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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.
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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
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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: 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: 06/24/2023] [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.
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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
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Lorza-Gil E, Kaiser G, Carlein C, Hoffmann MDA, König GM, Haug S, Prates Roma L, Rexen Ulven E, Ulven T, Kostenis E, Birkenfeld AL, Häring HU, Ullrich S, Gerst F. Glucose-stimulated insulin secretion depends on FFA1 and Gq in neonatal mouse islets. Diabetologia 2023; 66:1501-1515. [PMID: 37217659 PMCID: PMC10317898 DOI: 10.1007/s00125-023-05932-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/22/2023] [Indexed: 05/24/2023]
Abstract
AIMS/HYPOTHESIS After birth, the neonatal islets gradually acquire glucose-responsive insulin secretion, a process that is subjected to maternal imprinting. Although NEFA are major components of breastmilk and insulin secretagogues, their role for functional maturation of neonatal beta cells is still unclear. NEFA are the endogenous ligands of fatty acid receptor 1 (FFA1, encoded by Ffar1 in mice), a Gq-coupled receptor with stimulatory effect on insulin secretion. This study investigates the role of FFA1 in neonatal beta cell function and in the adaptation of offspring beta cells to parental high-fat feeding. METHODS Wild-type (WT) and Ffar1-/- mice were fed high-fat (HFD) or chow diet (CD) for 8 weeks before mating, and during gestation and lactation. Blood variables, pancreas weight and insulin content were assessed in 1-, 6-, 11- and 26-day old (P1-P26) offspring. Beta cell mass and proliferation were determined in P1-P26 pancreatic tissue sections. FFA1/Gq dependence of insulin secretion was evaluated in isolated islets and INS-1E cells using pharmacological inhibitors and siRNA strategy. Transcriptome analysis was conducted in isolated islets. RESULTS Blood glucose levels were higher in CD-fed Ffar1-/- P6-offspring compared with CD-fed WT P6-offspring. Accordingly, glucose-stimulated insulin secretion (GSIS) and its potentiation by palmitate were impaired in CD Ffar1-/- P6-islets. In CD WT P6-islets, insulin secretion was stimulated four- to fivefold by glucose and five- and sixfold over GSIS by palmitate and exendin-4, respectively. Although parental HFD increased blood glucose in WT P6-offspring, it did not change insulin secretion from WT P6-islets. In contrast, parental HFD abolished glucose responsiveness (i.e. GSIS) in Ffar1-/- P6-islets. Inhibition of Gq by FR900359 or YM-254890 in WT P6-islets mimicked the effect of Ffar1 deletion, i.e. suppression of GSIS and of palmitate-augmented GSIS. The blockage of Gi/o by pertussis toxin (PTX) enhanced (100-fold) GSIS in WT P6-islets and rendered Ffar1-/- P6-islets glucose responsive, suggesting constitutive activation of Gi/o. In WT P6-islets, FR900359 cancelled 90% of PTX-mediated stimulation, while in Ffar1-/- P6-islets it completely abolished PTX-elevated GSIS. The secretory defect of Ffar1-/- P6-islets did not originate from insufficient beta cells, since beta cell mass increased with the offspring's age irrespective of genotype and diet. In spite of that, in the breastfed offspring (i.e. P1-P11) beta cell proliferation and pancreatic insulin content had a genotype- and diet-driven dynamic. Under CD, the highest proliferation rate was reached by the Ffar1-/- P6 offspring (3.95% vs 1.88% in WT P6), whose islets also showed increased mRNA levels of genes (e.g. Fos, Egr1, Jun) typically high in immature beta cells. Although parental HFD increased beta cell proliferation in both WT (4.48%) and Ffar1-/- (5.19%) P11 offspring, only the WT offspring significantly increased their pancreatic insulin content upon parental HFD (5.18 µg under CD to 16.93 µg under HFD). CONCLUSIONS/INTERPRETATION FFA1 promotes glucose-responsive insulin secretion and functional maturation of newborn islets and is required for adaptive offspring insulin secretion in the face of metabolic challenge, such as parental HFD.
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Affiliation(s)
- Estela Lorza-Gil
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen (IDM), Tübingen, Germany
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Gabriele Kaiser
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen (IDM), Tübingen, Germany
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Christopher Carlein
- Department of Biophysics Faculty of Medicine, Saarland University, Homburg, Germany
| | - Markus D A Hoffmann
- Department of Biophysics Faculty of Medicine, Saarland University, Homburg, Germany
| | - Gabriele M König
- Institute of Pharmaceutical Biology, Bonn University, Bonn, Germany
| | - Sieglinde Haug
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Leticia Prates Roma
- Department of Biophysics Faculty of Medicine, Saarland University, Homburg, Germany
| | - Elisabeth Rexen Ulven
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Trond Ulven
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Evi Kostenis
- Institute of Pharmaceutical Biology, Bonn University, Bonn, Germany
| | - Andreas L Birkenfeld
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen (IDM), Tübingen, Germany
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | | | - Susanne Ullrich
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen (IDM), Tübingen, Germany
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany
| | - Felicia Gerst
- German Center for Diabetes Research (DZD e.V.), Tübingen, Germany.
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen (IDM), Tübingen, Germany.
- Department of Internal Medicine, Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany.
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Carroll DT, Elsakr JM, Miller A, Fuhr J, Lindsley SR, Kirigiti M, Takahashi DL, Dean TA, Wesolowski SR, McCurdy CE, Friedman JE, Aagaard KM, Kievit P, Gannon M. Maternal Western-style diet in nonhuman primates leads to offspring islet adaptations including altered gene expression and insulin hypersecretion. Am J Physiol Endocrinol Metab 2023; 324:E577-E588. [PMID: 37134140 PMCID: PMC10259856 DOI: 10.1152/ajpendo.00087.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/26/2023] [Accepted: 04/26/2023] [Indexed: 05/05/2023]
Abstract
Maternal overnutrition is associated with increased susceptibility to type 2 diabetes in the offspring. Rodent models have shown that maternal overnutrition influences islet function in offspring. To determine whether maternal Western-style diet (WSD) alters prejuvenile islet function in a model that approximates that of human offspring, we utilized a well-characterized Japanese macaque model. We compared islet function from offspring exposed to WSD throughout pregnancy and lactation and weaned to WSD (WSD/WSD) compared with islets from offspring exposed only to postweaning WSD (CD/WSD) at 1 yr of age. WSD/WSD offspring islets showed increased basal insulin secretion and an exaggerated increase in glucose-stimulated insulin secretion, as assessed by dynamic ex vivo perifusion assays, relative to CD/WSD-exposed offspring. We probed potential mechanisms underlying insulin hypersecretion using transmission electron microscopy to evaluate β-cell ultrastructure, qRT-PCR to quantify candidate gene expression, and Seahorse assay to assess mitochondrial function. Insulin granule density, mitochondrial density, and mitochondrial DNA ratio were similar between groups. However, islets from WSD/WSD male and female offspring had increased expression of transcripts known to facilitate stimulus-secretion coupling and changes in the expression of cell stress genes. Seahorse assay revealed increased spare respiratory capacity in islets from WSD/WSD male offspring. Overall, these results show that maternal WSD feeding confers changes to genes governing insulin secretory coupling and results in insulin hypersecretion as early as the postweaning period. The results suggest a maternal diet leads to early adaptation and developmental programming in offspring islet genes that may underlie future β-cell dysfunction.NEW & NOTEWORTHY Programed adaptations in islets in response to maternal WSD exposure may alter β-cell response to metabolic stress in offspring. We show that islets from maternal WSD-exposed offspring hypersecrete insulin, possibly due to increased components of stimulus-secretion coupling. These findings suggest that islet hyperfunction is programed by maternal diet, and changes can be detected as early as the postweaning period in nonhuman primate offspring.
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Affiliation(s)
- Darian T Carroll
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States
| | - Joseph M Elsakr
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States
| | - Allie Miller
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Jennifer Fuhr
- Department of Veterans Affairs Tennessee Valley, Nashville, Tennessee, United States
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Sarah Rene Lindsley
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Melissa Kirigiti
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Diana L Takahashi
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Tyler A Dean
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Stephanie R Wesolowski
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Carrie E McCurdy
- Department of Human Physiology, University of Oregon, Eugene, Oregon, United States
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, University of Oklahoma, Oklahoma City, Oklahoma, United States
| | - Kjersti M Aagaard
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, Texas, United States
| | - Paul Kievit
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, Oregon, United States
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States
- Department of Veterans Affairs Tennessee Valley, Nashville, Tennessee, United States
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee, United States
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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: 1] [Impact Index Per Article: 0.3] [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.
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Mechanisms Underlying the Expansion and Functional Maturation of β-Cells in Newborns: Impact of the Nutritional Environment. Int J Mol Sci 2022; 23:ijms23042096. [PMID: 35216239 PMCID: PMC8877060 DOI: 10.3390/ijms23042096] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/04/2022] [Accepted: 02/09/2022] [Indexed: 12/24/2022] Open
Abstract
The functional maturation of insulin-secreting β-cells is initiated before birth and is completed in early postnatal life. This process has a critical impact on the acquisition of an adequate functional β-cell mass and on the capacity to meet and adapt to insulin needs later in life. Many cellular pathways playing a role in postnatal β-cell development have already been identified. However, single-cell transcriptomic and proteomic analyses continue to reveal new players contributing to the acquisition of β-cell identity. In this review, we provide an updated picture of the mechanisms governing postnatal β-cell mass expansion and the transition of insulin-secreting cells from an immature to a mature state. We then highlight the contribution of the environment to β-cell maturation and discuss the adverse impact of an in utero and neonatal environment characterized by calorie and fat overload or by protein deficiency and undernutrition. Inappropriate nutrition early in life constitutes a risk factor for developing diabetes in adulthood and can affect the β-cells of the offspring over two generations. A better understanding of these events occurring in the neonatal period will help developing better strategies to produce functional β-cells and to design novel therapeutic approaches for the prevention and treatment of diabetes.
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Anwer H, Morris MJ, Noble DWA, Nakagawa S, Lagisz M. Transgenerational effects of obesogenic diets in rodents: A meta-analysis. Obes Rev 2022; 23:e13342. [PMID: 34595817 DOI: 10.1111/obr.13342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 12/22/2022]
Abstract
Obesity is a major health condition that affects millions worldwide. There is an increased interest in understanding the adverse outcomes associated with obesogenic diets. A multitude of studies have investigated the transgenerational impacts of maternal and parental obesogenic diets on subsequent generations of offspring, but results have largely been mixed. We conducted a systematic review and meta-analysis on rodent studies to elucidate how obesogenic diets impact the mean and variance of grand-offspring traits. Our study focused on transgenerational effects (i.e., F2 and F3 generations) in one-off and multigenerational exposure studies. From 33 included articles, we obtained 407 effect sizes representing pairwise comparisons of control and treatment grand-offspring groups pertaining to measures of body weight, adiposity, glucose, insulin, leptin, and triglycerides. We found evidence that male and female grand-offspring descended from grandparents exposed to an obesogenic diet displayed phenotypes consistent with metabolic syndrome, especially in cases where the obesogenic diet was continued across generations. Further, we found stronger evidence for the effects of grand-maternal than grand-paternal exposure on grand-offspring traits. A high-fat diet in one-off exposure studies did not seem to impact phenotypic variation, whereas in multigenerational exposure studies it reduced variation in several traits.
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Affiliation(s)
- Hamza Anwer
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Margaret J Morris
- School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Daniel W A Noble
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
- Division of Ecology and Evolution, Research School of Biology, The Australian National University, Canberra, Australian Capital Territory, Australia
| | - Shinichi Nakagawa
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
| | - Malgorzata Lagisz
- Evolution and Ecology Research Centre and School of Biological, Earth and Environmental Sciences, University of New South Wales, Sydney, New South Wales, Australia
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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.
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Pankey CL, Odhiambo JF, Smith AM, Ford SP. Effects of maternal obesity in an ovine model on metabolic outcomes in F2 adults and F3 neonates. Domest Anim Endocrinol 2021; 76:106628. [PMID: 33895699 PMCID: PMC8169583 DOI: 10.1016/j.domaniend.2021.106628] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 03/17/2021] [Accepted: 03/19/2021] [Indexed: 10/21/2022]
Abstract
Accumulating evidence suggests that indications of metabolic syndrome can be inherited through the germline as a result of maternal obesity. We hypothesized that diet-induced maternal obesity during gestation would program metabolic consequences for multiple generations of offspring, even when first, second, and third generation offspring (F1, F2, F3, respectively) were fed only to requirements. Control (CON) and obese (OB) ewes (generation 0; F0) were bred to a single ram to produce the first generation of offspring (F1). From 60 d prior to conception through term, CONF0 ate 100% National Research Council recommendations (NRC), while OBF0 ewes ate 150% NRC. All F1, F2, and F3 ate 100% NRC after weaning. All mature F1 ewes were bred to a single ram to generate CONF2 (n = 6) and OBF2 (n = 10). All mature F2 ewes were bred to a single ram to produce CONF3 (n = 6) and OBF3 (n = 10). OBF2 ewes exhibited greater (P < 0.0001) plasma cortisol than CONF2 throughout gestation. A glucose tolerance test at 90% gestation revealed OBF2 ewes had higher (P < 0.05) insulin response with similar glucose, resulting in greater (P < 0.05) insulin resistance. OBF3 neonates had similar weight, lean mass, and body fat mass to CONF3 neonates. These data suggest that multigenerational programming of adverse metabolic phenotypes occur in association with F0 maternal obesity, yet adiposity may return to CON levels in F3 neonates.
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Affiliation(s)
- C L Pankey
- Department of Biomedical Science, West Virginia School of Osteopathic Medicine, Lewisburg, WV, USA; Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA.
| | - J F Odhiambo
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA; College of Agriculture and Food Sciences, Florida Agricultural and Mechanical University, Tallahassee, FL, USA
| | - A M Smith
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA
| | - S P Ford
- Center for the Study of Fetal Programming, Department of Animal Science, University of Wyoming, Laramie, WY, USA
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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: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 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.
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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
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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.
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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
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12
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Kusuyama J, Alves-Wagner AB, Makarewicz NS, Goodyear LJ. Effects of maternal and paternal exercise on offspring metabolism. Nat Metab 2020; 2:858-872. [PMID: 32929233 PMCID: PMC7643050 DOI: 10.1038/s42255-020-00274-7] [Citation(s) in RCA: 73] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022]
Abstract
Maternal and paternal obesity and type 2 diabetes are recognized risk factors for the development of metabolic dysfunction in offspring, even when the offspring follow a healthful lifestyle. Multiple studies have demonstrated that regular physical activity in mothers and fathers has striking beneficial effects on offspring health, including preventing the development of metabolic disease in rodent offspring as they age. Here, we review the benefits of maternal and paternal exercise in combating the development of metabolic dysfunction in adult offspring, focusing on offspring glucose homeostasis and adaptations to metabolic tissues. We discuss recent findings regarding the roles of the placenta and sperm in mediating the effects of parental exercise on offspring metabolic health, as well as the mechanisms hypothesized to underlie these beneficial changes. Given the worldwide epidemics of obesity and type 2 diabetes, if these findings translate to humans, regular exercise during the reproductive years might limit the vicious cycles in which increased metabolic risk propagates across generations.
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Affiliation(s)
- Joji Kusuyama
- Integrative Physiology and Metabolism Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Ana Barbara Alves-Wagner
- Integrative Physiology and Metabolism Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Nathan S Makarewicz
- Integrative Physiology and Metabolism Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Laurie J Goodyear
- Integrative Physiology and Metabolism Section, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
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Schellong K, Melchior K, Ziska T, Rancourt RC, Henrich W, Plagemann A. Maternal but Not Paternal High-Fat Diet (HFD) Exposure at Conception Predisposes for 'Diabesity' in Offspring Generations. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2020; 17:E4229. [PMID: 32545776 PMCID: PMC7345576 DOI: 10.3390/ijerph17124229] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 01/02/2023]
Abstract
While environmental epigenetics mainly focuses on xenobiotic endocrine disruptors, dietary composition might be one of the most important environmental exposures for epigenetic modifications, perhaps even for offspring generations. We performed a large-scale rat study on key phenotypic consequences from parental (F0) high-caloric, high-fat diet (HFD) food intake, precisely and specifically at mating/conception, focusing on 'diabesity' risk in first- (F1) and second- (F2) generation offspring of both sexes. F0 rats (maternal or paternal, respectively) received HFD overfeeding, starting six weeks prior to mating with normally fed control rats. The maternal side F1 offspring of both sexes developed a 'diabesity' predisposition throughout life (obesity, hyperleptinemia, hyperglycemia, insulin resistance), while no respective alterations occurred in the paternal side F1 offspring, neither in males nor in females. Mating the maternal side F1 females with control males under standard feeding conditions led, again, to a 'diabesity' predisposition in the F2 generation, which, however, was less pronounced than in the F1 generation. Our observations speak in favor of the critical impact of maternal but not paternal metabolism around the time frame of reproduction for offspring metabolic health over generations. Such fundamental phenotypic observations should be carefully considered in front of detailed molecular epigenetic approaches on eventual mechanisms.
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Affiliation(s)
- Karen Schellong
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (K.S.); (K.M.); (T.Z.); (R.C.R.)
| | - Kerstin Melchior
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (K.S.); (K.M.); (T.Z.); (R.C.R.)
| | - Thomas Ziska
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (K.S.); (K.M.); (T.Z.); (R.C.R.)
| | - Rebecca C. Rancourt
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (K.S.); (K.M.); (T.Z.); (R.C.R.)
| | - Wolfgang Henrich
- Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany;
| | - Andreas Plagemann
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité–Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (K.S.); (K.M.); (T.Z.); (R.C.R.)
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Kaspar D, Hastreiter S, Irmler M, Hrabé de Angelis M, Beckers J. Nutrition and its role in epigenetic inheritance of obesity and diabetes across generations. Mamm Genome 2020; 31:119-133. [PMID: 32350605 PMCID: PMC7368866 DOI: 10.1007/s00335-020-09839-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 04/15/2020] [Indexed: 02/07/2023]
Abstract
Nutritional constraints including not only caloric restriction or protein deficiency, but also energy-dense diets affect metabolic health and frequently lead to obesity and insulin resistance, as well as glucose intolerance and type 2 diabetes. The effects of these environmental factors are often mediated via epigenetic modifiers that target the expression of metabolic genes. More recently, it was discovered that such parentally acquired metabolic changes can alter the metabolic health of the filial and grand-filial generations. In mammals, this epigenetic inheritance can either follow an intergenerational or transgenerational mode of inheritance. In the case of intergenerational inheritance, epimutations established in gametes persist through the first round of epigenetic reprogramming occurring during preimplantation development. For transgenerational inheritance, epimutations persist additionally throughout the reprogramming that occurs during germ cell development later in embryogenesis. Differentially expressed transcripts, genomic cytosine methylations, and several chemical modifications of histones are prime candidates for tangible marks which may serve as epimutations in inter- and transgenerational inheritance and which are currently being investigated experimentally. We review, here, the current literature in support of epigenetic inheritance of metabolic traits caused by nutritional constraints and potential mechanisms in man and in rodent model systems.
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Affiliation(s)
- Daniela Kaspar
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
| | - Sieglinde Hastreiter
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
| | - Martin Hrabé de Angelis
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany
- Chair of Experimental Genetics, Technische Universität München, Weihenstephan, Germany
- Deutsches Zentrum für Diabetesforschung E.V. (DZD), Neuherberg, Germany
| | - Johannes Beckers
- Institute of Experimental Genetics, Helmholtz Zentrum München GmbH, Neuherberg, Germany.
- Chair of Experimental Genetics, Technische Universität München, Weihenstephan, Germany.
- Deutsches Zentrum für Diabetesforschung E.V. (DZD), Neuherberg, Germany.
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15
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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.
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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
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16
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Nicholas LM, Nagao M, Kusinski LC, Fernandez-Twinn DS, Eliasson L, Ozanne SE. Exposure to maternal obesity programs sex differences in pancreatic islets of the offspring in mice. Diabetologia 2020; 63:324-337. [PMID: 31773193 PMCID: PMC6946752 DOI: 10.1007/s00125-019-05037-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Accepted: 10/02/2019] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS Obesity during pregnancy increases offspring type 2 diabetes risk. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of the in utero/early life environment on offspring islet function. Whilst a number of experimental studies have examined the effect of maternal obesity on offspring islet architecture and/or function, it has not previously been delineated whether these changes are independent of other confounding risk factors such as obesity, postnatal high-fat-feeding and ageing. Thus, we aimed to study the impact of exposure to maternal obesity on offspring islets in young, glucose-tolerant male and female offspring. METHODS Female C57BL/6J mice were fed ad libitum either chow or obesogenic diet prior to and throughout pregnancy and lactation. Offspring were weaned onto a chow diet and remained on this diet until the end of the study. An IPGTT was performed on male and female offspring at 7 weeks of age. At 8 weeks of age, pancreatic islets were isolated from offspring for measurement of insulin secretion and content, mitochondrial respiration, ATP content, reactive oxygen species levels, beta and alpha cell mass, granule and mitochondrial density (by transmission electron microscopy), and mRNA and protein expression by real-time RT-PCR and Western blotting, respectively. RESULTS Glucose tolerance was similar irrespective of maternal diet and offspring sex. However, blood glucose was lower (p < 0.001) and plasma insulin higher (p < 0.05) in female offspring of obese dams 15 min after glucose administration. This was associated with higher glucose- (p < 0.01) and leucine/glutamine-stimulated (p < 0.05) insulin secretion in these offspring. Furthermore, there was increased mitochondrial respiration (p < 0.01) and density (p < 0.05) in female offspring of obese dams compared with same-sex controls. Expression of mitochondrial and nuclear-encoded components of the electron transport chain, L-type Ca2+ channel subtypes that play a key role in stimulus-secretion coupling [Cacna1d (p < 0.05)], and oestrogen receptor α (p < 0.05) was also increased in islets from these female offspring of obese dams. Moreover, cleaved caspase-3 expression and BAX:Bcl-2 were decreased (p < 0.05) reflecting reduced susceptibility to apoptosis. In contrast, in male offspring, glucose and leucine/glutamine-stimulated insulin secretion was comparable between treatment groups. There was, however, compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration (p < 0.05) and increased uncoupled respiration (p < 0.01), reduced docked insulin granules (p < 0.001), decreased Cacna1c (p < 0.001) and Cacna1d (p < 0.001) and increased cleaved caspase-3 expression (p < 0.05). CONCLUSIONS/INTERPRETATION Maternal obesity programs sex differences in offspring islet function. Islets of female but not male offspring appear to be primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future type 2 diabetes risk.
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Affiliation(s)
- Lisa M Nicholas
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
| | - Mototsugu Nagao
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, CRC, Skåne University Hospital, Malmö, Sweden
| | - Laura C Kusinski
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Denise S Fernandez-Twinn
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Lena Eliasson
- Unit of Islet Cell Exocytosis, Department of Clinical Sciences Malmö, Lund University Diabetes Centre, CRC, Skåne University Hospital, Malmö, Sweden
| | - Susan E Ozanne
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Level 4, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
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17
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Insulin Resistance in Pregnancy: Implications for Mother and Offspring. CONTEMPORARY ENDOCRINOLOGY 2020. [DOI: 10.1007/978-3-030-25057-7_5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Zhu Z, Cao F, Li X. Epigenetic Programming and Fetal Metabolic Programming. Front Endocrinol (Lausanne) 2019; 10:764. [PMID: 31849831 PMCID: PMC6901800 DOI: 10.3389/fendo.2019.00764] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Accepted: 10/21/2019] [Indexed: 12/30/2022] Open
Abstract
Fetal metabolic programming caused by the adverse intrauterine environment can induce metabolic syndrome in adult offspring. Adverse intrauterine environment introduces fetal long-term relatively irreversible changes in organs and metabolism, and thus causes fetal metabolic programming leading metabolic syndrome in adult offspring. Fetal metabolic programming of obesity and insulin resistance plays a key role in this process. The mechanism of fetal metabolic programming is still not very clear. It is suggested that epigenetic programming, also induced by the adverse intrauterine environment, is a critical underlying mechanism of fetal metabolic programming. Fetal epigenetic programming affects gene expression changes and cellular function through epigenetic modifications without DNA nucleotide sequence changes. Epigenetic modifications can be relatively stably retained and transmitted through mitosis and generations, and thereby induce the development of metabolic syndrome in adult offspring. This manuscript provides an overview of the critical role of epigenetic programming in fetal metabolic programming.
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Affiliation(s)
- Ziqiang Zhu
- Children's Hospital of Soochow University, Suzhou, China
- Changzhou Maternity and Child Health Care Hospital affiliated to Nanjing Medical University, Changzhou, China
| | - Fang Cao
- Changzhou Maternity and Child Health Care Hospital affiliated to Nanjing Medical University, Changzhou, China
| | - Xiaozhong Li
- Children's Hospital of Soochow University, Suzhou, China
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19
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Moullé VS, Parnet P. Effects of Nutrient Intake during Pregnancy and Lactation on the Endocrine Pancreas of the Offspring. Nutrients 2019; 11:nu11112708. [PMID: 31717308 PMCID: PMC6893668 DOI: 10.3390/nu11112708] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 10/31/2019] [Accepted: 11/05/2019] [Indexed: 12/26/2022] Open
Abstract
The pancreas has an essential role in the regulation of glucose homeostasis by secreting insulin, the only hormone with a blood glucose lowering effect in mammals. Several circulating molecules are able to positively or negatively influence insulin secretion. Among them, nutrients such as fatty acids or amino acids can directly act on specific receptors present on pancreatic beta cells. Dietary intake, especially excessive nutrient intake, is known to modify energy balance in adults, resulting in pancreatic dysfunction. However, gestation and lactation are critical periods for fetal development and pup growth and specific dietary nutrients are required for optimal growth. Feeding alterations during these periods will impact offspring development and increase the risk of developing metabolic disorders in adulthood, leading to metabolic programming. This review will focus on the influence of nutrient intake during gestation and lactation periods on pancreas development and function in offspring, highlighting the molecular mechanism of imprinting on this organ.
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20
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Harville EW, Mishra GD, Yeung E, Mumford SL, Schisterman EF, Jukic AM, Hatch EE, Mikkelsen EM, Jiang H, Ehrenthal DB, Porucznik CA, Stanford JB, Wen SW, Harvey A, Downs DS, Yajnik C, Santillan D, Santillan M, McElrath TF, Woo JG, Urbina EM, Chavarro JE, Sotres-Alvarez D, Bazzano L, Zhang J, Steiner A, Gunderson EP, Wise LA. The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium. Paediatr Perinat Epidemiol 2019; 33:490-502. [PMID: 31659792 PMCID: PMC6901022 DOI: 10.1111/ppe.12592] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Revised: 08/13/2019] [Accepted: 08/28/2019] [Indexed: 01/18/2023]
Abstract
BACKGROUND Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. OBJECTIVES The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. POPULATION A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. DESIGN The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. METHODS Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. PRELIMINARY RESULTS Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. CONCLUSIONS The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.
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Affiliation(s)
- Emily W. Harville
- Department of Epidemiology, Tulane School of Public Health and Tropical Medicine, 1440 Canal St, New Orleans, LA, USA
| | - Gita D. Mishra
- School of Public Health, University of Queensland, 266 Herston Rd, Herston QLD 4006, Australia
| | - Edwina Yeung
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, Bethesda, MD 20817, USA
| | - Sunni L Mumford
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, Bethesda, MD 20817, USA
| | - Enrique F Schisterman
- Epidemiology Branch, Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 6710B Rockledge Dr, Bethesda, MD 20817, USA
| | - Anne Marie Jukic
- Epidemiology Branch, National Institute of Environmental Health Sciences, 111 T. W. Alexander Drive P.O. Box 12233 Mail Drop A3-05, Durham, N.C. 27709, USA
| | - Elizabeth E. Hatch
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, The Talbot Building, T3E & T4E, Boston, MA 02118, USA
| | - Ellen M. Mikkelsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes Allé 43-45, 8200 Aarhus N, Denmark
| | - Hong Jiang
- Department of Maternal, Child and Adolescent Health, School of Public Health; Key Laboratory of Public Health Safety (Ministry of Education); Global Health Institute, Fudan University, Dong’an Rd, Xuhui Qu, Shanghai Shi, China
| | - Deborah B. Ehrenthal
- Department of Population Health Sciences, University of Wisconsin-Madison, Warf Office Bldg, 610 Walnut St #707, Madison, WI 53726, USA
| | - Christina A. Porucznik
- Division of Public Health, Department of Family and Preventive Medicine, School of Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
| | - Joseph B. Stanford
- Division of Public Health, Department of Family and Preventive Medicine, School of Medicine, University of Utah, 375 Chipeta Way, Salt Lake City, UT 84108, USA
| | - Shi-Wu Wen
- OMNI Research Group, Department of Obstetrics & Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Canada; Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Canada; The Ottawa Hospital, General Campus, 501 Smyth Road, Box 241, Ottawa, Ontario Canada, K1H 8L6
| | - Alysha Harvey
- OMNI Research Group, Department of Obstetrics & Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Canada; Ottawa Hospital Research Institute, Clinical Epidemiology Program, Ottawa, Canada; The Ottawa Hospital, General Campus, 501 Smyth Road, Box 241, Ottawa, Ontario Canada, K1H 8L6
| | - Danielle Symons Downs
- Department of Kinesiology, College of Health and Human Development, Department of Obstetrics and Gynecology, College of Medicine, The Pennsylvania State University, 268Q Recreation Building, University Park, PA 16802, USA
| | - Chittaranjan Yajnik
- KEM Hospital Research Centre, 489 Sardar Moodliar Road, Rasta Peth, Pune, Maharashtra 411011, India
| | - Donna Santillan
- Department of Obstetrics and Gynecology, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA USA
| | - Mark Santillan
- Department of Obstetrics and Gynecology, University of Iowa Hospitals & Clinics, 200 Hawkins Drive, Iowa City, IA USA
| | - Thomas F. McElrath
- Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street CWN-3, Boston, MA 02115, USA
| | - Jessica G. Woo
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati, 160 Panzeca Way, Kettering Lab Building, Room 127, Cincinnati, OH 45267, USA
| | - Elaine M. Urbina
- Heart Institute, Cincinnati Children’s Hospital Medical Center and Department of Pediatrics, University of Cincinnati, 3333 Burnet Ave, Cincinnati, OH 45229, USA
| | - Jorge E. Chavarro
- Department of Nutrition and Epidemiology, Harvard School of Public Health, 655 Huntington Avenue, Boston, Massachusetts 02115, USA
| | - Daniela Sotres-Alvarez
- Department of Biostatistics, University of North Carolina-Chapel Hill, 123 W. Franklin Street, Suite 450, CB #8030, Chapel Hill, NC 27516, USA
| | - Lydia Bazzano
- Department of Epidemiology, Tulane School of Public Health and Tropical Medicine, 1440 Canal St, New Orleans, LA, USA
| | - Jun Zhang
- Ministry of Education and Shanghai Key Laboratory of Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Anne Steiner
- Duke University Hospital, 5704 Fayetteville Road, Durham, NC, USA
| | - Erica P. Gunderson
- Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA
| | - Lauren A. Wise
- Department of Epidemiology, Boston University School of Public Health, 715 Albany Street, The Talbot Building, T3E & T4E, Boston, MA 02118, USA
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Agarwal P, Brar N, Morriseau TS, Kereliuk SM, Fonseca MA, Cole LK, Jha A, Xiang B, Hunt KL, Seshadri N, Hatch GM, Doucette CA, Dolinsky VW. Gestational Diabetes Adversely Affects Pancreatic Islet Architecture and Function in the Male Rat Offspring. Endocrinology 2019; 160:1907-1925. [PMID: 31237608 PMCID: PMC6656426 DOI: 10.1210/en.2019-00232] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/17/2019] [Indexed: 12/14/2022]
Abstract
Fetal exposure to gestational diabetes mellitus (GDM) and poor postnatal diet are strong risk factors for type 2 diabetes development later in life, but the mechanisms connecting GDM exposure to offspring metabolic health remains unclear. In this study, we aimed to determine how GDM interacts with the postnatal diet to affect islet function in the offspring as well as characterize the gene expression changes in the islets. GDM was induced in female rats using a high-fat, high-sucrose (HFS) diet, and litters from lean or GDM dams were weaned onto a low-fat (LF) or HFS diet. Compared with the lean control offspring, GDM exposure reduced glucose-stimulated insulin secretion in islets isolated from 15-week-old offspring, which was additively worsened when GDM exposure was combined with postnatal HFS diet consumption. In the HFS diet-fed offspring of lean dams, islet size and number increased, an adaptation that was not observed in the HFS diet-fed offspring of GDM dams. Islet gene expression in the offspring of GDM dams was altered in such categories as inflammation (e.g., Il1b, Ccl2), mitochondrial function/oxidative stress resistance (e.g., Atp5f1, Sod2), and ribosomal proteins (e.g., Rps6, Rps14). These results demonstrate that GDM exposure induced marked changes in gene expression in the male young adult rat offspring that cumulatively interact to worsen islet function, whole-body glucose homeostasis, and adaptations to HFS diets.
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Affiliation(s)
- Prasoon Agarwal
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Navdeep Brar
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Taylor S Morriseau
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Stephanie M Kereliuk
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Mario A Fonseca
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Laura K Cole
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Aruni Jha
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Bo Xiang
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
| | - Kristin L Hunt
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Nivedita Seshadri
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Grant M Hatch
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Christine A Doucette
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, Manitoba, Canada
- Correspondence: Vernon W. Dolinsky, PhD, Department of Pharmacology and Therapeutics, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermot Avenue, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada. E-mail: ; or Christine A. Doucette, PhD, Department of Physiology and Pathophysiology, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, 603 John Buhler Research Centre, 715 McDermot Avenue, Winnipeg, Mantitoba R3E 3P4, Canada. E-mail:
| | - Vernon W Dolinsky
- Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, Manitoba, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Manitoba, Canada
- Correspondence: Vernon W. Dolinsky, PhD, Department of Pharmacology and Therapeutics, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, 601 John Buhler Research Centre, 715 McDermot Avenue, University of Manitoba, Winnipeg, Manitoba R3E 3P4, Canada. E-mail: ; or Christine A. Doucette, PhD, Department of Physiology and Pathophysiology, University of Manitoba, Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, 603 John Buhler Research Centre, 715 McDermot Avenue, Winnipeg, Mantitoba R3E 3P4, Canada. E-mail:
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Elsakr JM, Dunn JC, Tennant K, Zhao SK, Kroeten K, Pasek RC, Takahashi DL, Dean TA, Velez Edwards DR, McCurdy CE, Aagaard KM, Powers AC, Friedman JE, Kievit P, Gannon M. Maternal Western-style diet affects offspring islet composition and function in a non-human primate model of maternal over-nutrition. Mol Metab 2019; 25:73-82. [PMID: 31036449 PMCID: PMC6599455 DOI: 10.1016/j.molmet.2019.03.010] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 03/22/2019] [Accepted: 03/28/2019] [Indexed: 01/26/2023] Open
Abstract
OBJECTIVE In humans, offspring of women who are overweight or obese are more likely to develop metabolic disease later in life. Studies in lower animal species reveal that a calorically-dense maternal diet is associated with alterations in islet cell mass and function. The long-term effects of maternal diet on the structure and function of offspring islets with characteristics similar to humans are unknown. We used a well-established non-human primate (NHP) model to determine the consequences of exposure to Western-Style Diet (WSD) in utero and during lactation on islet cell mass and function in the offspring. METHODS Female Japanese Macaques (Macaca fuscata) were fed either control (CTR) or WSD before and throughout pregnancy and lactation. Offspring were weaned onto CTR or WSD to generate four different groups based on maternal/offspring diets: CTR/CTR, WSD/CTR, CTR/WSD, and WSD/WSD. Offspring were analyzed at three years of age. Pancreatic tissue sections were immunolabelled to measure α- and β-cell mass and proliferation as well as islet vascularization. Live islets were also isolated to test the effects of WSD-exposure on islet function ex vivo. Offspring glucose tolerance was correlated with various maternal characteristics. RESULTS α-cell mass was reduced as a result of maternal WSD exposure. α-cell proliferation was reduced in response to offspring WSD. Islet vasculature did not differ among the diet groups. Islets from WSD/CTR offspring secreted a greater amount of insulin in response to glucose ex vivo. We also found that maternal glucose tolerance and parity correlated with offspring glucose tolerance. CONCLUSIONS Maternal WSD exposure results in persistently decreased α-cell mass in the three-year old offspring. WSD/CTR islets secreted greater amounts of insulin ex vivo, suggesting that these islets are primed to hyper-secrete insulin under certain metabolic stressors. Although WSD did not induce overt impaired glucose tolerance in dams or offspring, offspring born to mothers with higher glucose excursions during a glucose tolerance test were more likely to also show higher glucose excursions.
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Affiliation(s)
- Joseph M Elsakr
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Jennifer C Dunn
- Department of Veterans Affairs Tennessee Valley, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Katherine Tennant
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Sifang Kathy Zhao
- Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Karly Kroeten
- Vanderbilt Summer Diabetes Research Program, Vanderbilt University, Nashville, TN, USA
| | - Raymond C Pasek
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Diana L Takahashi
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Tyler A Dean
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Digna R Velez Edwards
- Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Biomedical Informatics, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Carrie E McCurdy
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, USA
| | - Kjersti M Aagaard
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs Tennessee Valley, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Jacob E Friedman
- Department of Pediatrics, Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA
| | - Paul Kievit
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs Tennessee Valley, Nashville, TN, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Cell and Developmental Biology, Vanderbilt University, USA.
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23
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Agarwal P, Morriseau TS, Kereliuk SM, Doucette CA, Wicklow BA, Dolinsky VW. Maternal obesity, diabetes during pregnancy and epigenetic mechanisms that influence the developmental origins of cardiometabolic disease in the offspring. Crit Rev Clin Lab Sci 2018; 55:71-101. [DOI: 10.1080/10408363.2017.1422109] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Prasoon Agarwal
- Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
| | - Taylor S. Morriseau
- Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
| | - Stephanie M. Kereliuk
- Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
| | - Christine A. Doucette
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
- Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Canada
| | - Brandy A. Wicklow
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
- Department of Pediatrics & Child Health, University of Manitoba, Winnipeg, Canada
| | - Vernon W. Dolinsky
- Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Canada
- Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Research Theme of the Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada
- Manitoba Developmental Origins of Chronic Diseases in Children Network (DEVOTION), University of Manitoba, Winnipeg, Canada
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24
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Abubakar B, Zawawi N, Omar AR, Ismail M. Predisposition to insulin resistance and obesity due to staple consumption of rice: Amylose content versus germination status. PLoS One 2017; 12:e0181309. [PMID: 28727791 PMCID: PMC5519073 DOI: 10.1371/journal.pone.0181309] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 06/29/2017] [Indexed: 12/29/2022] Open
Abstract
Type 2 diabetes is a metabolic disorder with established, well-defined precursors. Obesity and insulin resistance are amongst most important factors in predisposition to diabetes. Rice is a staple for about half the global population and its consumption has been strongly linked with diabetogenesis. We assert that tackling the prevalence of predisposing factors by modifying certain rice cultivars could reduce the global burden of obesity and insulin resistance, and by extension type 2 diabetes. Several rice cultivars with various properties were fed to nulliparous rats (five weeks old at the start of the experiment) for 90 days. They were then returned to a diet of standard pellets and mated with males raised on a standard diet. The resulting pups and dams were investigated for obesity and insulin resistance markers. We found that germination did more to reduce predisposition to obesity and insulin resistance than high amylose content. The combined reducing effect of germination and high amylose content on predisposition to obesity and insulin resistance was greater than the sum of their independent effects. Polished (white) rice with a low amylose content predisposed dams on a high-fat diet to markers of insulin resistance and obesity and this predisposition was inherited (in biochemical terms) by their F1 offspring. Overall, the results suggest that harnessing the beneficial properties of germination and amylose in rice would reduce the burden of obesity and insulin resistance, which are known to be key risk factors for development of type 2 diabetes.
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Affiliation(s)
- Bilyaminu Abubakar
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
- Department of Pharmacology and Toxicology, Usmanu Danfodiyo University, Sokoto, Nigeria
- * E-mail: (MI); (BA)
| | - Norhasnida Zawawi
- Department of Food Science, Faculty of Food Science and Technology, Universiti Putra Malaysia, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Abdul Rahman Omar
- Department of Animal Science, Faculty of Veterinary Medicine, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
| | - Maznah Ismail
- Laboratory of Molecular Biomedicine, Institute of Bioscience, Universiti Putra Malaysia, Serdang, Selangor, Malaysia
- * E-mail: (MI); (BA)
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25
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Soeda J, Mouralidarane A, Cordero P, Li J, Nguyen V, Carter R, Kapur SR, Pombo J, Poston L, Taylor PD, Vinciguerra M, Oben JA. Maternal obesity alters endoplasmic reticulum homeostasis in offspring pancreas. J Physiol Biochem 2016; 72:281-91. [PMID: 26979740 PMCID: PMC4873529 DOI: 10.1007/s13105-016-0476-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Accepted: 02/29/2016] [Indexed: 12/11/2022]
Abstract
The prevalence of non-alcoholic fatty pancreas disease (NAFPD) is increasing in parallel with obesity rates. Stress-related alterations in endoplasmic reticulum (ER), such as the unfolded protein response (UPR), are associated with obesity. The aim of this study was to investigate ER imbalance in the pancreas of a mice model of adult and perinatal diet-induced obesity. Twenty female C57BL/6J mice were assigned to control (Con) or obesogenic (Ob) diets prior to and during pregnancy and lactation. Their offspring were weaned onto Con or Ob diets up to 6 months post-partum. Then, after sacrifice, plasma biochemical analyses, gene expression, and protein concentrations were measured in pancreata. Offspring of Ob-fed mice had significantly increased body weight (p < 0.001) and plasma leptin (p < 0.001) and decreased insulin (p < 0.01) levels. Maternal obesogenic diet decreased the total and phosphorylated Eif2α and increased spliced X-box binding protein 1 (XBP1). Pancreatic gene expression of downstream regulators of UPR (EDEM, homocysteine-responsive endoplasmic reticulum-resident (HERP), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP)) and autophagy-related proteins (LC3BI/LC3BII) were differently disrupted by obesogenic feeding in both mothers and offspring (from p < 0.1 to p < 0.001). Maternal obesity and Ob feeding in their offspring alter UPR in NAFPD, with involvement of proapoptotic and autophagy-related markers. Upstream and downstream regulators of PERK, IRE1α, and ATF6 pathways were affected differently following the obesogenic insults.
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Affiliation(s)
- Jumpei Soeda
- Institute for Liver and Digestive Health, University College London, London, UK
| | | | - Paul Cordero
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Jiawei Li
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Vi Nguyen
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Rebeca Carter
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Sabrina R Kapur
- Institute for Liver and Digestive Health, University College London, London, UK
| | - Joaquim Pombo
- Division of Women's Health, King's College London, London, UK
| | - Lucilla Poston
- Division of Women's Health, King's College London, London, UK
| | - Paul D Taylor
- Division of Women's Health, King's College London, London, UK
| | - Manlio Vinciguerra
- Institute for Liver and Digestive Health, University College London, London, UK.
- International Clinical Research Center (ICRC), Center for Translational Medicine (CTM), St. Anne's University Hospital, Brno, Czech Republic.
- Centro Studi Fegato (CSF)-Liver Research Center, Fondazione Italiana Fegato, Trieste, Italy.
| | - Jude A Oben
- Institute for Liver and Digestive Health, University College London, London, UK.
- Department of Gastroenterology and Hepatology, Guy's and St Thomas' Hospital, NHS Foundation Trust, London, UK.
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26
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Aiken CE, Tarry-Adkins JL, Ozanne SE. Transgenerational effects of maternal diet on metabolic and reproductive ageing. Mamm Genome 2016; 27:430-9. [PMID: 27114382 PMCID: PMC4935748 DOI: 10.1007/s00335-016-9631-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 03/29/2016] [Indexed: 12/19/2022]
Abstract
The early-life environment, in particular maternal diet during pregnancy, influences a wide range of organs and systems in adult offspring. Mounting evidence suggests that developmental programming can also influence health and disease in grand-offspring. Transgenerational effects can be defined as those persisting into an F2 generation, where the F0 mother experiences suboptimal diet during her pregnancy. In this review, we critically examine evidence for transgenerational developmental programming effects in human populations, focusing on metabolic and reproductive outcomes. We discuss evidence from historical cohorts suggesting that grandchildren of women exposed to famine and other dietary alterations during pregnancy may experience increased rates of later health complications than their control counterparts. The methodological difficulties with transgenerational studies in human cohorts are explored. In particular, the problems with assessing reproductive outcomes in human populations are discussed. In light of the relative paucity of evidence available from human cohorts, we consider key insights from transgenerational experimental animal models of developmental programming by maternal diet; data are drawn from a range of rodent models, as well as the guinea-pig and the sheep. The evidence for different potential mechanisms of transgenerational inheritance or re-propagation of developmental programming effects is evaluated. Transgenerational effects could be transmitted through methylation of the gametes via the paternal and maternal lineage, as well as other possible mechanisms via the maternal lineage. Finally, future directions for exploring these underlying mechanisms further are proposed, including utilizing large, well-characterized, prospective pregnancy cohorts that include biobanks, which have been established in various populations during the last few decades.
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Affiliation(s)
- Catherine E Aiken
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.,Department of Obstetrics and Gynaecology, The Rosie Hospital and NIHR Cambridge Comprehensive Biomedical Research Centre, University of Cambridge, Box 223, Cambridge, CB2 0SW, UK
| | - Jane L Tarry-Adkins
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Susan E Ozanne
- University of Cambridge Metabolic Research Laboratories and MRC Metabolic Diseases Unit, Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
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27
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Hanafi MY, Saad MI, Abdelkhalek TM, Saleh MM, Kamel MA. In Utero Nutritional Manipulation Provokes Dysregulated Adipocytokines Production in F1 Offspring in Rats. SCIENTIFICA 2016; 2016:3892890. [PMID: 27200209 PMCID: PMC4855010 DOI: 10.1155/2016/3892890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Revised: 04/01/2016] [Accepted: 04/03/2016] [Indexed: 06/05/2023]
Abstract
Background. Intrauterine environment plays a pivotal role in the origin of fatal diseases such as diabetes. Diabetes and obesity are associated with low-grade inflammatory state and dysregulated adipokines production. This study aims to investigate the effect of maternal obesity and malnutrition on adipokines production (adiponectin, leptin, and TNF-α) in F1 offspring in rats. Materials and Methods. Wistar rats were allocated in groups: F1 offspring of control mothers under control diet (CF1-CD) and under high-fat diet (CF1-HCD), F1 offspring of obese mothers under CD (OF1-CD) and under HCD (OF1-HCD), and F1 offspring of malnourished mothers under CD (MF1-CD) and under HCD (MF1-HCD). Every 5 weeks postnatally, blood samples were obtained for biochemical analysis. Results. At the end of the 30-week follow-up, OF1-HCD and MF1-HCD exhibited hyperinsulinemia, moderate dyslipidemia, insulin resistance, and impaired glucose homeostasis compared to CF1-CD and CF1-HCD. OF1-HCD and MF1-HCD demonstrated low serum levels of adiponectin and high levels of leptin compared to CF1-CD and CF1-HCD. OF1-CD, OF1-HCD, and MF1-HCD had elevated serum levels of TNF-α compared to CF1-CD and CF1-HCD (p < 0.05). Conclusion. Maternal nutritional manipulation predisposes the offspring to development of insulin resistance in their adult life, probably via instigating dysregulated adipokines production.
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Affiliation(s)
- Mervat Y. Hanafi
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Mohamed I. Saad
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Melbourne, VIC, Australia
| | - Taha M. Abdelkhalek
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Moustafa M. Saleh
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Maher A. Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, Alexandria, Egypt
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28
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Nicholas LM, Morrison JL, Rattanatray L, Zhang S, Ozanne SE, McMillen IC. The early origins of obesity and insulin resistance: timing, programming and mechanisms. Int J Obes (Lond) 2016; 40:229-38. [PMID: 26367335 DOI: 10.1038/ijo.2015.178] [Citation(s) in RCA: 98] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 08/06/2015] [Accepted: 08/13/2015] [Indexed: 02/07/2023]
Abstract
Maternal obesity is associated with an increased risk of developing gestational diabetes mellitus and it also results in an increased risk of giving birth to a large baby with increased fat mass. Furthermore, it is also contributes to an increased risk of obesity and insulin resistance in the offspring in childhood, adolescence and adult life. It has been proposed that exposure to maternal obesity may therefore result in an 'intergenerational cycle' of obesity and insulin resistance. There is significant interest in whether exposure to maternal obesity around the time of conception alone contributes directly to poor metabolic outcomes in the offspring and whether dieting in the obese mother before pregnancy or around the time of conception has metabolic benefits for the offspring. This review focusses on experimental and clinical studies that have investigated the specific impact of exposure to maternal obesity during the periconceptional period alone or extending beyond conception on adipogenesis, lipogenesis and on insulin signalling pathways in the fat, liver and muscle of the offspring. Findings from these studies highlight the need for a better evidence base for the development of dietary interventions in obese women before pregnancy and around the time of conception to maximize the metabolic benefits and minimize the metabolic costs for the next generation.
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Affiliation(s)
- L M Nicholas
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - J L Morrison
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - L Rattanatray
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.,Discipline of Physiology, School of Molecular and Life Sciences, University of Adelaide, Adelaide, SA, Australia
| | - S Zhang
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia
| | - S E Ozanne
- Department of Clinical Biochemistry, Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | - I C McMillen
- Sansom Institute for Health Research, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, SA, Australia.,The Chancellery, University of Newcastle, Callaghan, NSW, Australia
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Hanafi MY, Saleh MM, Saad MI, Abdelkhalek TM, Kamel MA. Transgenerational effects of obesity and malnourishment on diabetes risk in F2 generation. Mol Cell Biochem 2015; 412:269-80. [PMID: 26708218 DOI: 10.1007/s11010-015-2633-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Accepted: 12/15/2015] [Indexed: 01/19/2023]
Abstract
Transgenerational inheritance of various diseases and phenotypes has been demonstrated in diverse species and involves various epigenetic markers. Obesity and malnourishment are nutritional stresses that have effects on offspring through increasing their risk of diabetes and/or obesity. Obesity and malnourishment both affect glucose metabolism and alter oxidative stress parameters in key organs. We induced obesity and malnutrition in F0 female rats by the use of obesogenic diet and protein-deficient diet, respectively. F0 obese and malnourished females were mated with control males and their offspring (F1 generation) were maintained on control diets. The male and female F1 offspring were mated with controls and the resultant offspring (F2 generation) were maintained on control diet. Glucose-sensing markers, glucose metabolism, indicators of insulin resistance and oxidative stress parameters were assessed during fetal development and till the adulthood of the offspring. Glucose-sensing genes were significantly over-expressed in distinct fetal tissues of F2 offspring of malnourished F1 females (F2-MF1F), specifically in fetal pancreas, liver, and adipose tissue. Nuclear and mitochondrial 8-oxo-dG DNA content was significantly elevated in F2-MF1F fetal pancreas. Maternal FBG was significantly elevated in F2-MF1F and F2 offspring of obese F1 females (F2-OF1F) during pregnancy. Males and females offspring of F2-OF1 exhibited significantly elevated FBG and impaired OGTT. Offspring of F2-MF1F showed similar results, while that of F2-MF1M did not significantly deviate from controls. F2-OF1F and F2-MF1F offspring exhibited significant deviation in insulin levels and HOMA-IR levels from controls. Malnourishment has a stronger transgenerational effect through maternal line compared to obesity and malnourishment through paternal line in increasing risk of diabetes in F2 generation.
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Affiliation(s)
- Mervat Y Hanafi
- Department of Biochemistry, Medical Research Institute, Alexandria University, 165 Elhorreya Avenue, P.O. Box 21561, Alexandria, Egypt
| | - Moustafa M Saleh
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Mohamed I Saad
- Department of Biochemistry, Medical Research Institute, Alexandria University, 165 Elhorreya Avenue, P.O. Box 21561, Alexandria, Egypt.
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, Melbourne, VIC, Australia.
| | - Taha M Abdelkhalek
- Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Maher A Kamel
- Department of Biochemistry, Medical Research Institute, Alexandria University, 165 Elhorreya Avenue, P.O. Box 21561, Alexandria, Egypt
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