChina
| | - Shan Gao
- Department of EndocrinologyShaanxi Provincial People's HospitalXi'an CityChina
| |
Collapse
|
|
12
|
Peng LH, Tan Y, Bajinka O. The influence of maternal diet on offspring's gut microbiota in early life. Arch Gynecol Obstet 2024; 309:1183-1190. [PMID: 38057588 DOI: 10.1007/s00404-023-07305-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 11/12/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND The influence of maternal diet on offspring's health is an area of study that is linked to epigenetics. Maternal diet contributes to determining the health status of offspring and maternally linked mechanisms and is a global health challenge that requires attention. The impact of gut microbiota on host metabolism and offspring health is still not established. OBJECTIVE In this review, we intend to discuss the evidence on the impact of maternal diet and the health of offspring gut microbiota. The paper focuses on the gut microbiome of animal models. It captures the maternal diet and its influence on the offspring's gut microbiota, behavior that is supported by cell experimental results. Both inflammation and immune status of offspring induced by maternal diet are discussed. Finally, this review used predicted biological pathways involved in maternal diet and offspring health, and the influence of maternal diet on gut microbiota and offspring behavior. Obesity, diabetes, asthma and allergies, and neurodegenerative disorders and prospects for maternal diet, and microbiota and offspring health were discussed. CONCLUSION The review was able to gather that a high-fat diet during pregnancy created a long-lasting metabolic signature on the infant's innate immune system, altering inflammation in the offspring microbiota, which predisposed offspring to obesity and metabolic diseases in adulthood.
Collapse
Affiliation(s)
- Li-Hua Peng
- Department of Physiology, Hunan Yongzhou Vocational Technical College, Yongzhou, China
| | - Yurong Tan
- Department of Medical Microbiology, Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.
- China-Africa Research Centre of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China.
| | - Ousman Bajinka
- Department of Medical Microbiology, Xiangya School of Medicine, Central South University, Changsha, 410078, Hunan, China.
- China-Africa Research Centre of Infectious Diseases, School of Basic Medical Sciences, Central South University, Changsha, 410078, Hunan, China.
- School of Medicine and Allied Health Sciences, University of The Gambia, Serrekunda, Gambia.
| |
Collapse
|
|
13
|
Andreani GA, Mahmood S, Patel MS, Rideout TC. Maternal pea fiber supplementation to a high calorie diet in obese pregnancies protects male offspring from metabolic dysfunction in adulthood. J Dev Orig Health Dis 2023; 14:711-718. [PMID: 38234128 DOI: 10.1017/s2040174423000399] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2024]
Abstract
We investigated the influence of maternal yellow-pea fiber supplementation in obese pregnancies on offspring metabolic health in adulthood. Sixty newly-weaned female Sprague-Dawley rats were randomized to either a low-calorie control diet (CON) or high calorie obesogenic diet (HC) for 6-weeks. Obese animals were then fed either the HC diet alone or the HC diet supplemented with yellow-pea fiber (HC + FBR) for an additional 4-weeks prior to breeding and throughout gestation and lactation. On postnatal day (PND) 21, 1 male and 1 female offspring from each dam were weaned onto the CON diet until adulthood (PND 120) for metabolic phenotyping. Adult male, but not female, HC offspring demonstrated increased body weight and feed intake vs CON offspring, however no protection was offered by maternal FBR supplementation. HC male and female adult offspring demonstrated increased serum glucose and insulin resistance (HOMA-IR) compared with CON offspring. Maternal FBR supplementation improved glycemic control in male, but not female offspring. Compared with CON offspring, male offspring from HC dams demonstrated marked dyslipidemia (higher serum cholesterol, increased number of TG-rich lipoproteins, and smaller LDL particles) which was largely normalized in offspring from HC + FBR mothers. Male offspring born to obese mothers (HC) had higher hepatic TG, which tended to be lowered (p = 0.07) by maternal FBR supplementation.Supplementation of a maternal high calorie diet with yellow-pea fiber in prepregnancy and throughout gestation and lactation protects male offspring from metabolic dysfunction in the absence of any change in body weight status in adulthood.
Collapse
Affiliation(s)
- Gabriella A Andreani
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, Buffalo, NY, USA
| | - Saleh Mahmood
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, Buffalo, NY, USA
| | - Mulchand S Patel
- Biochemistry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Todd C Rideout
- Departments of Exercise and Nutrition Sciences, School of Public Health and Health Professions, Buffalo, NY, USA
| |
Collapse
|
|
14
|
Escalona R, Larqué C, Cortes D, Vilchis R, Granados-Delgado E, Sánchez A, Sánchez-Bringas G, Lugo-Martínez H. High-fat diet impairs glucose homeostasis by increased p16 beta-cell expression and alters glucose homeostasis of the progeny in a parental-sex dependent manner. Front Endocrinol (Lausanne) 2023; 14:1246194. [PMID: 37876538 PMCID: PMC10591070 DOI: 10.3389/fendo.2023.1246194] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 09/21/2023] [Indexed: 10/26/2023] Open
Abstract
Introduction Obesity consists in the accumulation of adipose tissue accompanied by low grade chronic inflammation and is considered a pandemic disease. Recent studies have observed that obesity affects females and males in a sex-dependent manner. In addition, several works have demonstrated that parental obesity increases the risk to develop obesity, insulin resistance, diabetes, and reproductive disorders. Considering that intergenerational effects of obesity may occur in a sex-dependent manner, we studied male Wistar rat progeny (F1) obtained from mothers or fathers (F0) fed on a high-fat diet (HFD). Methods Five-week-old female and male Wistar rats were fed on a HFD (with 60% of calories provided by fat) for 18 weeks (F0). At the end of the treatment, animals were mated with young rats to obtain their progeny (F1). After weaning, F1 animals were fed on standard chow until 18 weeks of age. Body weight gain, fasting plasma glucose, insulin and leptin levels, glucose tolerance, insulin sensitivity, and adiposity were evaluated. In addition, beta-cell expression of nuclear p16 was assessed by immunofluorescence. Results and conclusions HFD altered plasma fasting glucose, insulin and leptin levels, glucose tolerance, adiposity, and beta-cell expression of p16 in F0 rats. Particularly, HFD showed sexual dimorphic effects on body weight gain and insulin sensitivity. Moreover, we observed that parental HFD feeding exerts parental-sex-specific metabolic impairment in the male progeny. Finally, parental metabolic dysfunction could be in part attributed to the increased beta-cell expression of p16; other mechanisms could be involved in the offspring glucose homeostasis.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | - Haydée Lugo-Martínez
- Laboratory of Embryology and Genetics, Departamento de Embriología y Genética, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| |
Collapse
|
|
15
|
Berumen J, Orozco L, Gallardo-Rincón H, Rivas F, Barrera E, Benuto RE, García-Ortiz H, Marin-Medina M, Juárez-Torres E, Alvarado-Silva A, Ramos-Martinez E, MartÍnez-Juárez LA, Lomelín-Gascón J, Montoya A, Ortega-Montiel J, Alvarez-Hernández DA, Larriva-Shad J, Tapia-Conyer R. Sex differences in the influence of type 2 diabetes (T2D)-related genes, parental history of T2D, and obesity on T2D development: a case-control study. Biol Sex Differ 2023; 14:39. [PMID: 37291636 DOI: 10.1186/s13293-023-00521-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 05/24/2023] [Indexed: 06/10/2023] Open
Abstract
BACKGROUND This study investigated the effect of sex and age at type 2 diabetes (T2D) diagnosis on the influence of T2D-related genes, parental history of T2D, and obesity on T2D development. METHODS In this case-control study, 1012 T2D cases and 1008 healthy subjects were selected from the Diabetes in Mexico Study database. Participants were stratified by sex and age at T2D diagnosis (early, ≤ 45 years; late, ≥ 46 years). Sixty-nine T2D-associated single nucleotide polymorphisms were explored and the percentage contribution (R2) of T2D-related genes, parental history of T2D, and obesity (body mass index [BMI] and waist-hip ratio [WHR]) on T2D development was calculated using univariate and multivariate logistic regression models. RESULTS T2D-related genes influenced T2D development most in males who were diagnosed early (R2 = 23.5%; females, R2 = 13.5%; males and females diagnosed late, R2 = 11.9% and R2 = 7.3%, respectively). With an early diagnosis, insulin production-related genes were more influential in males (76.0% of R2) while peripheral insulin resistance-associated genes were more influential in females (52.3% of R2). With a late diagnosis, insulin production-related genes from chromosome region 11p15.5 notably influenced males while peripheral insulin resistance and genes associated with inflammation and other processes notably influenced females. Influence of parental history was higher among those diagnosed early (males, 19.9%; females, 17.5%) versus late (males, 6.4%; females, 5,3%). Unilateral maternal T2D history was more influential than paternal T2D history. BMI influenced T2D development for all, while WHR exclusively influenced males. CONCLUSIONS The influence of T2D-related genes, maternal T2D history, and fat distribution on T2D development was greater in males than females.
Collapse
Affiliation(s)
- Jaime Berumen
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Cuauhtémoc, 06720, Ciudad de Mexico, México.
| | - Lorena Orozco
- Instituto Nacional de Medicina Genómica, Ciudad de Mexico, México
| | - Héctor Gallardo-Rincón
- Universidad of Guadalajara, Health Sciences University Center, Guadalajara, Jalisco, México.
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México.
| | - Fernando Rivas
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Cuauhtémoc, 06720, Ciudad de Mexico, México
| | - Elizabeth Barrera
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Cuauhtémoc, 06720, Ciudad de Mexico, México
| | | | | | | | | | | | - Espiridión Ramos-Martinez
- Unidad de Investigación en Medicina Experimental, Facultad de Medicina, Universidad Nacional Autónoma de México, Cuauhtémoc, 06720, Ciudad de Mexico, México
| | - Luis Alberto MartÍnez-Juárez
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México
| | - Julieta Lomelín-Gascón
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México
| | - Alejandra Montoya
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México
| | - Janinne Ortega-Montiel
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México
| | - Diego-Abelardo Alvarez-Hernández
- Fundación Carlos Slim, Lago Zurich 245, Presa Falcon Building (Floor 20), Col. Ampliacion Granada, Miguel Hidalgo, 11529, Mexico City, México
| | - Jorge Larriva-Shad
- Instituto de Neurobiología, Universidad Nacional Autónoma de México, Juriquilla, Querétaro, México
| | - Roberto Tapia-Conyer
- Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de Mexico, México
| |
Collapse
|
|
16
|
Wang L, O'Kane AM, Zhang Y, Ren J. Maternal obesity and offspring health: Adapting metabolic changes through autophagy and mitophagy. Obes Rev 2023:e13567. [PMID: 37055041 DOI: 10.1111/obr.13567] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/08/2022] [Accepted: 03/25/2023] [Indexed: 04/15/2023]
Abstract
Maternal obesity leads to obstetric complications and a high prevalence of metabolic anomalies in the offspring. Among various contributing factors for maternal obesity-evoked health sequelae, developmental programming is considered as one of the leading culprit factors for maternal obesity-associated chronic comorbidities. Although a unified theory is still lacking to systematically address multiple unfavorable postnatal health sequelae, a cadre of etiological machineries have been put forward, including lipotoxicity, inflammation, oxidative stress, autophagy/mitophagy defect, and cell death. Hereinto, autophagy and mitophagy play an essential housekeeping role in the clearance of long-lived, damaged, and unnecessary cell components to maintain and restore cellular homeostasis. Defective autophagy/mitophagy has been reported in maternal obesity and negatively impacts fetal development and postnatal health. This review will provide an update on metabolic disorders in fetal development and postnatal health issues evoked by maternal obesity and/or intrauterine overnutrition and discuss the possible contribution of autophagy/mitophagy in metabolic diseases. Moreover, relevant mechanisms and potential therapeutic strategies will be discussed in an effort to target autophagy/mitophagy and metabolic disturbances in maternal obesity.
Collapse
Affiliation(s)
- Litao Wang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Aislinn M O'Kane
- Department of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, 46202, USA
| | - Yingmei Zhang
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| | - Jun Ren
- Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China
| |
Collapse
|
|
17
|
Lamri A, De Paoli M, De Souza R, Werstuck G, Anand S, Pigeyre M. Insight into genetic, biological, and environmental determinants of sexual-dimorphism in type 2 diabetes and glucose-related traits. Front Cardiovasc Med 2022; 9:964743. [PMID: 36505380 PMCID: PMC9729955 DOI: 10.3389/fcvm.2022.964743] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 10/21/2022] [Indexed: 11/25/2022] Open
Abstract
There is growing evidence that sex and gender differences play an important role in risk and pathophysiology of type 2 diabetes (T2D). Men develop T2D earlier than women, even though there is more obesity in young women than men. This difference in T2D prevalence is attenuated after the menopause. However, not all women are equally protected against T2D before the menopause, and gestational diabetes represents an important risk factor for future T2D. Biological mechanisms underlying sex and gender differences on T2D physiopathology are not yet fully understood. Sex hormones affect behavior and biological changes, and can have implications on lifestyle; thus, both sex-specific environmental and biological risk factors interact within a complex network to explain the differences in T2D risk and physiopathology in men and women. In addition, lifetime hormone fluctuations and body changes due to reproductive factors are generally more dramatic in women than men (ovarian cycle, pregnancy, and menopause). Progress in genetic studies and rodent models have significantly advanced our understanding of the biological pathways involved in the physiopathology of T2D. However, evidence of the sex-specific effects on genetic factors involved in T2D is still limited, and this gap of knowledge is even more important when investigating sex-specific differences during the life course. In this narrative review, we will focus on the current state of knowledge on the sex-specific effects of genetic factors associated with T2D over a lifetime, as well as the biological effects of these different hormonal stages on T2D risk. We will also discuss how biological insights from rodent models complement the genetic insights into the sex-dimorphism effects on T2D. Finally, we will suggest future directions to cover the knowledge gaps.
Collapse
Affiliation(s)
- Amel Lamri
- Department of Medicine, McMaster University, Hamilton, ON, Canada,Population Health Research Institute (PHRI), Hamilton, ON, Canada
| | - Monica De Paoli
- Department of Medicine, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute (TaARI), Hamilton, ON, Canada
| | - Russell De Souza
- Population Health Research Institute (PHRI), Hamilton, ON, Canada,Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Geoff Werstuck
- Department of Medicine, McMaster University, Hamilton, ON, Canada,Thrombosis and Atherosclerosis Research Institute (TaARI), Hamilton, ON, Canada
| | - Sonia Anand
- Department of Medicine, McMaster University, Hamilton, ON, Canada,Population Health Research Institute (PHRI), Hamilton, ON, Canada,Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Marie Pigeyre
- Department of Medicine, McMaster University, Hamilton, ON, Canada,Population Health Research Institute (PHRI), Hamilton, ON, Canada,*Correspondence: Marie Pigeyre
| |
Collapse
|
|
18
|
Denizli M, Capitano ML, Kua KL. Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring. Front Cell Infect Microbiol 2022; 12:940937. [PMID: 36189369 PMCID: PMC9523142 DOI: 10.3389/fcimb.2022.940937] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 08/23/2022] [Indexed: 12/02/2022] Open
Abstract
The prevalence of obesity is increasingly common in the United States, with ~25% of women of reproductive age being overweight or obese. Metaflammation, a chronic low grade inflammatory state caused by altered metabolism, is often present in pregnancies complicated by obesity. As a result, the fetuses of mothers who are obese are exposed to an in-utero environment that has altered nutrients and cytokines. Notably, both human and preclinical studies have shown that children born to mothers with obesity have higher risks of developing chronic illnesses affecting various organ systems. In this review, the authors sought to present the role of cytokines and inflammation during healthy pregnancy and determine how maternal obesity changes the inflammatory landscape of the mother, leading to fetal reprogramming. Next, the negative long-term impact on offspring’s health in numerous disease contexts, including offspring’s risk of developing neuropsychiatric disorders (autism, attention deficit and hyperactive disorder), metabolic diseases (obesity, type 2 diabetes), atopy, and malignancies will be discussed along with the potential of altered immune/inflammatory status in offspring as a contributor of these diseases. Finally, the authors will list critical knowledge gaps in the field of developmental programming of health and diseases in the context of offspring of mothers with obesity, particularly the understudied role of hematopoietic stem and progenitor cells.
Collapse
Affiliation(s)
- Merve Denizli
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis IN, United States
| | - Maegan L. Capitano
- Department of Microbiology & Immunology, Indiana University School of Medicine, Indianapolis IN, United States
| | - Kok Lim Kua
- Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis IN, United States
- *Correspondence: Kok Lim Kua,
| |
Collapse
|
|
19
|
Perinatal exposure to isocaloric diet with moderate-fat promotes pancreatic islets insulin hypersecretion and susceptibility to islets exhaustion in response to fructose intake in adult male rat offspring. Life Sci 2022; 307:120873. [PMID: 35952730 DOI: 10.1016/j.lfs.2022.120873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/31/2022] [Accepted: 08/05/2022] [Indexed: 11/21/2022]
Abstract
AIMS Perinatal maternal hypercaloric diets increase the susceptibility to metabolic disorders in the offspring. We hypothesized that maternal intake of an isocaloric moderate-fat diet (mMFD) would disturb the glucose homeostasis and favor the β-cell failure in response to fructose overload in adult male offspring. METHODS Female Wistar rats received an isocaloric diet (3.9 kcal/g) containing 29 % (mMFD) or 9 % as fat (mSTD) prior mating and throughout gestation and lactation. After weaning, male offspring received standard chow and fructose-drinking water (15 %) between 120 and 150 days old. KEY FINDINGS mMFD offspring had higher body weight, visceral adiposity and, fasting glycemia, with normal insulinemia. Fructose increased glycemia at 15 min from oral glucose administration, but only mMFD had returned to basal glucose levels at 120 min. Fructose increased HOMA-IR index regardless diet, but only mMFD exhibited hyperinsulinemia and a higher HOMA-β index. mMFD pancreatic islets showed increased area and insulin immunostaining density, suggesting β-cell hypertrophy. Fructose induced the expected compensatory hypertrophy in mSTD islets, while the opposite occurred in mMFD islets, associated with reduced insulin immunostaining, suggesting lower insulin storage. Pancreatic islets isolated from mMFD offspring exhibited higher glucose-stimulated insulin release at physiological concentrations. However, at higher glucose concentrations, the islets from fructose-treated mMFD reduced dramatically their insulin release, suggesting exhaustion. SIGNIFICANCE Isocaloric mMFD induced adaptive mechanism in the offspring allowing insulin hypersecretion, but under metabolic challenge with fructose, β-cell compensation shifts to exhaustion, favoring dysfunction. Therefore, a maternal MFD may contribute to developing diabetes under fructose overload in the adult offspring.
Collapse
|
|
20
|
Programming by maternal obesity: a pathway to poor cardiometabolic health in the offspring. Proc Nutr Soc 2022; 81:227-242. [DOI: 10.1017/s0029665122001914] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
There is an ever increasing prevalence of maternal obesity worldwide such that in many populations over half of women enter pregnancy either overweight or obese. This review aims to summarise the impact of maternal obesity on offspring cardiometabolic outcomes. Maternal obesity is associated with increased risk of adverse maternal and pregnancy outcomes. However, beyond this exposure to maternal obesity during development also increases the risk of her offspring developing long-term adverse cardiometabolic outcomes throughout their adult life. Both human studies and those in experimental animal models have shown that maternal obesity can programme increased risk of offspring developing obesity and adipose tissue dysfunction; type 2 diabetes with peripheral insulin resistance and β-cell dysfunction; CVD with impaired cardiac structure and function and hypertension via impaired vascular and kidney function. As female offspring themselves are therefore likely to enter pregnancy with poor cardiometabolic health this can lead to an inter-generational cycle perpetuating the transmission of poor cardiometabolic health across generations. Maternal exercise interventions have the potential to mitigate some of the adverse effects of maternal obesity on offspring health, although further studies into long-term outcomes and how these translate to a clinical context are still required.
Collapse
|
|
21
|
Chen Y, Duan F, Liu L, Chen G, He Z, Huang H, Wang H. Sex differences and heritability of adrenal steroidogenesis in offspring rats induced by prenatal nicotine exposure. J Steroid Biochem Mol Biol 2022; 221:106102. [PMID: 35367371 DOI: 10.1016/j.jsbmb.2022.106102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/24/2022] [Accepted: 03/28/2022] [Indexed: 12/28/2022]
Abstract
The epidemiological investigation has suggested prenatal nicotine exposure (PNE) induces multiorgan developmental toxicity and increases the risk of metabolic diseases in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with abnormal adrenal development in offspring. However, the long-term harmful effects on adrenal development in offspring induced by PNE remain unclear. Pregnant Wistar rats were injected subcutaneously with nicotine (2 mg/kg·d) from gestation day (GD) 9 to GD20 to obtain the adrenal gland from fetal and adult offspring rats of F1 and F2 generations. We found that the adrenal insulin-like growth factor 1 (IGF1) signaling pathway and steroidogenic function were increased in male while decreased in female of PNE fetal rats, which could extend into adulthood. Furthermore, the primary adrenal cells of fetal rats were treated with nicotine to observe the phenomena and clarify the possible mechanism of the sex difference. The results suggested that there are sex differences in IGF1 signaling pathway and steroidogenic function induced by PNE, which may be associated with sex differences in nAChRβ1 expression. In addition, the adrenal steroidogenic function was reduced in F2 offspring of F1 PNE female rats (regardless of mating with control or Male PNE rats). Therefore, the decrease of adrenal steroidogenic function in female offspring rats induced by PNE has maternal heritability. In conclusion, PNE could lead to sex differences and heritability of adrenal steroidogenic function in offspring rats.
Collapse
Affiliation(s)
- Yawen Chen
- Department of Pharmacology, Basic Medical College of Wuhan University, Wuhan 430071, China
| | - Fangfang Duan
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Lian Liu
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China; Department of Pharmacology, Medical College of Yangtze University, Jingzhou 434023, China
| | - Guanghui Chen
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Zheng He
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Hegui Huang
- Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China
| | - Hui Wang
- Department of Pharmacology, Basic Medical College of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
| |
Collapse
|
|
22
|
Saullo C, Cruz LLD, Damasceno DC, Volpato GT, Sinzato YK, Karki B, Gallego FQ, Vesentini G. Effects of a maternal high-fat diet on adipose tissue in murine offspring: A systematic review and meta-analysis. Biochimie 2022; 201:18-32. [PMID: 35779649 DOI: 10.1016/j.biochi.2022.06.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 05/10/2022] [Accepted: 06/21/2022] [Indexed: 12/09/2022]
Abstract
The aim of this systematic review and meta-analysis was to analyze the influence of a maternal and/or offspring high-fat diet (HFD) on the morphology of the offspring adipocytes and amount of food and energy consumption. The search was conducted through Pubmed, EMBASE, and Web of Science databases up to October 31st, 2021. The outcomes were extracted and pooled as a standardized mean difference with random effect models. 5,004 articles were found in the databases. Of these, only 31 were selected for this systematic review and 21 were included in the meta-analysis. A large discrepancy in the percentage of fat composing the HFD (from 14% to 62% fat content) was observed. Considering the increase of adipose tissue by hyperplasia (cell number increase) and hypertrophy (cell size increase) in HFD models, the meta-analysis showed that excessive consumption of a maternal HFD influences the development of visceral white adipose tissue in offspring, related to adipocyte hypertrophy, regardless of their HFD or control diet consumption. Upon following a long-term HFD, hyperplasia was confirmed in the offspring. When analyzing the secondary outcome in terms of the amount of food and energy consumed, there was an increase of caloric intake in the offspring fed with HFD whose mothers consumed HFD. Furthermore, the adipocyte hypertrophy in different regions of the adipose tissue is related to the sex of the pups. Thus, the adipose tissue obesity phenotypes in offspring are programmed by maternal consumption of a high-fat diet, independent of postnatal diet.
Collapse
Affiliation(s)
- Carolina Saullo
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil
| | - Larissa Lopes da Cruz
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil; Laboratory of System Physiology and Reproductive Toxicology, Institute of Biological and Health Sciences, Federal University of Mato Grosso (UFMT), Barra do Garças, Mato Grosso State, Brazil
| | - Débora Cristina Damasceno
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil
| | - Gustavo Tadeu Volpato
- Laboratory of System Physiology and Reproductive Toxicology, Institute of Biological and Health Sciences, Federal University of Mato Grosso (UFMT), Barra do Garças, Mato Grosso State, Brazil
| | - Yuri Karen Sinzato
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil
| | - Barshana Karki
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil
| | - Franciane Quintanilha Gallego
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil
| | - Giovana Vesentini
- Laboratory of Experimental Research on Gynecology and Obstetrics, Postgraduate Course on Tocogynecology, Botucatu Medical School, Sao Paulo State University (UNESP), Botucatu, São Paulo State, Brazil.
| |
Collapse
|
|
23
|
Rodents on a high-fat diet born to mothers with gestational diabetes exhibit sex-specific lipidomic changes in reproductive organs. Acta Biochim Biophys Sin (Shanghai) 2022; 54:736-747. [PMID: 35643955 PMCID: PMC9828243 DOI: 10.3724/abbs.2022052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Maternal gestatonal diabetes mellitus (GDM) and offspring high-fat diet (HFD) have been shown to have sex-specific detrimental effects on the health of the offspring. Maternal GDM combined with an offspring HFD alters the lipidomic profiles of offspring reproductive organs with sex hormones and increases insulin signaling, resulting in offspring obesity and diabetes. The pre-pregnancy maternal GDM mice model is established by feeding maternal C57BL/6 mice and their offspring are fed with either a HFD or a low-fat diet (LFD). Testis, ovary and liver are collected from offspring at 20 weeks of age. The lipidomic profiles of the testis and ovary are characterized using gas chromatography-mass spectrometry. Male offspring following a HFD have elevated body weight. In reproductive organs and hormones, male offspring from GDM mothers have decreased testes weights and testosterone levels, while female offspring from GDM mothers show increased ovary weights and estrogen levels. Maternal GDM aggravates the effects of an offspring HFD in male offspring on the AKT pathway, while increasing the risk of developing inflammation when expose to a HFD in female offspring liver. Testes are prone to the effect of maternal GDM, whereas ovarian metabolite profiles are upregulated in maternal GDM and downregulated in offspring following an HFD. Maternal GDM and an offspring HFD have different metabolic effects on offspring reproductive organs, and PUFAs may protect against detrimental outcomes in the offspring, such as obesity and diabetes.
Collapse
|
|
24
|
Sasaki A, Murphy KE, Briollais L, McGowan PO, Matthews SG. DNA methylation profiles in the blood of newborn term infants born to mothers with obesity. PLoS One 2022; 17:e0267946. [PMID: 35500004 PMCID: PMC9060365 DOI: 10.1371/journal.pone.0267946] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 04/19/2022] [Indexed: 01/03/2023] Open
Abstract
Maternal obesity is an important risk factor for childhood obesity and influences the prevalence of metabolic diseases in offspring. As childhood obesity is influenced by postnatal factors, it is critical to determine whether children born to women with obesity during pregnancy show alterations that are detectable at birth. Epigenetic mechanisms such as DNA methylation modifications have been proposed to mediate prenatal programming. We investigated DNA methylation signatures in male and female infants from mothers with a normal Body Mass Index (BMI 18.5-24.9 kg/m2) compared to mothers with obesity (BMI≥30 kg/m2). BMI was measured during the first prenatal visit from women recruited into the Ontario Birth Study (OBS) at Mount Sinai Hospital in Toronto, ON, Canada. DNA was extracted from neonatal dried blood spots collected from heel pricks obtained 24 hours after birth at term (total n = 40) from women with a normal BMI and women with obesity matched for parity, age, and neonatal sex. Reduced representation bisulfite sequencing was used to identify genomic loci associated with differentially methylated regions (DMRs) in CpG-dense regions most likely to influence gene regulation. DMRs were predominantly localized to intergenic regions and gene bodies, with only 9% of DMRs localized to promoter regions. Genes associated with DMRs were compared to those from a large publicly available cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC; total n = 859). Hypergeometric tests revealed a significant overlap in genes associated with DMRs in the OBS and ALSPAC cohorts. PTPRN2, a gene involved in insulin secretion, and MAD1L1, which plays a role in the cell cycle and tumor suppression, contained DMRs in males and females in both cohorts. In males, KEGG pathway analysis revealed significant overrepresentation of genes involved in endocytosis and pathways in cancer, including IGF1R, which was previously shown to respond to diet-induced metabolic stress in animal models and in lymphocytes in the context of childhood obesity. These preliminary findings are consistent with Developmental Origins of Health and Disease paradigm, which posits that adverse prenatal exposures set developmental health trajectories.
Collapse
Affiliation(s)
- Aya Sasaki
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Kellie E. Murphy
- Department of Obstetrics & Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Laurent Briollais
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
| | - Patrick O. McGowan
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Psychology, University of Toronto, Toronto, Ontario, Canada
- Departments of Biological Sciences and Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada
| | - Stephen G. Matthews
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
- Department of Obstetrics & Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
25
|
Korsmo HW, Dave B, Trasino S, Saxena A, Liu J, Caviglia JM, Edwards K, Dembitzer M, Sheeraz S, Khaldi S, Jiang X. Maternal Choline Supplementation and High-Fat Feeding Interact to Influence DNA Methylation in Offspring in a Time-Specific Manner. Front Nutr 2022; 9:841787. [PMID: 35165655 PMCID: PMC8837519 DOI: 10.3389/fnut.2022.841787] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/07/2022] [Indexed: 11/18/2022] Open
Abstract
Maternal methyl donor supplementation during pregnancy has demonstrated lasting influence on offspring DNA methylation. However, it is unknown whether an adverse postnatal environment, such as high-fat (HF) feeding, overrides the influence of prenatal methyl donor supplementation on offspring epigenome. In this study, we examined whether maternal supplementation of choline (CS), a methyl donor, interacts with prenatal and postnatal HF feeding to alter global and site-specific DNA methylation in offspring. We fed wild-type C57BL/6J mouse dams a HF diet with or without CS throughout gestation. After weaning, the offspring were exposed to HF feeding for 6 weeks resembling a continued obesogenic environment. Our results suggest that maternal CS under the HF condition (HFCS) increased global DNA methylation and DNA methyltransferase 1 (Dnmt1) expression in both fetal liver and brain. However, during the postnatal period, HFCS offspring demonstrated lower global DNA methylation and Dnmt1 expression was unaltered in both the liver and visceral adipose tissue. Site-specific DNA methylation analysis during both fetal and postnatal periods demonstrated that HFCS offspring had higher methylation of CpGs in the promoter of Srebf1, a key mediator of de novo lipogenesis. In conclusion, the influence of maternal CS on offspring DNA methylation is specific to HF feeding status during prenatal and postnatal periods. Without continued CS during the postnatal period, global DNA methylation enhanced by prenatal CS in the offspring was overridden by postnatal HF feeding.
Collapse
Affiliation(s)
- Hunter W. Korsmo
- Department of Biochemistry, The Graduate Center, City University of New York (CUNY), New York, NY, United States
- Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Bhoomi Dave
- Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Steven Trasino
- School of Urban Public Health, Hunter College of the CUNY, New York, NY, United States
| | - Anjana Saxena
- Department of Biochemistry, The Graduate Center, City University of New York (CUNY), New York, NY, United States
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Jia Liu
- Advanced Science Research Center at the Graduate Center of the CUNY, New York, NY, United States
| | - Jorge Matias Caviglia
- Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Kaydine Edwards
- Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Moshe Dembitzer
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Shameera Sheeraz
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Sarah Khaldi
- Department of Biology, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| | - Xinyin Jiang
- Department of Biochemistry, The Graduate Center, City University of New York (CUNY), New York, NY, United States
- Department of Health and Nutrition Sciences, Brooklyn College of the City University of New York, Brooklyn, NY, United States
| |
Collapse
|
|
26
|
Oxidative Stress Profile of Mothers and Their Offspring after Maternal Consumption of High-Fat Diet in Rodents: A Systematic Review and Meta-Analysis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:9073859. [PMID: 34868458 PMCID: PMC8636978 DOI: 10.1155/2021/9073859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 09/27/2021] [Accepted: 10/26/2021] [Indexed: 01/03/2023]
Abstract
Maternal exposure to the high-fat diet (HFD) during gestation or lactation can be harmful to both a mother and offspring. The aim of this systematic review was to identify and evaluate the studies with animal models (rodents) that were exposed to the high-fat diet during pregnancy and/or lactation period to investigate oxidative stress and lipid and liver enzyme profile of mothers and their offspring. The electronic search was performed in the PUBMED (Public/Publisher MEDLINE), EMBASE (Ovid), and Web of Science databases. Data from 77 studies were included for qualitative analysis, and of these, 13 studies were included for meta-analysis by using a random effects model. The pooled analysis revealed higher malondialdehyde levels in offspring of high-fat diet groups. Furthermore, the pooled analysis showed increased reactive oxygen species and lower superoxide dismutase and catalase in offspring of mothers exposed to high-fat diet during pregnancy and/or lactation. Despite significant heterogeneity, the systematic review shows oxidative stress in offspring induced by maternal HFD.
Collapse
|
|
27
|
Schoonejans JM, Ozanne SE. Developmental programming by maternal obesity: Lessons from animal models. Diabet Med 2021; 38:e14694. [PMID: 34553414 DOI: 10.1111/dme.14694] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/29/2021] [Accepted: 09/20/2021] [Indexed: 12/15/2022]
Abstract
The obesity epidemic has led to more women entering pregnancy overweight or obese. In addition to adverse short-term outcomes, maternal obesity and/or gestational diabetes predispose offspring to developing obesity, type 2 diabetes and cardiovascular disease in adulthood through developmental programming. Human epidemiological studies, although vital in identifying associations, are often unable to address causality and mechanistic studies can be limited by the lack of accessibility of key metabolic tissues. Furthermore, multi-generational studies take many years to complete. Integration of findings from human studies with those from animal models has therefore been critical in moving forward this field that has been termed the 'Developmental Origins of Health and Disease'. This review summarises the evidence from animal models and highlights how animal models provide valuable insight into the maternal factors responsible for developmental programming, potential critical developmental windows, sexual dimorphism, molecular mechanisms and age-related offspring outcomes throughout life. Moreover, we describe how animal models are vital to explore clinically relevant interventions to prevent adverse offspring outcomes in obese or glucose intolerant pregnancy, such as antioxidant supplementation, exercise and maternal metformin treatment.
Collapse
Affiliation(s)
- Josca Mariëtte Schoonejans
- Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| | - Susan Elizabeth Ozanne
- Wellcome-MRC Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Cambridge, UK
| |
Collapse
|
|
28
|
Ramalingam L, Menikdiwela KR, Spainhour S, Eboh T, Moustaid-Moussa N. Sex Differences in Early Programming by Maternal High Fat Diet Induced-Obesity and Fish Oil Supplementation in Mice. Nutrients 2021; 13:3703. [PMID: 34835957 PMCID: PMC8625698 DOI: 10.3390/nu13113703] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/06/2021] [Accepted: 10/10/2021] [Indexed: 12/16/2022] Open
Abstract
Pre-pregnancy obesity is a contributing factor for impairments in offspring metabolic health. Interventional strategies during pregnancy are a potential approach to alleviate and/or prevent obesity and obesity related metabolic alterations in the offspring. Fish oil (FO), rich in omega-3 polyunsaturated fatty acids (n-3 PUFAs) exerts metabolic health benefits. However, the role of FO in early life remains still unknown. Hence, this study objective was to determine the effect of FO supplementation in mice from pre-pregnancy through lactation, and to study the post-natal metabolic health effects in gonadal fat and liver of offspring fed high fat (HF) diet with or without FO. Female C57BL6J mice aged 4-5 weeks were fed a HF (45% fat) diet supplemented with or without FO (30 g/kg of diet) and low fat (LF; 10% fat) pre-pregnancy through lactation. After weaning, offspring (male and female) from HF or FO dams either continued the same diet (HF-HF and FO-FO) or switched to the other diet (HF-FO and FO-HF) for 13 weeks, creating four groups of treatment, and LF-LF was used as a control group. Serum, gonadal fat and liver tissue were collected at termination for metabolic analyses. Offspring of both sexes fed HF with or without fish oil gained (p < 0.05) more weight post weaning, compared to LF-LF-fed mice. All the female offspring groups supplemented with FO had reduced body weight compared to the respective male groups. Further, FO-FO supplementation in both sexes (p < 0.05) improved glucose clearance and insulin sensitivity compared to HF-HF. All FO-FO fed mice had significantly reduced adipocyte size compared to HF-HF group in both male and females. Inflammation, measured by mRNA levels of monocyte chemoattractant protein 1 (Mcp1), was reduced (p < 0.05) with FO supplementation in both sexes in gonadal fat and in the liver. Markers of fatty acid synthesis, fatty acid synthase (Fasn) showed no sex specific differences in gonadal fat and liver of mice supplemented with HF. Female mice had lower liver triglycerides than male counterparts. Supplementation of FO in mice improved metabolic health of offspring by lowering markers of lipid synthesis and inflammation.
Collapse
Affiliation(s)
- Latha Ramalingam
- Department of Nutritional Sciences and Obesity Research Institute, Texas Tech University, Lubbock, TX 74909, USA; (L.R.); (K.R.M.); (S.S.); (T.E.)
- Department of Nutrition and Food Studies, Syracuse University, Syracuse, NY 13244, USA
| | - Kalhara R. Menikdiwela
- Department of Nutritional Sciences and Obesity Research Institute, Texas Tech University, Lubbock, TX 74909, USA; (L.R.); (K.R.M.); (S.S.); (T.E.)
| | - Stephani Spainhour
- Department of Nutritional Sciences and Obesity Research Institute, Texas Tech University, Lubbock, TX 74909, USA; (L.R.); (K.R.M.); (S.S.); (T.E.)
| | - Tochi Eboh
- Department of Nutritional Sciences and Obesity Research Institute, Texas Tech University, Lubbock, TX 74909, USA; (L.R.); (K.R.M.); (S.S.); (T.E.)
| | - Naima Moustaid-Moussa
- Department of Nutritional Sciences and Obesity Research Institute, Texas Tech University, Lubbock, TX 74909, USA; (L.R.); (K.R.M.); (S.S.); (T.E.)
| |
Collapse
|
|
29
|
Smith BL. Improving translational relevance: The need for combined exposure models for studying prenatal adversity. Brain Behav Immun Health 2021; 16:100294. [PMID: 34589787 PMCID: PMC8474200 DOI: 10.1016/j.bbih.2021.100294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 06/28/2021] [Accepted: 06/29/2021] [Indexed: 12/18/2022] Open
Abstract
Prenatal environmental adversity is a risk factor for neurodevelopmental disorders (NDDs), with the neuroimmune environment proposed to play a role in this risk. Adverse maternal exposures are associated with cognitive consequences in the offspring that are characteristics of NDDs and simultaneous neuroimmune changes that may underlie NDD risk. In both animal models and human studies the association between prenatal environmental exposure and NDD risk has been shown to be complex. Maternal overnutrition/obesity and opioid use are two different examples of complex exposure epidemics, each with their own unique comorbidities. This review will examine maternal obesity and maternal opioid use separately, illustrating the pervasive comorbidities with each exposure to argue a need for animal models of compound prenatal exposures. Many of these comorbidities can impact neuroimmune function, warranting systematic investigation of combined exposures to begin to understand this complexity. While traditional approaches in animal models have focused on modeling a single prenatal exposure or second exposure later in life, a translational approach would begin to incorporate the most prevalent co-occurring prenatal exposures. Long term follow-up in humans is extremely challenging, so animal models can provide timely insight into neurodevelopmental consequences of complex prenatal exposures. Animal models that represent this translational context of comorbid exposures behind maternal obesity or comorbid exposures behind maternal opioid use may reveal potential synergistic neuroimmune interactions that contribute to cognitive consequences and NDD risk. Finally, translational co-exposure models can identify concerning exposure combinations to guide treatment in complex cases, and identify high risk children starting in the prenatal period where early interventions improve prognosis.
Collapse
Affiliation(s)
- Brittany L. Smith
- Department of Pharmacology & Systems Physiology, University of Cincinnati, Cincinnati, OH, USA
| |
Collapse
|
|
30
|
Understanding the Long-Lasting Effects of Fetal Nutrient Restriction versus Exposure to an Obesogenic Diet on Islet-Cell Mass and Function. Metabolites 2021; 11:metabo11080514. [PMID: 34436455 PMCID: PMC8401811 DOI: 10.3390/metabo11080514] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/14/2022] Open
Abstract
Early life represents a window of phenotypic plasticity. Thus, exposure of the developing fetus to a compromised nutritional environment can have long term consequences for their health. Indeed, undernutrition or maternal intake of an obesogenic diet during pregnancy leads to a heightened risk of type 2 diabetes (T2D) and obesity in her offspring in adult life. Given that abnormalities in beta-cell function are crucial in delineating the risk of T2D, studies have investigated the impact of these exposures on islet morphology and beta-cell function in the offspring in a bid to understand why they are more at risk of T2D. Interestingly, despite the contrasting maternal metabolic phenotype and, therefore, intrauterine environment associated with undernutrition versus high-fat feeding, there are a number of similarities in the genes/biological pathways that are disrupted in offspring islets leading to changes in function. Looking to the future, it will be important to define the exact mechanisms involved in mediating changes in the gene expression landscape in islet cells to determine whether the road to T2D development is the same or different in those exposed to different ends of the nutritional spectrum.
Collapse
|
|
31
|
Martins MG, Cruz AGD, Oliveira GPD, Woodside B, Horta-Júnior JDADCE, Kiss ACI. Effects of snack intake during pregnancy and lactation on reproductive outcome in mild hyperglycemic rats. Physiol Behav 2021; 240:113544. [PMID: 34332976 DOI: 10.1016/j.physbeh.2021.113544] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 07/23/2021] [Accepted: 07/25/2021] [Indexed: 11/17/2022]
Abstract
Metabolic disorders, like diabetes, as well as maternal diet, alter nutrient availability in utero, inducing adaptations in the offspring. Whether the effects of maternal hyperglycemia are modulated by diet, however, has yet to be explored. In the current study, we examined this issue by giving females rats, treated neonatally with STZ to induce mild hyperglycemia, and control littermates either ad libitum access to standard chow (Control n = 17; STZ n = 16) or standard chow and snacks (Control-snack n = 18; STZ-snack n = 19) (potato chips and a red fruit-flavored sucrose syrup solution 1.5%) throughout pregnancy and lactation. We hypothesized that the maternal glucose intolerance typically seen in female rats treated neonatally with STZ would be exacerbated by snack intake, and that the combination of snack intake and STZ treatment would lead to alterations in maternal behavior and offspring development. Maternal body weight and food intake were measured daily through pregnancy and lactation and litter weight throughout lactation. At birth, litter size, offspring weight, body length, and anogenital distance were obtained and offspring were classified according to their weight. Measures of nursing and retrieval behavior, as well as exploration in the open field and the elevated plus-maze were also recorded. As predicted, snack intake tended to aggravate the glucose intolerance of STZ-treated rats during pregnancy. Both Control and STZ-treated females that had access to snacks ate more calories and fat, but less carbohydrate and protein than females having access to chow alone. Overall, STZ-treated dams gave birth to fewer pups. Chow-fed STZ females gave birth to a greater proportion of large for pregnancy age pups, whereas dams in the Control-snack group gave birth to a greater proportion of small pups. The birth weight classification of pups born to STZ-snack rats, however, resembled that of the Control chow-fed females. Although all litters gained weight during lactation, litters from snack-fed dams gained less weight regardless of maternal hyperglycemia and did not show catch-up growth by weaning. Overall, STZ rats spent more time nest building, whereas the average inter milk ejection interval was higher in snack-fed females. STZ-snack dams retrieved the complete litter faster than dams in the other groups. Together, these data suggest that when mild hyperglycemic females are given access to snacks throughout pregnancy and lactation their intake is similar to that of Control females given snack access. The combination of hyperglycemia and snack access tended to decrease glucose tolerance in pregnancy, and normalized birth weight classification, but produced few other effects that were not seen as a function of snack intake or hyperglycemia alone. Since birth weight is a strong predictor of health issues, future studies will further investigate offspring behavioral and metabolic outcomes later in life.
Collapse
Affiliation(s)
- Marina Galleazzo Martins
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil.
| | - Alessandra Gonçalves da Cruz
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Giovana Pereira de Oliveira
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Barbara Woodside
- Center for Studies in Behavioral Neurobiology, Psychology Department, Concordia University, 7141 Sherbrooke St. W., Montreal, Quebec, Canada H4B 1R6
| | - José de Anchieta de Castro E Horta-Júnior
- São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| | - Ana Carolina Inhasz Kiss
- Department of Physiology, Institute of Biosciences of the University of São Paulo (IB/USP), Rua do Matão, trav. 14, 321, Cidade Universitária, São Paulo, São Paulo, 05508-090, Brazil; São Paulo State University (Unesp), Institute of Biosciences, Department of Structural and Functional Biology, Rua Prof. Dr. Antonio Celso Wagner Zanin, s/n, Botucatu, São Paulo, 18618-689, Brazil
| |
Collapse
|
|
32
|
Maternal Metformin Intervention during Obese Glucose-Intolerant Pregnancy Affects Adiposity in Young Adult Mouse Offspring in a Sex-Specific Manner. Int J Mol Sci 2021; 22:ijms22158104. [PMID: 34360870 PMCID: PMC8347264 DOI: 10.3390/ijms22158104] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/18/2021] [Accepted: 07/26/2021] [Indexed: 11/17/2022] Open
Abstract
Background: Metformin is commonly used to treat gestational diabetes mellitus. This study investigated the effect of maternal metformin intervention during obese glucose-intolerant pregnancy on the gonadal white adipose tissue (WAT) of 8-week-old male and female mouse offspring. Methods: C57BL/6J female mice were provided with a control (Con) or obesogenic diet (Ob) to induce pre-conception obesity. Half the obese dams were treated orally with 300 mg/kg/d of metformin (Ob-Met) during pregnancy. Gonadal WAT depots from 8-week-old offspring were investigated for adipocyte size, macrophage infiltration and mRNA expression of pro-inflammatory genes using RT-PCR. Results: Gestational metformin attenuated the adiposity in obese dams and increased the gestation length without correcting the offspring in utero growth restriction and catch-up growth caused by maternal obesity. Despite similar body weight, the Ob and Ob-Met offspring of both sexes showed adipocyte hypertrophy in young adulthood. Male Ob-Met offspring had increased WAT depot weight (p < 0.05), exaggerated adipocyte hyperplasia (p < 0.05 vs. Con and Ob offspring), increased macrophage infiltration measured via histology (p < 0.05) and the mRNA expression of F4/80 (p < 0.05). These changes were not observed in female Ob-Met offspring. Conclusions: Maternal metformin intervention during obese pregnancy causes excessive adiposity, adipocyte hyperplasia and WAT inflammation in male offspring, highlighting sex-specific effects of prenatal metformin exposure on offspring WAT.
Collapse
|
|
33
|
Liu G, Li Y, Zhang T, Li M, Li S, He Q, Liu S, Xu M, Xiao T, Shao Z, Shi W, Li W. Single-cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells. GENOMICS, PROTEOMICS & BIOINFORMATICS 2021; 19:408-422. [PMID: 34571259 PMCID: PMC8864195 DOI: 10.1016/j.gpb.2021.07.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/02/2021] [Accepted: 08/01/2021] [Indexed: 12/25/2022]
Abstract
Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.
Collapse
Affiliation(s)
- Gang Liu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Yana Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tengjiao Zhang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China
| | - Mushan Li
- Department of Statistics, The Pennsylvania State University, University Park, PA 16802, USA
| | - Sheng Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Qing He
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Shuxin Liu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Minglu Xu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Tinghui Xiao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China
| | - Zhen Shao
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Weiyang Shi
- Ministry of Education Key Laboratory of Marine Genetics and Breeding, College of Marine Life Sciences, Ocean University of China, Qingdao 266003, China.
| | - Weida Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China; Tsingtao Advanced Research Institute, Tongji University, Qingdao 266073, China.
| |
Collapse
|
|
34
|
Peng H, Xu H, Wu J, Li J, Zhou Y, Ding Z, Siwko SK, Yuan X, Schalinske KL, Alpini G, Zhang KK, Xie L. Maternal high-fat diet disrupted one-carbon metabolism in offspring, contributing to nonalcoholic fatty liver disease. Liver Int 2021; 41:1305-1319. [PMID: 33529448 PMCID: PMC8137550 DOI: 10.1111/liv.14811] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/12/2021] [Accepted: 01/28/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Pregnant women may transmit their metabolic phenotypes to their offspring, enhancing the risk for nonalcoholic fatty liver disease (NAFLD); however, the molecular mechanisms remain unclear. METHODS Prior to pregnancy female mice were fed either a maternal normal-fat diet (NF-group, "no effectors"), or a maternal high-fat diet (HF-group, "persistent effectors"), or were transitioned from a HF to a NF diet before pregnancy (H9N-group, "effectors removal"), followed by pregnancy and lactation, and then offspring were fed high-fat diets after weaning. Offspring livers were analysed by functional studies, as well as next-generation sequencing for gene expression profiles and DNA methylation changes. RESULTS The HF, but not the H9N offspring, displayed glucose intolerance and hepatic steatosis. The HF offspring also displayed a disruption of lipid homeostasis associated with an altered methionine cycle and abnormal one-carbon metabolism that caused DNA hypermethylation and L-carnitine depletion associated with deactivated AMPK signalling and decreased expression of PPAR-α and genes for fatty acid oxidation. These changes were not present in H9N offspring. In addition, we identified maternal HF diet-induced genes involved in one-carbon metabolism that were associated with DNA methylation modifications in HF offspring. Importantly, the DNA methylation modifications and their associated gene expression changes were reversed in H9N offspring livers. CONCLUSIONS Our results demonstrate for the first time that maternal HF diet disrupted the methionine cycle and one-carbon metabolism in offspring livers which further altered lipid homeostasis. CpG islands of specific genes involved in one-carbon metabolism modified by different maternal diets were identified.
Collapse
Affiliation(s)
- Hui Peng
- Department of Nutrition, Texas A&M University, College Station, TX,Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Huiting Xu
- Department of Pathology, University of North Dakota, Grand Forks, North Dakota,Hubei Cancer Hospital, Wuhan, Hubei, China
| | - Jie Wu
- Institute of Biosciences & Technology, Texas A&M University, Houston, TX
| | - Jiangyuan Li
- Department of Nutrition, Texas A&M University, College Station, TX,Department of Statistics, Texas A&M University, College Station, TX
| | - Yi Zhou
- Department of Nutrition, Texas A&M University, College Station, TX,Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zehuan Ding
- Department of Nutrition, Texas A&M University, College Station, TX
| | - Stefan K. Siwko
- Institute of Biosciences & Technology, Texas A&M University, Houston, TX
| | - Xianglin Yuan
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kevin L. Schalinske
- Department of Food Science and Human Nutrition, Iowa State University, Ames, IA
| | - Gianfranco Alpini
- Richard L. Roudebush VA Medical Center, and Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Ke K. Zhang
- Department of Nutrition, Texas A&M University, College Station, TX,Institute of Biosciences & Technology, Texas A&M University, Houston, TX,Department of Pathology, University of North Dakota, Grand Forks, North Dakota,Co-corresponding author: These authors contributed equally to this work
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX,Co-corresponding author: These authors contributed equally to this work
| |
Collapse
|
|
35
|
Casasnovas J, Damron CL, Jarrell J, Orr KS, Bone RN, Archer-Hartmann S, Azadi P, Kua KL. Offspring of Obese Dams Exhibit Sex-Differences in Pancreatic Heparan Sulfate Glycosaminoglycans and Islet Insulin Secretion. Front Endocrinol (Lausanne) 2021; 12:658439. [PMID: 34108935 PMCID: PMC8181410 DOI: 10.3389/fendo.2021.658439] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Offspring of obese mothers suffer higher risks of type 2 diabetes due to increased adiposity and decreased β cell function. To date, the sex-differences in offspring islet insulin secretion during early life has not been evaluated extensively, particularly prior to weaning at postnatal day 21 (P21). To determine the role of maternal obesity on offspring islet insulin secretion, C57BL/6J female dams were fed chow or western diet from 4 weeks prior to mating to induce maternal obesity. First, offspring of chow-fed and obese dams were evaluated on postnatal day 21 (P21) prior to weaning for body composition, glucose and insulin tolerance, and islet phasic insulin-secretion. Compared to same-sex controls, both male and female P21 offspring born to obese dams (MatOb) had higher body adiposity and exhibited sex-specific differences in glucose tolerance and insulin secretion. The male MatOb offspring developed the highest extent of glucose intolerance and lowest glucose-induced insulin secretion. In contrast, P21 female offspring of obese dams had unimpaired insulin secretion. Using SAX-HPLC, we found that male MatOb had a decrease in pancreatic heparan sulfate glycosaminoglycan, which is a macromolecule critical for islet health. Notably, 8-weeks-old offspring of obese dams continued to exhibit a similar pattern of sex-differences in glucose intolerance and decreased islet insulin secretion. Overall, our study suggests that maternal obesity induces sex-specific changes to pancreatic HSG in offspring and a lasting effect on offspring insulin secretion, leading to the sex-differences in glucose intolerance.
Collapse
Affiliation(s)
- Jose Casasnovas
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Christopher Luke Damron
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - James Jarrell
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Kara S. Orr
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Robert N. Bone
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| | | | - Parastoo Azadi
- Complex Carbohydrate Research Center, University of Georgia, Athens, GA, United States
| | - Kok Lim Kua
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
| |
Collapse
|
|
36
|
Lecoutre S, Maqdasy S, Breton C. Maternal obesity as a risk factor for developing diabetes in offspring: An epigenetic point of view. World J Diabetes 2021; 12:366-382. [PMID: 33889285 PMCID: PMC8040079 DOI: 10.4239/wjd.v12.i4.366] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 01/30/2021] [Accepted: 02/19/2021] [Indexed: 02/06/2023] Open
Abstract
According to the developmental origin of health and disease concept, the risk of many age-related diseases is not only determined by genetic and adult lifestyle factors but also by factors acting during early development. In particular, maternal obesity and neonatal accelerated growth predispose offspring to overweight and type 2 diabetes (T2D) in adulthood. This concept mainly relies on the developmental plasticity of adipose tissue and pancreatic β-cell programming in response to suboptimal milieu during the perinatal period. These changes result in unhealthy hypertrophic adipocytes with decreased capacity to store fat, low-grade inflammation and loss of insulin-producing pancreatic β-cells. Over the past years, many efforts have been made to understand how maternal obesity induces long-lasting adipose tissue and pancreatic β-cell dysfunction in offspring and what are the molecular basis of the transgenerational inheritance of T2D. In particular, rodent studies have shed light on the role of epigenetic mechanisms in linking maternal nutritional manipulations to the risk for T2D in adulthood. In this review, we discuss epigenetic adipocyte and β-cell remodeling during development in the progeny of obese mothers and the persistence of these marks as a basis of obesity and T2D predisposition.
Collapse
Affiliation(s)
- Simon Lecoutre
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
| | - Salwan Maqdasy
- Department of Medicine (H7), Karolinska Institutet, Stockholm 141-86, Sweden
- Clermont-Ferrand CHU, Department of Endocrinology, Diabetology and Metabolic Diseases, Clermont-Ferrand 63003, France
| | - Christophe Breton
- University of Lille, EA4489, Maternal Malnutrition and Programming of Metabolic Diseases, Lille 59000, France
- U1283-UMR8199-EGID, University of Lille, Institut National de la Santé Et de la Recherche Médicale, Centre National de la Recherche Scientifique, Lille 59000, France
| |
Collapse
|
|
37
|
Ye L, Zhang Q, Xin F, Cao B, Qian L, Dong Y. Neonatal Milk Fat Globule Membrane Supplementation During Breastfeeding Ameliorates the Deleterious Effects of Maternal High-Fat Diet on Metabolism and Modulates Gut Microbiota in Adult Mice Offspring in a Sex-Specific Way. Front Cell Infect Microbiol 2021; 11:621957. [PMID: 33816333 PMCID: PMC8017235 DOI: 10.3389/fcimb.2021.621957] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/01/2021] [Indexed: 12/16/2022] Open
Abstract
Exposure to adverse events in early life increases the risk of chronic metabolic disease in adulthood. The objective of this study was to determine the significance of milk fat globule membrane (MFGM)-mediated alterations in the gut microbiome to the metabolic health of offspring in the long-term. Female C57BL/6 mice were fed either a high-fat diet (HFD) or a control diet for 3 weeks before pregnancy and throughout pregnancy and lactation. During lactation, pups from the HFD group were breast-fed with or without 1,000 mg/kg BW/day MFGM supplementation (HFD and HFD-MS group, respectively). After weaning, the offspring in each group were divided into male and female subgroups. The weaned mice were then shifted to a control diet for 8 weeks. At the eleventh week, stool samples were collected for 16S rRNA gene sequencing. Serum biochemical parameters were analyzed, and intraperitoneal glucose and insulin tolerance tests were performed. Neonatal supplementation with MFGM ameliorated metabolic disorder and improved glucose tolerance in offspring exposed to maternal HFD in a sex-specific manner. Furthermore, maternal HFD induced gut microbiota perturbation in offspring in adulthood. Neonatal MFGM supplementation significantly enriched g-Parabacteroides, g-Bifidobacterium, g-Faecalibaculum, and g-Lactobacillus in male offspring exposed to maternal HFD, while significantly enriched g-Parabacteroides and g-Alistipes in female offspring exposed to maternal HFD. These bacteria may be associated with the favorable changes in metabolism that occur in adulthood. Sex differences in the changes of metagenomic pathways related to oxidative phosphorylation, citrate cycle, electron transfer carries, and ubiquinone biosynthesis were also observed in the offspring. Maternal HFD has an adverse effect on the metabolism of offspring in later life. Neonatal MFGM supplementation could modulate the structure of gut microbiota communities and may have long-term protective effects on lipid and glucose metabolism, but these effects are sex dimorphic.
Collapse
Affiliation(s)
- Lin Ye
- Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Qianren Zhang
- Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Fengzhi Xin
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Baige Cao
- Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Linxi Qian
- Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Yan Dong
- Xinhua Hospital, Shanghai Institute for Pediatric Research, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| |
Collapse
|
|
38
|
Effect of Postnatal Nutritional Environment Due to Maternal Diabetes on Beta Cell Mass Programming and Glucose Intolerance Risk in Male and Female Offspring. Biomolecules 2021; 11:biom11020179. [PMID: 33525575 PMCID: PMC7911592 DOI: 10.3390/biom11020179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 11/20/2022] Open
Abstract
Besides the fetal period, the suckling period is a critical time window in determining long-term metabolic health. We undertook the present study to elucidate the impact of a diabetic suckling environment alone or associated with an in utero diabetic environment on beta cell mass development and the risk of diabetes in the offspring in the long term. To that end, we have compared two experimental settings. In setting 1, we used Wistar (W) rat newborns resulting from W ovocytes (oW) transferred into diabetic GK rat mothers (pGK). These oW/pGK neonates were then suckled by diabetic GK foster mothers (oW/pGK/sGK model) and compared to oW/pW neonates suckled by normal W foster mothers (oW/pW/sW model). In setting 2, normal W rat newborns were suckled by diabetic GK rat foster mothers (nW/sGK model) or normal W foster mothers (nW/sW model). Our data revealed that the extent of metabolic disorders in term of glucose intolerance and beta cell mass are similar between rats which have been exposed to maternal diabetes both pre- and postnatally (oW/pGK/sGK model) and those which have been exposed only during postnatal life (nW/sW model). In other words, being nurtured by diabetic GK mothers from birth to weaning was sufficient to significantly alter the beta cell mass, glucose-induced insulin secretion and glucose homeostasis of offspring. No synergistic deleterious effects of pre-and postnatal exposure was observed in our setting.
Collapse
|
|
39
|
Akhaphong B, Gregg B, Kumusoglu D, Jo S, Singer K, Scheys J, DelProposto J, Lumeng C, Bernal-Mizrachi E, Alejandro EU. Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice. Front Endocrinol (Lausanne) 2021; 12:780300. [PMID: 35111136 PMCID: PMC8801938 DOI: 10.3389/fendo.2021.780300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/24/2021] [Indexed: 01/31/2023] Open
Abstract
The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.
Collapse
Affiliation(s)
- Brian Akhaphong
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Brigid Gregg
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Doga Kumusoglu
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Kanakadurga Singer
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Joshua Scheys
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
| | - Jennifer DelProposto
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Carey Lumeng
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ernesto Bernal-Mizrachi
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
- Diabetes, VA Ann Arbor Healthcare System, Ann Arbor, MI, United States
- Miami VA Healthcare System and Division Endocrinology, Metabolism and Diabetes, University of Miami, Miami, FL, United States
- *Correspondence: Ernesto Bernal-Mizrachi, ; Emilyn U. Alejandro,
| | - Emilyn U. Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
- *Correspondence: Ernesto Bernal-Mizrachi, ; Emilyn U. Alejandro,
| |
Collapse
|
|
40
|
Zhang J, Cao L, Tan Y, Zheng Y, Gui Y. N-acetylcysteine protects neonatal mice from ventricular hypertrophy induced by maternal obesity in a sex-specific manner. Biomed Pharmacother 2021; 133:110989. [PMID: 33378994 DOI: 10.1016/j.biopha.2020.110989] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 10/28/2020] [Accepted: 11/05/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Maternal obesity induces adverse cardiac programming in offspring, and effective interventions are needed to prevent cardiovascular ill-health. Herein we hypothesized that exposure to maternal obesogenic diet-induced obesity in mice results in left ventricular remodelling and hypertrophy in early childhood, and that maternal N-acetylcysteine (NAC) treatment alleviates these effects in a sex-dependent manner. METHODS AND RESULTS The maternal obesity was induced in mice by the consumption of a Western diet accompanied by a 20 % sucrose solution. To determine the effect of NAC on the cardiac outcomes induced by maternal obesity, obese dams were continuously exposed to the obesogenic diet, with or without the oral NAC treatment during pregnancy. Left ventricular remodelling and hypertrophy occurred as early as 7 days after birth in the male offspring of obese dams (O-OB) compared with controls (O-CO). An over-expression of key genes and markers related to cardiac fibrosis accompanied by more disorganized myofibrils was observed in the hearts of neonatal male O-OB mice. When we next evaluated the level of oxidative stress in the hearts of neonatal mice, the activity of enzymatic antioxidants declined and expression of NOX enzyme complex was up-regulated in O-OB offspring hearts, but was normal in the offspring of NAC treated mice (O-OB/NAC). Maternal obesity also activated cardiac Akt and mammalian target of rapamycin (mTOR) signalling in offspring, and NAC treatment restored offspring cardiac Akt-mTOR signalling to normal irrespective of sex. NAC treatment did not prevent cardiomyocyte hypertrophy but did alleviate increased heart weight, interventricular septal thickness, and collagen content in male O-OB/NAC pups. CONCLUSIONS Collectively, our results indicated that NAC blunted cardiac fibrosis and related ventricular hypertrophy of male neonatal offspring in the setting of maternal obesity, potentially acting by reducing oxidative stress. The present study provides a basis for investigating the role of NAC in nutrition-related cardiac programming.
Collapse
MESH Headings
- Acetylcysteine/pharmacology
- Animal Nutritional Physiological Phenomena
- Animals
- Animals, Newborn
- Antioxidants/pharmacology
- Disease Models, Animal
- Female
- Fibrosis
- Heart Ventricles/drug effects
- Heart Ventricles/metabolism
- Heart Ventricles/physiopathology
- Hypertrophy, Left Ventricular/etiology
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/physiopathology
- Hypertrophy, Left Ventricular/prevention & control
- Male
- Maternal Nutritional Physiological Phenomena
- Mice, Inbred C57BL
- Obesity, Maternal/complications
- Obesity, Maternal/physiopathology
- Oxidative Stress/drug effects
- Pregnancy
- Prenatal Exposure Delayed Effects
- Sex Factors
- Ventricular Function, Left/drug effects
- Ventricular Remodeling/drug effects
- Mice
Collapse
Affiliation(s)
- Jialing Zhang
- Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, China; MOH Key Laboratory of Neonatal Diseases at Children's Hospital, Fudan University, Shanghai, China
| | - Li Cao
- Ultrasound Department, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Yanfeng Tan
- Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China
| | - Yuanzheng Zheng
- Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, China; MOH Key Laboratory of Neonatal Diseases at Children's Hospital, Fudan University, Shanghai, China
| | - Yonghao Gui
- Cardiovascular Center, Children's Hospital of Fudan University, Shanghai, China; MOH Key Laboratory of Neonatal Diseases at Children's Hospital, Fudan University, Shanghai, China.
| |
Collapse
|
|
41
|
Abdel Hafez SMN, Allam FAFA, Elbassuoni E. Sex differences impact the pancreatic response to chronic immobilization stress in rats. Cell Stress Chaperones 2021; 26:199-215. [PMID: 32986228 PMCID: PMC7736456 DOI: 10.1007/s12192-020-01169-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Revised: 09/21/2020] [Accepted: 09/24/2020] [Indexed: 12/27/2022] Open
Abstract
Chronic stress has been related to multiple diseases. Inflammation is proposed strongly to link stress to stress-related diseases in different organs, such as small intestine, colon, and brain. However, stress cellular effect on the pancreatic tissue, especially the exocrine one, had received relatively little attention. This work aimed to evaluate the cellular effect of chronic immobilization stress on the pancreatic tissue function and structure along with evaluating the sex role in this type of pancreatic injury. Thirty rats were equally divided into 5 groups: control male, control female, stressed male, stressed female, and stressed female with bilateral ovariectomy. Stressed rats were exposed to immobilization for 1 h/day, 6 days/week, for 3 weeks. Rats were then decapitated for further biochemical, histological, histo-morphometric, and immunohistochemical study. The results showed that, in male and female rats, chronic immobilization stress produced hypoinsulinemia and hyperglycemia, with increasing exocrine pancreatic injury markers by increasing oxidative and inflammatory status of the pancreatic tissue, and exhibited a degenerative effect on the pancreatic tissue. However, the stress-induced pancreatic effects were more obvious in male rats and female rats with bilateral ovariectomy than that in female rats. It could be concluded that male animals were more susceptible to stress-induced pancreatic damage than females. The ovarian hormones are responsible, at least partly, for pancreatic tissue protection since the stress-induced pancreatic injury in females was exacerbated by ovariectomy. In this study, inflammatory and oxidative stress differences in both sexes could provide a plausible explanation for sex differences.
Collapse
Affiliation(s)
| | | | - Eman Elbassuoni
- Physiology Department, Faculty of Medicine, Minia University, Minia, Egypt
| |
Collapse
|
|
42
|
Christoforou ER, Sferruzzi-Perri AN. Molecular mechanisms governing offspring metabolic programming in rodent models of in utero stress. Cell Mol Life Sci 2020; 77:4861-4898. [PMID: 32494846 PMCID: PMC7658077 DOI: 10.1007/s00018-020-03566-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/23/2020] [Accepted: 05/27/2020] [Indexed: 12/13/2022]
Abstract
The results of different human epidemiological datasets provided the impetus to introduce the now commonly accepted theory coined as 'developmental programming', whereby the presence of a stressor during gestation predisposes the growing fetus to develop diseases, such as metabolic dysfunction in later postnatal life. However, in a clinical setting, human lifespan and inaccessibility to tissue for analysis are major limitations to study the molecular mechanisms governing developmental programming. Subsequently, studies using animal models have proved indispensable to the identification of key molecular pathways and epigenetic mechanisms that are dysregulated in metabolic organs of the fetus and adult programmed due to an adverse gestational environment. Rodents such as mice and rats are the most used experimental animals in the study of developmental programming. This review summarises the molecular pathways and epigenetic mechanisms influencing alterations in metabolic tissues of rodent offspring exposed to in utero stress and subsequently programmed for metabolic dysfunction. By comparing molecular mechanisms in a variety of rodent models of in utero stress, we hope to summarise common themes and pathways governing later metabolic dysfunction in the offspring whilst identifying reasons for incongruencies between models so to inform future work. With the continued use and refinement of such models of developmental programming, the scientific community may gain the knowledge required for the targeted treatment of metabolic diseases that have intrauterine origins.
Collapse
Affiliation(s)
- Efthimia R Christoforou
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK
| | - Amanda N Sferruzzi-Perri
- Department of Physiology, Development and Neuroscience, Centre for Trophoblast Research, University of Cambridge, Downing Site, Cambridge, UK.
| |
Collapse
|
|
43
|
Zhang Q, Xiao X, Zheng J, Li M, Yu M, Ping F, Wang T, Wang X. Maternal sitagliptin treatment attenuates offspring glucose metabolism and intestinal proinflammatory cytokines IL-6 and TNF-α expression in male rats. PeerJ 2020; 8:e10310. [PMID: 33240638 PMCID: PMC7666563 DOI: 10.7717/peerj.10310] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 10/15/2020] [Indexed: 12/28/2022] Open
Abstract
Increasing evidence shows that maternal overnutrition may increase the risk of diabetes in offspring. We hypothesized that maternal sitagliptin intervention may improve glucose intolerance through gut targeting. Female Sprague-Dawley (SD) rats were fed a normal diet (ND) or a high-fat diet (HFD) for 4 weeks before mating. ND pregnant rats were divided into two subgroups: ND group (ND alone) and the ND-sitagliptin group (ND combined with 10 mg/kg/day sitagliptin treatment). HFD pregnant rats were randomized to one of two groups: HFD group (HFD alone) and the HFD-sitagliptin group (HFD combined with 10 mg/kg/day sitagliptin treatment) during pregnancy and lactation. Glucose metabolism was assessed in offspring at weaning. Intestinal gene expression levels were investigated. Maternal sitagliptin intervention moderated glucose intolerance and insulin resistance in male pups. Moreover, maternal sitagliptin treatment inhibited offspring disordered intestinal expression of proinflammatory markers, including interleukin-6 (Il6), ll1b, and tumor necrosis factor (Tnf), at weaning and reduced intestinal IL-6, TNF-α expression by immunohistochemical staining and serum IL-6, TNF-α levels. However, maternal sitagliptin intervention did not affect offspring serum anti-inflammatory cytokine IL-10 level. Our results are the first to show that maternal sitagliptin intervention moderated glucose metabolism in male offspring. It may be involved with moderating intestinal IL-6 and TNF-α expression in male rat offspring.
Collapse
Affiliation(s)
- Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Zheng
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Li
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Miao Yu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Fan Ping
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Tong Wang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaojing Wang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
44
|
Developmental Programming and Glucolipotoxicity: Insights on Beta Cell Inflammation and Diabetes. Metabolites 2020; 10:metabo10110444. [PMID: 33158303 PMCID: PMC7694373 DOI: 10.3390/metabo10110444] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/23/2020] [Accepted: 10/09/2020] [Indexed: 12/12/2022] Open
Abstract
Stimuli or insults during critical developmental transitions induce alterations in progeny anatomy, physiology, and metabolism that may be transient, sometimes reversible, but often durable, which defines programming. Glucolipotoxicity is the combined, synergistic, deleterious effect of simultaneously elevated glucose (chronic hyperglycemia) and saturated fatty acids (derived from high-fat diet overconsumption and subsequent metabolism) that are harmful to organs, micro-organs, and cells. Glucolipotoxicity induces beta cell death, dysfunction, and failure through endoplasmic reticulum and oxidative stress and inflammation. In beta cells, the misfolding of pro/insulin proteins beyond the cellular threshold triggers the unfolded protein response and endoplasmic reticulum stress. Consequentially there is incomplete and inadequate pro/insulin biosynthesis and impaired insulin secretion. Cellular stress triggers cellular inflammation, where immune cells migrate to, infiltrate, and amplify in beta cells, leading to beta cell inflammation. Endoplasmic reticulum stress reciprocally induces beta cell inflammation, whereas beta cell inflammation can self-activate and further exacerbate its inflammation. These metabolic sequelae reflect the vicious cycle of beta cell stress and inflammation in the pathophysiology of diabetes.
Collapse
|
|
45
|
Chi ZC. Research status and prgoress of nonalcoholic fatty pancreatic disease. Shijie Huaren Xiaohua Zazhi 2020; 28:933-950. [DOI: 10.11569/wcjd.v28.i19.933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty pancreatic disease (NAFPD) is a disease characterized by an increase in pancreatic fat accumulation. It is a component of the metabolic syndrome and often coexists with nonalcoholic fatty liver disease. Once the diagnosis is established, it is closely related to acute and chronic pancreatitis, type 2 diabetes mellitus, pancreatic fibrosis, and pancreatic cancer. In recent years, it has been confirmed that NAFPD is closely related to cardiovascular disease, liver fibrosis, and liver cancer. The prevalence of NAFPD ranges between 11% and 69%, and increases with age. It is worth noting that the prevalence in obese children is twice as high as that in non-obese children. The high prevalence rate and complexity of the disease have aroused people's high attention. Therefore, to improve the understanding of NAFPD, fully understand the clinical significance of NAFPD, and further study its pathogenesis, diagnosis, and treatment require the collaboration and joint efforts of multiple disciplines, including hepatopathy, gastroenterology, endocrine metabolism, cardiovascular disease, imaging, pathology, and others. In this paper, we review the clinical significance, pathogenesis, and imaging diagnosis of NAFPD and propose our personal understanding of the key points in future research.
Collapse
Affiliation(s)
- Zhao-Chun Chi
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao 266011, Shandong Province, China
| |
Collapse
|
|
46
|
Pregestational diet transition to normal-fat diet avoids the deterioration of pancreatic β-cell function in male offspring induced by maternal high-fat diet. J Nutr Biochem 2020; 86:108495. [PMID: 32949717 DOI: 10.1016/j.jnutbio.2020.108495] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 06/18/2020] [Accepted: 08/07/2020] [Indexed: 12/17/2022]
Abstract
Novel progress has been made to understand the adverse pathophysiology in the pancreas of offspring exposed to overnutrition in utero. Our study is the first to evaluate whether the adverse effects of maternal overnutrition on offspring β-cell function are reversible or preventable through preconception maternal diet interventions. Herein, offspring mice were exposed in utero to one of the following: maternal normal-fat diet (NF group), maternal high-fat diet (HF group) or maternal diet transition from an HF to NF diet 9 weeks before pregnancy (H9N group). Offspring mice were subjected to postweaning HF diet for 12 weeks. HF offspring, but not H9N, displayed glucose intolerance and insulin resistance. HF male offspring had enlarged islet β-cells with reduced β-cell density, whereas, H9N male offspring did not show these changes. Co-immunofluorescent (Co-IF) staining of glucose transporter 2 (Glut2) and insulin (Ins) revealed significantly more Glut2+Ins- cells, indicative of insulin degranulation, in HF male offspring but not H9N. In addition, Co-IF of insulin and p-H3S10 indicated that β cells of HF male offspring, but not H9N, had proliferation defects likely due to inhibited protein kinase B (AKT) phosphorylation. In summary, our study demonstrates that maternal H9N diet effectively prevents functional deterioration of β cells seen in HF male offspring by avoiding β-cell proliferation defects and degranulation.
Collapse
|
|
47
|
Nicholas LM, Ozanne SE. Early life programming in mice by maternal overnutrition: mechanistic insights and interventional approaches. Philos Trans R Soc Lond B Biol Sci 2020; 374:20180116. [PMID: 30966886 DOI: 10.1098/rstb.2018.0116] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Animal models have been indispensable in elucidating the potential causative mechanisms underlying the effects of maternal diet on offspring health. Of these, the mouse has been widely used to model maternal overnutrition and/or maternal obesity and to study its effects across one or more generations. This review discusses recent findings from mouse models, which resemble the human situation, i.e. overnutrition/obesity across pregnancy and lactation. It also highlights the importance of embryo transfer models in identifying critical developmental period(s) during which specific metabolic changes are programmed in the offspring. The mouse is also an excellent tool for maternal intervention studies aimed at elucidating the longer-term effects on the offspring and for defining possible maternal factors underling the programming of metabolic adversity in offspring. While knowledge of the mouse genome and the molecular tools available have allowed great progress to be made in the field, it is clear that we need to define if the effects on the offspring are mediated by maternal obesity per se or if specific components of the maternal metabolic environment are more important. We can then begin to identify at-risk offspring and to design more effective interventions for the mother and/or her child. This article is part of the theme issue 'Developing differences: early-life effects and evolutionary medicine'.
Collapse
Affiliation(s)
- Lisa M Nicholas
- Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Addenbrooke's Hospital, Cambridge , UK
| | - Susan E Ozanne
- Metabolic Research Laboratories, MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge , Addenbrooke's Hospital, Cambridge , UK
| |
Collapse
|
|
48
|
Aberrant activation of bone marrow Ly6C high monocytes in diabetic mice contributes to impaired glucose tolerance. PLoS One 2020; 15:e0229401. [PMID: 32097444 PMCID: PMC7041861 DOI: 10.1371/journal.pone.0229401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 02/05/2020] [Indexed: 12/03/2022] Open
Abstract
Accumulating evidence indicates that diabetes and obesity are associated with chronic low-grade inflammation and multiple organ failure. Tissue-infiltrated inflammatory M1 macrophages are aberrantly activated in these conditions and contribute to hyperglycemia and insulin resistance. However, it is unclear at which stage these cells become aberrantly activated: as precursor monocytes in the bone marrow or as differentiated macrophages in tissues. We examined the abundance, activation state, and function of bone marrow-derived Ly6Chigh monocytes in mice with diabetes and/or obesity. Ly6Chigh monocytes were FACS-purified from six groups of male mice consisting of type 2 diabetes model db/db mice, streptozotocin (STZ) induced insulin depletion mice, high fat diet (HFD) induced obesity mice and each control mice. Ly6Chigh monocytes were then analyzed for the expression of inflammation markers by qRT-PCR. In addition, bone marrow-derived Ly6Chigh monocytes from db/+ and db/db mice were fluorescently labeled and injected into groups of db/db recipient mice. Cell trafficking to tissues and levels of markers were examined in the recipient mice. The expression of many inflammation-related genes was significantly increased in Ly6Chigh monocytes from db/db mice, compared with the control. Bone marrow-derived Ly6Chigh monocytes isolated from db/db mice, but not from db/+ mice, displayed prominent infiltration into peripheral tissues at 1 week after transfer into db/db mice. The recipients of db/db Ly6Chigh monocytes also exhibited significantly increased serum glucose levels and worsening tolerance compared with mice receiving db/+ Ly6Chigh monocytes. These novel observations suggest that activated Ly6Chigh monocytes may contribute to the glucose intolerance observed in diabetes.
Collapse
|
|
49
|
Zhang Q, Xiao X, Zheng J, Li M, Yu M, Ping F, Wang T, Wang X. Maternal Inulin Supplementation Alters Hepatic DNA Methylation Profile and Improves Glucose Metabolism in Offspring Mice. Front Physiol 2020; 11:70. [PMID: 32116778 PMCID: PMC7020697 DOI: 10.3389/fphys.2020.00070] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/22/2020] [Indexed: 12/13/2022] Open
Abstract
Scope As a prebiotic, inulin may have a protective effect on glucose metabolism. However, the mechanism of inulin treatment on glucose intolerance in offspring exposed to a maternal high-fat (HF) diet is still not clear. Here, we examined the hepatic DNA methylation profile to determine how maternal inulin supplementation modified glucose metabolism in offspring mice. Procedures Female mice were fed a HF diet, control diet (CON), or a HF diet with inulin supplementation (HF-inulin) during gestation and lactation. Upon weaning, pup livers were obtained. A hepatic genome DNA methylation array was performed. Results Pups exposed to a maternal HF diet exhibited glucose intolerance and insulin resistance. Maternal inulin treatment moderated glucose metabolism. A DNA methylation array identified differentially methylated regions associated with 970 annotated genes from pups exposed to a HF diet in response to maternal inulin treatment. In particular, the wingless-type MMTV integration site family member 5A (Wnt5a) gene was hypermethylated, and the phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 alpha (Pik3c2a), phosphatidylinositol-4-phosphate 3-kinase catalytic subunit type 2 beta (Pik3c2b), and phosphoinositide-3-kinase regulatory subunit 2 (Pik3r2) genes were hypomethylated in inulin-treated pups. Consistently, hepatic Wnt5a gene expression was reduced and Pik3c2a, Pik3c2b, and Pik3r2 gene expression were increased in the inulin group. Conclusion Maternal inulin treatment improved glucose intolerance by changing DNA methylation and gene expression of Wnt5a and Pi3k in mice exposed to a maternal HF diet.
Collapse
Affiliation(s)
- Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Jia Zheng
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Li
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Tong Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaojing Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
50
|
Zheng J, Alves-Wagner AB, Stanford KI, Prince NB, So K, Mul JD, Dirice E, Hirshman MF, Kulkarni RN, Goodyear LJ. Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype. BMJ Open Diabetes Res Care 2020; 8:8/1/e000890. [PMID: 32111717 PMCID: PMC7050345 DOI: 10.1136/bmjdrc-2019-000890] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 12/20/2019] [Accepted: 02/04/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE Poor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects of combined maternal and paternal exercise on offspring health and the effects of parental exercise on offspring pancreas phenotype, a major tissue regulating glucose homeostasis. RESEARCH DESIGN AND METHODS Breeders were high fat fed and housed±running wheels before breeding (males) and before and during gestation (females). Offspring groups were: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); and maternal+paternal exercise (Mat+Pat Ex). Offspring were sedentary, chow fed, and studied at weaning, 12, 20 and 52 weeks. RESULTS While there was no effect of parental exercise on glucose tolerance at younger ages, at 52 weeks, offspring of Mat Ex, Pat Ex and Mat+Pat Ex displayed lower glycemia and improved glucose tolerance. The greatest effects were in offspring from parents that both exercised (Mat+Pat Ex). Offspring from Mat Ex, Pat Ex, and Mat+Pat Ex had decreased beta cell size, whereas islet size and beta cell mass only decreased in Mat+Pat Ex offspring. CONCLUSIONS Maternal and paternal exercise have additive effects to improve glucose tolerance in offspring as they age, accompanied by changes in the offspring endocrine pancreas. These findings have important implications for the prevention and treatment of type 2 diabetes.
Collapse
Affiliation(s)
- Jia Zheng
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Ana Barbara Alves-Wagner
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Kristin I Stanford
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Noah B Prince
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Kawai So
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Joram D Mul
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Ercument Dirice
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Michael F Hirshman
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Rohit N Kulkarni
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Section on Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Laurie J Goodyear
- Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|