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Jousse C, Parry L, Cueff G, Brandolini-Bunlon M, Tournayre J, Bruhat A, Maurin AC, Vituret C, Averous J, Muranishi Y, Fafournoux P. Identification of a specific set of genes predicting obesity before phenotype appearance. iScience 2025; 28:112377. [PMID: 40330877 PMCID: PMC12053654 DOI: 10.1016/j.isci.2025.112377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/29/2024] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
Obesity poses significant health and socioeconomic challenges, necessitating early detection of predisposition for effective personalized prevention. To identify candidate predictive markers, our study used two mouse models: one exhibiting interindividual variability in obesity predisposition and another inducing metabolic phenotypes through maternal nutritional stresses. In both cases, predisposition was assessed by challenging mice with a high-fat diet. Using multivariate analyses of transcriptomic data from white adipose tissue, we identified a set of genes whose expression correlates with an elevated susceptibility to obesity. Importantly, the expression of these genes was impacted prior to the appearance of any symptoms. A prediction model, incorporating both mouse and publicly available human datasets, confirmed the discriminative capacities of our set of genes across species, sexes, and adipose tissue deposits. These genes are promising candidates to serve as diagnostic tools for identifying individuals at risk of obesity.
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Affiliation(s)
- Céline Jousse
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Laurent Parry
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Gwendal Cueff
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Marion Brandolini-Bunlon
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Jérémy Tournayre
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Alain Bruhat
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Anne-Catherine Maurin
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Cyrielle Vituret
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Julien Averous
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Yuki Muranishi
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
| | - Pierre Fafournoux
- UMR1019 Unité de Nutrition Humaine (UNH), INRAE, Université Clermont Auvergne, Clermont-Ferrand, France
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Jiao P, Lu H, Hao L, Degen AA, Cheng J, Yin Z, Mao S, Xue Y. Nutrigenetic and Epigenetic Mechanisms of Maternal Nutrition-Induced Glucolipid Metabolism Changes in the Offspring. Nutr Rev 2025; 83:728-748. [PMID: 38781288 DOI: 10.1093/nutrit/nuae048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/25/2024] Open
Abstract
Maternal nutrition during pregnancy regulates the offspring's metabolic homeostasis, including insulin sensitivity and the metabolism of glucose and lipids. The fetus undergoes a crucial period of plasticity in the uterus; metabolic changes in the fetus during pregnancy caused by maternal nutrition not only influence fetal growth and development but also have a long-term or even life-long impact for the offspring. Epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNAs, play important roles in intergenerational and transgenerational effects. In this context, this narrative review comprehensively summarizes and analyzes the molecular mechanisms underlying how maternal nutrition, including a high-fat diet, polyunsaturated fatty acid diet, methyl donor nutrient supplementation, feed restriction, and protein restriction during pregnancy, impacts the genes involved in glucolipid metabolism in the liver, adipose tissue, hypothalamus, muscle, and oocytes of the offspring in terms of the epigenetic modifications. This will provide a foundation for the further exploration of nutrigenetic and epigenetic mechanisms for integrative mother-child nutrition and promotion of the offspring's health through the regulation of maternal nutrition during pregnancy. Note: This paper is part of the Nutrition Reviews Special Collection on Precision Nutrition.
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Affiliation(s)
- Peng Jiao
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Huizhen Lu
- Biotechnology Center, Anhui Agricultural University, Hefei, China
| | - Lizhuang Hao
- Key Laboratory of Plateau Grazing Animal Nutrition and Feed Science of Qinghai Province, Qinghai Plateau Yak Research Center, Qinghai Academy of Science and Veterinary Medicine of Qinghai University, Xining, China
| | - A Allan Degen
- Desert Animal Adaptations and Husbandry, Wyler Department of Dryland Agriculture, Blaustein Institutes for Desert Research, Ben-Gurion University of the Negev, Beer Sheva, Israel
| | - Jianbo Cheng
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Zongjun Yin
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
| | - Shengyong Mao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China
| | - Yanfeng Xue
- College of Animal Science and Technology, Anhui Agricultural University, Hefei, China
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Tain YL, Lin YJ, Hsu CN. Animal Models for Studying Developmental Origins of Cardiovascular-Kidney-Metabolic Syndrome. Biomedicines 2025; 13:452. [PMID: 40002865 PMCID: PMC11853432 DOI: 10.3390/biomedicines13020452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 02/27/2025] Open
Abstract
Cardiovascular-kidney-metabolic syndrome (CKMS) has become a significant global health challenge. Since CKMS often originates early in life, as outlined by the developmental origins of health and disease (DOHaD) concept, prevention is a more effective strategy than treatment. Various animal models, classified by environmental exposures or mechanisms, are used to explore the developmental origins of CKMS. However, no single model can fully replicate all aspects of CKMS or its clinical stages, limiting the advancement of preventive and therapeutic strategies. This review aims to assist researchers by comparing the strengths and limitations of common animal models used in CKMS programming studies and highlighting key considerations for selecting suitable models.
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Affiliation(s)
- You-Lin Tain
- Division of Pediatric Nephrology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Pediatrics, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
| | - Ying-Jui Lin
- Division of Critical Care, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan;
- Division of Cardiology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- Department of Early Childhood Care and Education, Cheng Shiu University, Kaohsiung 833, Taiwan
| | - Chien-Ning Hsu
- Department of Pharmacy, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Depatrtment of Pharmacy, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan
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Gutiérrez-Hernández ID, Rodríguez-Antolín J, Cervantes-Rodríguez M, Díaz R, Díaz-Godínez G. Antihyperlipidemic Effect of Oyster Culinary-Medicinal Mushroom Pleurotus ostreatus (Agaricomycetes) Extract in Rats with Postnatal Sucrose Consumption Whose Mothers Also Consumed Sucrose. Int J Med Mushrooms 2025; 27:39-51. [PMID: 39912606 DOI: 10.1615/intjmedmushrooms.2024057783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2025]
Abstract
Male offspring of rats whose mothers consumed sucrose (5% solution) during gestation and lactation were also given the sucrose solution instead of drinking water for 3 months, and subsequently, for 1 month, they were given an aqueous extract obtained from dehydrated fruiting bodies of Pleurotus ostreatus. The offspring that consumed sucrose (experimental group) did not show differences in body weight compared with those that did not consume sucrose (control group), however, total adiposity was higher in the experimental group. In rats that consumed the aqueous extract, a decrease in the amount of cholesterol and triglycerides in blood plasma was observed, total adiposity also decreased and the average size of adipocytes in the visceral area was reduced. Consumption of the aqueous extract of P. ostreatus showed an antihyperlipidemic effect when triglyceride, cholesterol and adipose tissue levels were increased by the consumption of sucrose in rats descended from mothers who also consumed sucrose.
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Affiliation(s)
- Itzel Daysi Gutiérrez-Hernández
- Master in Biological Sciences, Autonomous University of Tlaxcala, Tlaxcala, Mexico; University Health Complex, Teziutlan Headquarters, Autonomous University of Puebla, Puebla, Mexico
| | | | | | - Rubén Díaz
- Research Center for Biological Sciences, Autonomous University of Tlaxcala, Tlaxcala, Mexico
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Quarta A, Quarta MT, Mastromauro C, Chiarelli F, Giannini C. Influence of Nutrition on Growth and Development of Metabolic Syndrome in Children. Nutrients 2024; 16:3801. [PMID: 39599588 PMCID: PMC11597107 DOI: 10.3390/nu16223801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Revised: 10/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024] Open
Abstract
Obesity is currently an increasing public health burden due to its related metabolic and cardiovascular complications. In Western countries, a significant number of people are overweight or obese, and this trend is, unfortunately, becoming increasingly common even among the pediatric population. In this narrative review, we analyzed the role of nutrition during growth and its impact on the risk of developing metabolic syndrome and cardiovascular complications later in life. An impactful role in determining the phenotypic characteristics of the offspring is the parental diet carried out before conception. During intrauterine growth, the main risk factors are represented by an unbalanced maternal diet, excessive gestational weight gain, and impaired glycemic status. Breastfeeding, on the other hand, has many beneficial effects, but at the same time the quality of breast milk may be modified if maternal overweight or obesity subsists. Complementary feeding is likewise pivotal because an early introduction before 4 months of age and a high protein intake contribute to weight gain later. Knowledge of these mechanisms may allow early modification of risk factors by implementing targeted preventive strategies.
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Affiliation(s)
| | | | | | | | - Cosimo Giannini
- Department of Pediatrics, University of Chieti—Pescara, G. D’Annunzio, 66100 Chieti, Italy; (A.Q.); (M.T.Q.); (C.M.); (F.C.)
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Burton JJN, Alonso LC. Overnutrition in the early postnatal period influences lifetime metabolic risk: Evidence for impact on pancreatic β-cell mass and function. J Diabetes Investig 2024; 15:263-274. [PMID: 38193815 PMCID: PMC10906026 DOI: 10.1111/jdi.14136] [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: 11/17/2023] [Accepted: 12/05/2023] [Indexed: 01/10/2024] Open
Abstract
Overconsumption of energy-rich foods that disrupt caloric balance is a fundamental cause of overweight, obesity and diabetes. Dysglycemia and the resulting cardiovascular disease cause substantial morbidity and mortality worldwide, as well as high societal cost. The prevalence of obesity in childhood and adolescence is increasing, leading to younger diabetes diagnosis, and higher severity of microvascular and macrovascular complications. An important goal is to identify early life conditions that increase future metabolic risk, toward the goal of preventing diabetes and cardiovascular disease. An ample body of evidence implicates prenatal and postnatal childhood growth trajectories in the programming of adult metabolic disease. Human epidemiological data show that accelerated childhood growth increases risk of type 2 diabetes in adulthood. Type 2 diabetes results from the combination of insulin resistance and pancreatic β-cell failure, but specific mechanisms by which accelerated postnatal growth impact one or both of these processes remain uncertain. This review explores the metabolic impact of overnutrition during postnatal life in humans and in rodent models, with specific attention to the connection between accelerated childhood growth and future adiposity, insulin resistance, β-cell mass and β-cell dysfunction. With improved knowledge in this area, we might one day be able to modulate nutrition and growth in the critical postnatal window to maximize lifelong metabolic health.
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Affiliation(s)
- Joshua JN Burton
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health, Weill Cornell MedicineNew York CityNew YorkUSA
| | - Laura C Alonso
- Division of Endocrinology, Diabetes and Metabolism and the Joan and Sanford I. Weill Center for Metabolic Health, Weill Cornell MedicineNew York CityNew YorkUSA
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7
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Ersoy U, Kanakis I, Alameddine M, Pedraza-Vazquez G, Ozanne SE, Peffers MJ, Jackson MJ, Goljanek-Whysall K, Vasilaki A. Lifelong dietary protein restriction accelerates skeletal muscle loss and reduces muscle fibre size by impairing proteostasis and mitochondrial homeostasis. Redox Biol 2024; 69:102980. [PMID: 38064763 PMCID: PMC10755587 DOI: 10.1016/j.redox.2023.102980] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 11/27/2023] [Accepted: 11/27/2023] [Indexed: 01/01/2024] Open
Abstract
The early life environment significantly affects the development of age-related skeletal muscle disorders. However, the long-term effects of lactational protein restriction on skeletal muscle are still poorly defined. Our study revealed that male mice nursed by dams fed a low-protein diet during lactation exhibited skeletal muscle growth restriction. This was associated with a dysregulation in the expression levels of genes related to the ribosome, mitochondria and skeletal muscle development. We reported that lifelong protein restriction accelerated loss of type-IIa muscle fibres and reduced muscle fibre size by impairing mitochondrial homeostasis and proteostasis at 18 months of age. However, feeding a normal-protein diet following lactational protein restriction prevented accelerated fibre loss and fibre size reduction in later life. These findings provide novel insight into the mechanisms by which lactational protein restriction hinders skeletal muscle growth and includes evidence that lifelong dietary protein restriction accelerated skeletal muscle loss in later life.
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Affiliation(s)
- Ufuk Ersoy
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK
| | - Ioannis Kanakis
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK; Chester Medical School, Faculty of Medicine and Life Sciences, University of Chester, Chester, UK
| | - Moussira Alameddine
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK
| | - Gibran Pedraza-Vazquez
- Department of Physiology, School of Medicine and REMEDI, CMNHS, University of Galway, Galway, Ireland
| | - Susan E Ozanne
- MRC Metabolic Diseases Unit, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Treatment Centre, Addenbrooke's Hospital, University of Cambridge Metabolic Research Laboratories, Cambridge, UK
| | - Mandy Jayne Peffers
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK
| | - Malcolm J Jackson
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK
| | - Katarzyna Goljanek-Whysall
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK; Department of Physiology, School of Medicine and REMEDI, CMNHS, University of Galway, Galway, Ireland
| | - Aphrodite Vasilaki
- Department of Musculoskeletal & Ageing Science, Institute of Life Course & Medical Sciences (ILCaMS), The MRC - Versus Arthritis Centre for Integrated Research Into Musculoskeletal Ageing (CIMA), University of Liverpool, Liverpool, UK.
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Pierre TH, Toren E, Kepple J, Hunter CS. Epigenetic Regulation of Pancreas Development and Function. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2024; 239:1-30. [PMID: 39283480 DOI: 10.1007/978-3-031-62232-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/04/2024]
Abstract
The field of epigenetics broadly seeks to define heritable phenotypic modifications that occur within cells without changes to the underlying DNA sequence. These modifications allow for precise control and specificity of function between cell types-ultimately creating complex organ systems that all contain the same DNA but only have access to the genes and sequences necessary for their cell-type-specific functions. The pancreas is an organ that contains varied cellular compartments with functions ranging from highly regulated glucose-stimulated insulin secretion in the β-cell to the pancreatic ductal cells that form a tight epithelial lining for the delivery of digestive enzymes. With diabetes cases on the rise worldwide, understanding the epigenetic mechanisms driving β-cell identity, function, and even disease is particularly valuable. In this chapter, we will discuss the known epigenetic modifications in pancreatic islet cells, how they are deposited, and the environmental and metabolic contributions to epigenetic mechanisms. We will also explore how a deeper understanding of epigenetic effectors can be used as a tool for diabetes therapeutic strategies.
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Affiliation(s)
- Tanya Hans Pierre
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Eliana Toren
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Jessica Kepple
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chad S Hunter
- Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, AL, USA.
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9
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Jo S, Alejandro EU. RISING STARS: Mechanistic insights into maternal-fetal cross talk and islet beta-cell development. J Endocrinol 2023; 259:e230069. [PMID: 37855321 PMCID: PMC10692651 DOI: 10.1530/joe-23-0069] [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: 05/22/2023] [Accepted: 10/18/2023] [Indexed: 10/20/2023]
Abstract
The metabolic health trajectory of an individual is shaped as early as prepregnancy, during pregnancy, and lactation period. Both maternal nutrition and metabolic health status are critical factors in the programming of offspring toward an increased propensity to developing type 2 diabetes in adulthood. Pancreatic beta-cells, part of the endocrine islets, which are nutrient-sensitive tissues important for glucose metabolism, are primed early in life (the first 1000 days in humans) with limited plasticity later in life. This suggests the high importance of the developmental window of programming in utero and early in life. This review will focus on how changes to the maternal milieu increase offspring's susceptibility to diabetes through changes in pancreatic beta-cell mass and function and discuss potential mechanisms by which placental-driven nutrient availability, hormones, exosomes, and immune alterations that may impact beta-cell development in utero, thereby affecting susceptibility to type 2 diabetes in adulthood.
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Affiliation(s)
- Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Emilyn U Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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Simões-Alves AC, Costa-Silva JH, Bassot A, Leandro CG, Pirola L, Fernandes MP, Morio B. Diet enriched in saturated fatty acids induces liver oxidative stress and elicits inflammatory pathways prior to metabolic disruption in perinatal protein undernutrition. Nutr Res 2023; 118:104-115. [PMID: 37634306 DOI: 10.1016/j.nutres.2023.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 07/31/2023] [Accepted: 08/01/2023] [Indexed: 08/29/2023]
Abstract
The impact of diets high in saturated fatty acids in individuals who have undergone maternal protein restriction is not clear. Here, we tested the hypothesis that a saturated fatty acid-enriched hyperlipidic diet (HL) affects liver expression of genes of the redox balance and inflammatory pathway in postweaning rat offspring subjected to maternal protein restriction. Pregnant Wistar rats received either a control (C; 19% protein) or low protein (LP; 8% protein) diet during gestation and lactation. At weaning, pups received either C or HL diets up to 90 days of life. The LP+HL group showed an upregulation of transcription of peroxisome proliferator-activated receptor γ (+48%) and peroxisome proliferator-activated receptor γ coactivator α (+96%) compared with the LP+C group (P < .05), respectively. Similarly, gene expression of the markers of inflammation, nuclear factor-kappa B1 (+194%) and tumor necrosis factor-α (+192%), was enhanced (P < .05). Although other antioxidant enzymes were not modified in gene expression, catalase (CAT) was 66% higher in LP+HL compared with LP+C. In contrast, CAT protein content in the liver was 50% lower in LP groups compared with C, and superoxide dismutase 2 (SOD2) was twice as high in LP groups compared with C. Postweaning HL after maternal protein restriction induces hepatic metabolic adaptation characterized by enhanced oxidative stress, unbalanced expression in the antioxidant enzymes SOD1, SOD2 and CAT, and activation of inflammatory pathways but does not impact circulating markers of lipid metabolism and liver function.
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Affiliation(s)
- Aiany C Simões-Alves
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitoria de Santo Antão, Pernambuco, Brazil; Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN), INSERM U1060, INRA U1397, Université Claude Bernard Lyon1, Pierre Bénite, France; Laboratory of General Biochemistry, Molecular Biology and Exercise, Federal University of Pernambuco-UFPE, Vitória de Santo Antão, Pernambuco, Brazil
| | - João H Costa-Silva
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitoria de Santo Antão, Pernambuco, Brazil; Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN), INSERM U1060, INRA U1397, Université Claude Bernard Lyon1, Pierre Bénite, France.
| | - Arthur Bassot
- Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN), INSERM U1060, INRA U1397, Université Claude Bernard Lyon1, Pierre Bénite, France
| | - Carol Góis Leandro
- Laboratory of Nutrition, Physical Activity and Phenotypic Plasticity, Federal University of Pernambuco, Vitoria de Santo Antão, Pernambuco, Brazil
| | - Luciano Pirola
- Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN), INSERM U1060, INRA U1397, Université Claude Bernard Lyon1, Pierre Bénite, France
| | - Mariana P Fernandes
- Laboratory of General Biochemistry, Molecular Biology and Exercise, Federal University of Pernambuco-UFPE, Vitória de Santo Antão, Pernambuco, Brazil
| | - Beatrice Morio
- Laboratoire de Recherche en Cardiovasculaire, Métabolisme, Diabétologie et Nutrition (CarMeN), INSERM U1060, INRA U1397, Université Claude Bernard Lyon1, Pierre Bénite, France
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11
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Mulcahy MC, El Habbal N, Snyder D, Redd JR, Sun H, Gregg BE, Bridges D. Gestational Early-Time Restricted Feeding Results in Sex-Specific Glucose Intolerance in Adult Male Mice. J Obes 2023; 2023:6666613. [PMID: 37808966 PMCID: PMC10558268 DOI: 10.1155/2023/6666613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/31/2023] [Accepted: 09/07/2023] [Indexed: 10/10/2023] Open
Abstract
The timing of food intake is a novel dietary component that impacts health. Time-restricted feeding (TRF), a form of intermittent fasting, manipulates food timing. The timing of eating may be an important factor to consider during critical periods, such as pregnancy. Nutrition during pregnancy, too, can have a lasting impact on offspring health. The timing of food intake has not been thoroughly investigated in models of pregnancy, despite evidence that interest in the practice exists. Therefore, using a mouse model, we tested body composition and glycemic health of gestational early TRF (eTRF) in male and female offspring from weaning to adulthood on a chow diet and after a high-fat, high-sucrose (HFHS) diet challenge. Body composition was similar between groups in both sexes from weaning to adulthood, with minor increases in food intake in eTRF females and slightly improved glucose tolerance in males while on a chow diet. However, after 10 weeks of HFHS, male eTRF offspring developed glucose intolerance. Further studies should assess the susceptibility of males, and apparent resilience of females, to gestational eTRF and assess mechanisms underlying these changes in adult males.
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Affiliation(s)
- Molly C. Mulcahy
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
| | - Noura El Habbal
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
| | - Detrick Snyder
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
| | - JeAnna R. Redd
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
| | - Haijing Sun
- Michigan Medicine, Department of Pediatrics, Division of Diabetes, Endocrinology and Metabolism, Ann Arbor, MI, USA
| | - Brigid E. Gregg
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
- Michigan Medicine, Department of Pediatrics, Division of Diabetes, Endocrinology and Metabolism, Ann Arbor, MI, USA
| | - Dave Bridges
- University of Michigan School of Public Health, Department of Nutritional Sciences, Ann Arbor, MI, USA
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12
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Beydag-Tasöz BS, Yennek S, Grapin-Botton A. Towards a better understanding of diabetes mellitus using organoid models. Nat Rev Endocrinol 2023; 19:232-248. [PMID: 36670309 PMCID: PMC9857923 DOI: 10.1038/s41574-022-00797-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2022] [Indexed: 01/22/2023]
Abstract
Our understanding of diabetes mellitus has benefited from a combination of clinical investigations and work in model organisms and cell lines. Organoid models for a wide range of tissues are emerging as an additional tool enabling the study of diabetes mellitus. The applications for organoid models include studying human pancreatic cell development, pancreatic physiology, the response of target organs to pancreatic hormones and how glucose toxicity can affect tissues such as the blood vessels, retina, kidney and nerves. Organoids can be derived from human tissue cells or pluripotent stem cells and enable the production of human cell assemblies mimicking human organs. Many organ mimics relevant to diabetes mellitus are already available, but only a few relevant studies have been performed. We discuss the models that have been developed for the pancreas, liver, kidney, nerves and vasculature, how they complement other models, and their limitations. In addition, as diabetes mellitus is a multi-organ disease, we highlight how a merger between the organoid and bioengineering fields will provide integrative models.
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Affiliation(s)
- Belin Selcen Beydag-Tasöz
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Siham Yennek
- The Novo Nordisk Foundation Center for Stem Cell Biology, Copenhagen, Denmark
| | - Anne Grapin-Botton
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
- Paul Langerhans Institute Dresden, Dresden, Germany.
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13
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Zeng Y, Wu Y, Zhang Q, Xiao X. Non-coding RNAs: The link between maternal malnutrition and offspring metabolism. Front Nutr 2022; 9:1022784. [PMID: 36438765 PMCID: PMC9684648 DOI: 10.3389/fnut.2022.1022784] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 10/27/2022] [Indexed: 06/13/2025] Open
Abstract
Early life nutrition is associated with the development and metabolism in later life, which is known as the Developmental Origin of Health and Diseases (DOHaD). Epigenetics have been proposed as an important explanation for this link between early life malnutrition and long-term diseases. Non-coding RNAs (ncRNAs) may play a role in this epigenetic programming. The expression of ncRNAs (such as long non-coding RNA H19, microRNA-122, and circular RNA-SETD2) was significantly altered in specific tissues of offspring exposed to maternal malnutrition. Changes in these downstream targets of ncRNAs lead to abnormal development and metabolism. This review aims to summarize the existing knowledge on ncRNAs linking the maternal nutrition condition and offspring metabolic diseases, such as obesity, type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD).
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Affiliation(s)
| | | | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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14
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Albrecht ED, Aberdeen GW, Babischkin JS, Prior SJ, Lynch TJ, Baranyk IA, Pepe GJ. Estrogen Promotes Microvascularization in the Fetus and Thus Vascular Function and Insulin Sensitivity in Offspring. Endocrinology 2022; 163:6553898. [PMID: 35325097 PMCID: PMC9272192 DOI: 10.1210/endocr/bqac037] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Indexed: 11/19/2022]
Abstract
We have shown that normal weight offspring born to estrogen-deprived baboons exhibited insulin resistance, although liver and adipose function and insulin receptor and glucose transporter expression were unaltered. The blood microvessels have an important role in insulin action by delivering insulin and glucose to target cells. Although little is known about the regulation of microvessel development during fetal life, estrogen promotes capillary proliferation and vascular function in the adult. Therefore, we tested the hypothesis that estrogen promotes fetal microvessel development and thus vascular function and insulin sensitivity in offspring. Capillary/myofiber ratio was decreased 75% (P < 0.05) in skeletal muscle, a major insulin target tissue, of fetal baboons in which estradiol levels were depleted by administration of aromatase inhibitor letrozole. This was sustained after birth, resulting in a 50% reduction (P < 0.01) in microvessel expansion; 65% decrease (P < 0.01) in arterial flow-mediated dilation, indicative of vascular endothelial dysfunction; and 35% increase (P < 0.01) in blood pressure in offspring from estrogen-deprived baboons, changes prevented by letrozole and estradiol administration. Along with vascular dysfunction, peak insulin and glucose levels during a glucose tolerance test were greater (P < 0.05 to P < 0.01) and the homeostasis model of insulin resistance 2-fold higher (P < 0.01) in offspring of letrozole-treated than untreated animals, indicative of insulin resistance. This study makes the novel discovery that estrogen promotes microvascularization in the fetus and thus normal vascular development and function required for eliciting insulin sensitivity in offspring and that placental hormonal secretions, independent from improper fetal growth, are an important determinant of risk of developing insulin resistance.
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Affiliation(s)
- Eugene D Albrecht
- Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
- Correspondence: Eugene Albrecht, PhD, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Maryland School of Medicine, Bressler Research Laboratories 11-045A, 655 West Baltimore St, Baltimore, MD 21201, USA.
| | - Graham W Aberdeen
- Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jeffery S Babischkin
- Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Steven J Prior
- Department of Kinesiology, University of Maryland School of Public Health, College Park, MD, USA
| | - Terrie J Lynch
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA
| | - Irene A Baranyk
- Departments of Obstetrics, Gynecology, Reproductive Sciences and Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Gerald J Pepe
- Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, USA
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15
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Vipin VA, Blesson CS, Yallampalli C. Maternal low protein diet and fetal programming of lean type 2 diabetes. World J Diabetes 2022; 13:185-202. [PMID: 35432755 PMCID: PMC8984567 DOI: 10.4239/wjd.v13.i3.185] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/30/2021] [Accepted: 02/10/2022] [Indexed: 02/06/2023] Open
Abstract
Maternal nutrition is found to be the key factor that determines fetal health in utero and metabolic health during adulthood. Metabolic diseases have been primarily attributed to impaired maternal nutrition during pregnancy, and impaired nutrition has been an immense issue across the globe. In recent years, type 2 diabetes (T2D) has reached epidemic proportion and is a severe public health problem in many countries. Although plenty of research has already been conducted to tackle T2D which is associated with obesity, little is known regarding the etiology and pathophysiology of lean T2D, a variant of T2D. Recent studies have focused on the effects of epigenetic variation on the contribution of in utero origins of lean T2D, although other mechanisms might also contribute to the pathology. Observational studies in humans and experiments in animals strongly suggest an association between maternal low protein diet and lean T2D phenotype. In addition, clear sex-specific disease prevalence was observed in different studies. Consequently, more research is essential for the understanding of the etiology and pathophysiology of lean T2D, which might help to develop better disease prevention and treatment strategies. This review examines the role of protein insufficiency in the maternal diet as the central driver of the developmental programming of lean T2D.
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Affiliation(s)
- Vidyadharan Alukkal Vipin
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
| | - Chellakkan Selvanesan Blesson
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
- Family Fertility Center, Texas Children's Hospital, Houston, TX 77030, United States
| | - Chandra Yallampalli
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX 77030, United States
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16
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Brown MR, Matveyenko AV. It's What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets. Front Endocrinol (Lausanne) 2022; 13:842603. [PMID: 35355560 PMCID: PMC8960041 DOI: 10.3389/fendo.2022.842603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/07/2022] [Indexed: 01/07/2023] Open
Abstract
Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in "what" and "when" we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism's glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs. Both successful and failed adaptation to dynamic environmental stimuli has been postulated to occur due to changes in the transcriptional and epigenetic regulation of pathways associated with islet secretory function and survival. Therefore, in this review we examined and evaluated the current evidence elucidating the key epigenetic mechanisms and transcriptional programs underlying the islet's coordinated response to the interaction between the timing and the composition of dietary nutrients common to modern lifestyles. With the explosion of next generation sequencing, along with the development of novel informatic and -omic approaches, future work will continue to unravel the environmental-epigenetic relationship in islet biology with the goal of identifying transcriptional and epigenetic targets associated with islet perturbations in T2DM.
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Affiliation(s)
- Matthew R. Brown
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
| | - Aleksey V. Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
- Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
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17
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Placental Insulin Receptor Transiently Regulates Glucose Homeostasis in the Adult Mouse Offspring of Multiparous Dams. Biomedicines 2022; 10:biomedicines10030575. [PMID: 35327377 PMCID: PMC8945682 DOI: 10.3390/biomedicines10030575] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/25/2022] [Accepted: 02/27/2022] [Indexed: 02/04/2023] Open
Abstract
In pregnancies complicated by maternal obesity and gestational diabetes mellitus, there is strong evidence to suggest that the insulin signaling pathway in the placenta may be impaired. This may have potential effects on the programming of the metabolic health in the offspring; however, a direct link between the placental insulin signaling pathway and the offspring health remains unknown. Here, we aimed to understand whether specific placental loss of the insulin receptor (InsR) has a lasting effect on the offspring health in mice. Obesity and glucose homeostasis were assessed in the adult mouse offspring on a normal chow diet (NCD) followed by a high-fat diet (HFD) challenge. Compared to their littermate controls, InsR KOplacenta offspring were born with normal body weight and pancreatic β-cell mass. Adult InsR KOplacenta mice exhibited normal glucose homeostasis on an NCD. Interestingly, under a HFD challenge, adult male InsR KOplacenta offspring demonstrated lower body weight and a mildly improved glucose homeostasis associated with parity. Together, our data show that placenta-specific insulin receptor deletion does not adversely affect offspring glucose homeostasis during adulthood. Rather, there may potentially be a mild and transient protective effect in the mouse offspring of multiparous dams under the condition of a diet-induced obesogenic challenge.
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18
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Zapaterini JR, Fonseca ARB, Bidinotto LT, Colombelli KT, Rossi ALD, Kass L, Justulin LA, Barbisan LF. Maternal Low-Protein Diet Deregulates DNA Repair and DNA Replication Pathways in Female Offspring Mammary Gland Leading to Increased Chemically Induced Rat Carcinogenesis in Adulthood. Front Cell Dev Biol 2022; 9:756616. [PMID: 35178394 PMCID: PMC8844450 DOI: 10.3389/fcell.2021.756616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 12/09/2021] [Indexed: 11/13/2022] Open
Abstract
Studies have shown that maternal malnutrition, especially a low-protein diet (LPD), plays a key role in the developmental mechanisms underlying mammary cancer programming in female offspring. However, the molecular pathways associated with this higher susceptibility are still poorly understood. Thus, this study investigated the adverse effects of gestational and lactational low protein intake on gene expression of key pathways involved in mammary tumor initiation after a single dose of N-methyl-N-nitrosourea (MNU) in female offspring rats. Pregnant Sprague-Dawley rats were fed a normal-protein diet (NPD) (17% protein) or LPD (6% protein) from gestational day 1 to postnatal day (PND) 21. After weaning (PND 21), female offspring (n = 5, each diet) were euthanized for histological analysis or received NPD (n = 56 each diet). At PND 28 or 35, female offspring received a single dose of MNU (25 mg/kg body weight) (n = 28 each diet/timepoint). After 24 h, some females (n = 10 each diet/timepoint) were euthanized for histological, immunohistochemical, and molecular analyses at PDN 29 or 36. The remaining animals (n = 18 each diet/timepoint) were euthanized when tumors reached ≥2 cm or at PND 250. Besides the mammary gland development delay observed in LPD 21 and 28 groups, the gene expression profile demonstrated that maternal LPD deregulated 21 genes related to DNA repair and DNA replication pathways in the mammary gland of LPD 35 group after MNU. We further confirmed an increased γ-H2AX (DNA damage biomarker) and in ER-α immunoreactivity in mammary epithelial cells in the LPD group at PND 36. Furthermore, these early postnatal events were followed by significantly higher mammary carcinogenesis susceptibility in offspring at adulthood. Thus, the results indicate that maternal LPD influenced the programming of chemically induced mammary carcinogenesis in female offspring through increase in DNA damage and deregulation of DNA repair and DNA replication pathways. Also, Cidea upregulation gene in the LPD 35 group may suggest that maternal LPD could deregulate genes possibly leading to increased risk of mammary cancer development and/or poor prognosis. These findings increase the body of evidence of early-transcriptional mammary gland changes influenced by maternal LPD, resulting in differential response to breast tumor initiation and susceptibility and may raise discussions about lifelong prevention of breast cancer risk.
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Affiliation(s)
- Joyce R Zapaterini
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Antonio R B Fonseca
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Lucas T Bidinotto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Botucatu, Brazil.,Barretos School of Health Sciences, Dr. Paulo Prata-FACISB, Barretos, Brazil
| | - Ketlin T Colombelli
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | | | - Laura Kass
- Instituto de Salud y Ambiente del Litoral (UNL-CONICET), Facultad de Bioquímica y Ciencias Biológicas, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Luis A Justulin
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
| | - Luis F Barbisan
- Department of Structural and Functional Biology, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, Brazil
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19
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Wu Y, Zhang Q, Xiao X. The Effect and Potential Mechanism of Maternal Micronutrient Intake on Offspring Glucose Metabolism: An Emerging Field. Front Nutr 2021; 8:763809. [PMID: 34746215 PMCID: PMC8568771 DOI: 10.3389/fnut.2021.763809] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 09/27/2021] [Indexed: 11/13/2022] Open
Abstract
Diabetes has become the most common metabolic disease around the world. In addition to genetic and environmental factors in adulthood, the early life environment is critical to the progression of diabetes in adults, especially the environment during the fetal period; this concept is called “fetal programming.” Substantial evidence has illustrated the key role of early life macronutrient in programming metabolic diseases. Recently, the effect of maternal micronutrient intake on offspring glucose metabolism during later life has become an emerging field. This review focuses on updated human and animal evidence about the effect of maternal micronutrient status on offspring glucose metabolism and the underlying mechanism.
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Affiliation(s)
- Yifan Wu
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Ministry of Health, Department of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
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20
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Sałówka A, Martinez-Sanchez A. Molecular Mechanisms of Nutrient-Mediated Regulation of MicroRNAs in Pancreatic β-cells. Front Endocrinol (Lausanne) 2021; 12:704824. [PMID: 34803905 PMCID: PMC8600252 DOI: 10.3389/fendo.2021.704824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 08/02/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cells within the islets of Langerhans respond to rising blood glucose levels by secreting insulin that stimulates glucose uptake by peripheral tissues to maintain whole body energy homeostasis. To different extents, failure of β-cell function and/or β-cell loss contribute to the development of Type 1 and Type 2 diabetes. Chronically elevated glycaemia and high circulating free fatty acids, as often seen in obese diabetics, accelerate β-cell failure and the development of the disease. MiRNAs are essential for endocrine development and for mature pancreatic β-cell function and are dysregulated in diabetes. In this review, we summarize the different molecular mechanisms that control miRNA expression and function, including transcription, stability, posttranscriptional modifications, and interaction with RNA binding proteins and other non-coding RNAs. We also discuss which of these mechanisms are responsible for the nutrient-mediated regulation of the activity of β-cell miRNAs and identify some of the more important knowledge gaps in the field.
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Affiliation(s)
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
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21
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Beetch M, Alejandro EU. Placental mTOR Signaling and Sexual Dimorphism in Metabolic Health across the Lifespan of Offspring. CHILDREN 2021; 8:children8110970. [PMID: 34828683 PMCID: PMC8619510 DOI: 10.3390/children8110970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/23/2021] [Accepted: 10/24/2021] [Indexed: 11/17/2022]
Abstract
Robust evidence of fetal programming of adult disease has surfaced in the last several decades. Human and preclinical investigations of intrauterine insults report perturbations in placental nutrient sensing by the mechanistic target of rapamycin (mTOR). This review focuses on pregnancy complications associated with placental mTOR regulation, such as fetal growth restriction (FGR), fetal overgrowth, gestational diabetes mellitus (GDM), polycystic ovarian syndrome (PCOS), maternal nutrient restriction (MNR), preeclampsia (PE), maternal smoking, and related effects on offspring birthweight. The link between mTOR-associated birthweight outcomes and offspring metabolic health trajectory with a focus on sexual dimorphism are discussed. Both human physiology and animal models are summarized to facilitate in depth understanding. GDM, PCOS and fetal overgrowth are associated with increased placental mTOR, whereas FGR, MNR and maternal smoking are linked to decreased placental mTOR activity. Generally, birth weight is reduced in complications with decreased mTOR (i.e., FGR, MNR, maternal smoking) and higher with increased mTOR (GDM, PCOS). Offspring display obesity or a higher body mass index in childhood and adulthood, impaired glucose and insulin tolerance in adulthood, and deficiencies in pancreatic beta-cell mass and function compared to offspring from uncomplicated pregnancies. Defining causal players in the fetal programming of offspring metabolic health across the lifespan will aid in stopping the vicious cycle of obesity and type II diabetes.
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22
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Zheng J, Zhang L, Liu J, Li Y, Zhang J. Long-Term Effects of Maternal Low-Protein Diet and Post-weaning High-Fat Feeding on Glucose Metabolism and Hypothalamic POMC Promoter Methylation in Offspring Mice. Front Nutr 2021; 8:657848. [PMID: 34485357 PMCID: PMC8415226 DOI: 10.3389/fnut.2021.657848] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 07/13/2021] [Indexed: 12/22/2022] Open
Abstract
Substantial evidence indicated that maternal malnutrition could increase the susceptibility to obesity, insulin resistance, and type 2 diabetes in adulthood. It is increasingly apparent that the brain, especially the hypothalamus, plays a critical role in glucose homeostasis. However, little information is known about the mechanisms linking maternal protein restriction combined with post-weaning high-fat (HF) feeding with altered expression of brain neurotransmitters, and investigations into the epigenetic modifications of hypothalamus in offspring have not been fully elucidated. Our objective was to explore the effects of maternal protein restriction combined with post-weaning HF feeding on glucose metabolism and hypothalamic POMC methylation in male offspring mice. C57/BL6 mice were fed on either low-protein (LP) or normal chow (NC) diet throughout gestation and lactation. Then, the male offspring were randomly weaned to either NC or high-fat (HF) diet until 32 weeks of age. Gene expressions and DNA methylation of hypothalamic proopiomelanocortin (POMC) and melanocortin receptor 4 (MC4R) were determined in male offspring. The results showed that birth weights and body weights at weaning were both significantly lower in male offspring mice of the dams fed with a LP diet. Maternal protein restriction combined with post-weaning high-fat feeding, predisposes higher body weight, persistent glucose intolerance (from weaning to 32 weeks of age), hyperinsulinemia, and hyperleptinemia in male offspring mice. POMC and MC4R expressions were significantly increased in offspring mice fed with maternal LP and postnatal high-fat diet (P < 0.05). Furthermore, maternal protein restriction combined with post-weaning high-fat feeding induced hypomethylation of POMC promoter in the hypothalamus (P < 0.05) and POMC-specific methylation (%) was negatively correlated with the glucose response to a glucose load in male offspring mice (r = -0.42, P = 0.039). In conclusion, maternal LP diet combined with post-weaning high-fat feeding predisposed the male offspring to impaired glucose metabolism and hypothalamic POMC hypomethylation. These findings can advance our thinking about hypothalamic POMC gene methylation between maternal LP diet combined with post-weaning high-fat feeding and metabolic health in offspring.
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Affiliation(s)
- Jia Zheng
- Department of Endocrinology, Peking University First Hospital, Beijing, China
| | - Ling Zhang
- Department of Endocrinology, Peking University First Hospital, Beijing, China
| | - Jiayi Liu
- Department of Endocrinology, Peking University First Hospital, Beijing, China
| | - Yanli Li
- Department of Endocrinology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Junqing Zhang
- Department of Endocrinology, Peking University First Hospital, Beijing, China
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23
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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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24
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Yu Y, Zhang J, Wang J, Sun B. MicroRNAs: The novel mediators for nutrient-modulating biological functions. Trends Food Sci Technol 2021. [DOI: 10.1016/j.tifs.2021.05.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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25
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Akhaphong B, Baumann DC, Beetch M, Lockridge AD, Jo S, Wong A, Zemanovic T, Mohan R, Fondevilla DL, Sia M, Pineda-Cortel MRB, Alejandro EU. Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice. JCI Insight 2021; 6:149271. [PMID: 34032632 PMCID: PMC8410096 DOI: 10.1172/jci.insight.149271] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/19/2021] [Indexed: 11/17/2022] Open
Abstract
Fetal growth restriction, or low birth weight, is a strong determinant for eventual obesity and type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulates fetal birth weight and the metabolic health trajectory of the offspring. In the current study, we used a genetic model with loss of placental mTOR function (mTOR-KOPlacenta) to test the direct role of mTOR signaling on birth weight and metabolic health in the adult offspring. mTOR-KOPlacenta animals displayed reduced placental area and total weight, as well as fetal body weight at embryonic day (E) 17.5. Birth weight and serum insulin levels were reduced; however, β cell mass was normal in mTOR-KOPlacenta newborns. Adult mTOR-KOPlacenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared with littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.
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Affiliation(s)
- Brian Akhaphong
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Daniel C Baumann
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Megan Beetch
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Amber D Lockridge
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Alicia Wong
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Tate Zemanovic
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Ramkumar Mohan
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Danica L Fondevilla
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Michelle Sia
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - Maria Ruth B Pineda-Cortel
- Research Center for the Natural and Applied Sciences and.,Department of Medical Technology, University of Santo Tomas, Manila, Philippines
| | - Emilyn U Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
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26
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Disruption of O-Linked N-Acetylglucosamine Signaling in Placenta Induces Insulin Sensitivity in Female Offspring. Int J Mol Sci 2021; 22:ijms22136918. [PMID: 34203166 PMCID: PMC8267851 DOI: 10.3390/ijms22136918] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/19/2021] [Accepted: 06/20/2021] [Indexed: 12/15/2022] Open
Abstract
Placental dysfunction can lead to fetal growth restriction which is associated with perinatal morbidity and mortality. Fetal growth restriction increases the risk of obesity and diabetes later in life. Placental O-GlcNAc transferase (OGT) has been identified as a marker and a mediator of placental insufficiency in the setting of prenatal stress, however, its role in the fetal programming of metabolism and glucose homeostasis remains unknown. We aim to determine the long-term metabolic outcomes of offspring with a reduction in placental OGT. Mice with a partial reduction and a full knockout of placenta-specific OGT were generated utilizing the Cre-Lox system. Glucose homeostasis and metabolic parameters were assessed on a normal chow and a high-fat diet in both male and female adult offspring. A reduction in placental OGT did not demonstrate differences in the metabolic parameters or glucose homeostasis compared to the controls on a standard chow. The high-fat diet provided a metabolic challenge that revealed a decrease in body weight gain (p = 0.02) and an improved insulin tolerance (p = 0.03) for offspring with a partially reduced placental OGT but not when OGT was fully knocked out. Changes in body weight were not associated with changes in energy homeostasis. Offspring with a partial reduction in placental OGT demonstrated increased hepatic Akt phosphorylation in response to insulin treatment (p = 0.02). A partial reduction in placental OGT was protective from weight gain and insulin intolerance when faced with the metabolic challenge of a high-fat diet. This appears to be, in part, due to increased hepatic insulin signaling. The findings of this study contribute to the greater understanding of fetal metabolic programming and the effect of placental OGT on peripheral insulin sensitivity and provides a target for future investigation and clinical applications.
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Elsakr JM, Zhao SK, Ricciardi V, Dean TA, Takahashi DL, Sullivan E, Wesolowski SR, McCurdy CE, Kievit P, Friedman JE, Aagaard KM, Edwards DRV, Gannon M. Western-style diet consumption impairs maternal insulin sensitivity and glucose metabolism during pregnancy in a Japanese macaque model. Sci Rep 2021; 11:12977. [PMID: 34155315 PMCID: PMC8217225 DOI: 10.1038/s41598-021-92464-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/04/2021] [Indexed: 12/26/2022] Open
Abstract
The prevalence of maternal obesity is increasing in the United States. Offspring born to women with obesity or poor glycemic control have greater odds of becoming obese and developing metabolic disease later in life. Our group has utilized a macaque model to study the metabolic effects of consumption of a calorically-dense, Western-style diet (WSD; 36.3% fat) during pregnancy. Here, our objective was to characterize the effects of WSD and obesity, alone and together, on maternal glucose tolerance and insulin levels in dams during each pregnancy. Recognizing the collinearity of maternal measures, we adjusted for confounding factors including maternal age and parity. Based on intravenous glucose tolerance tests, dams consuming a WSD showed lower glucose area under the curve during first study pregnancies despite increased body fat percentage and increased insulin area under the curve. However, with (1) prolonged WSD feeding, (2) multiple diet switches, and/or (3) increasing age and parity, WSD was associated with increasingly higher insulin levels during glucose tolerance testing, indicative of insulin resistance. Our results suggest that prolonged or recurrent calorically-dense WSD and/or increased parity, rather than obesity per se, drive excess insulin resistance and metabolic dysfunction. These observations in a highly relevant species are likely of clinical and public health importance given the comparative ease of maternal dietary modifications relative to the low likelihood of successfully reversing obesity in the course of any given pregnancy.
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Affiliation(s)
- Joseph M Elsakr
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA
| | - Sifang Kathy Zhao
- Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 600, Nashville, TN, 37203-1738, USA
| | - Valerie Ricciardi
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, 7465 MRBIV, Nashville, TN, 37232-0475, USA
| | - Tyler A Dean
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Diana L Takahashi
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Elinor Sullivan
- Division of Neuroscience, Oregon National Primate Research Center, Beaverton, OR, USA
| | | | - Carrie E McCurdy
- Department of Human Physiology, University of Oregon, Eugene, OR, 97403, USA
| | - Paul Kievit
- Division of Cardiometabolic Health, Oregon National Primate Research Center, Beaverton, OR, USA
| | - Jacob E Friedman
- Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA
| | - Kjersti M Aagaard
- Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, and Molecular and Human Genetics, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, 77030, USA
| | - Digna R Velez Edwards
- Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, 2525 West End Avenue, Suite 600, Nashville, TN, 37203-1738, USA.
- Department of Biomedical Informatics, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN, USA.
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, 7465 MRBIV, Nashville, TN, 37232-0475, USA.
- Department of Veterans Affairs Tennessee Valley, Nashville, TN, USA.
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
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28
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Akhaphong B, Gregg B, Kumusoglu D, Jo S, Singer K, Scheys J, DelProposto J, Lumeng C, Bernal-Mizrachi E, Alejandro EU. Maternal High-Fat Diet During Pre-Conception and Gestation Predisposes Adult Female Offspring to Metabolic Dysfunction in Mice. Front Endocrinol (Lausanne) 2021; 12:780300. [PMID: 35111136 PMCID: PMC8801938 DOI: 10.3389/fendo.2021.780300] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 11/24/2021] [Indexed: 01/31/2023] Open
Abstract
The risk of obesity in adulthood is subject to programming in the womb. Maternal obesity contributes to programming of obesity and metabolic disease risk in the adult offspring. With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of maternal high-fat diet (HFD) during pregnancy on offspring's metabolic heath trajectory. In the present study, we determined the long-term metabolic outcomes on adult male and female offspring of dams fed with HFD during pregnancy. C57BL/6J dams were fed either Ctrl or 60% Kcal HFD for 4 weeks before and throughout pregnancy, and we tested glucose homeostasis in the adult offspring. Both Ctrl and HFD-dams displayed increased weight during pregnancy, but HFD-dams gained more weight than Ctrl-dams. Litter size and offspring birthweight were not different between HFD-dams or Ctrl-dams. A significant reduction in random blood glucose was evident in newborns from HFD-dams compared to Ctrl-dams. Islet morphology and alpha-cell fraction were normal but a reduction in beta-cell fraction was observed in newborns from HFD-dams compared to Ctrl-dams. During adulthood, male offspring of HFD-dams displayed comparable glucose tolerance under normal chow. Male offspring re-challenged with HFD displayed glucose intolerance transiently. Adult female offspring of HFD-dams demonstrated normal glucose tolerance but displayed increased insulin resistance relative to controls under normal chow diet. Moreover, adult female offspring of HFD-dams displayed increased insulin secretion in response to high-glucose treatment, but beta-cell mass were comparable between groups. Together, these data show that maternal HFD at pre-conception and during gestation predisposes the female offspring to insulin resistance in adulthood.
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Affiliation(s)
- Brian Akhaphong
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Brigid Gregg
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Doga Kumusoglu
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
| | - Seokwon Jo
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
| | - Kanakadurga Singer
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Joshua Scheys
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
| | - Jennifer DelProposto
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Carey Lumeng
- Department of Pediatrics, Division of Diabetes, Endocrinology, and Metabolism, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Ernesto Bernal-Mizrachi
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
- Diabetes, VA Ann Arbor Healthcare System, Ann Arbor, MI, United States
- Miami VA Healthcare System and Division Endocrinology, Metabolism and Diabetes, University of Miami, Miami, FL, United States
- *Correspondence: Ernesto Bernal-Mizrachi, ; Emilyn U. Alejandro,
| | - Emilyn U. Alejandro
- Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, United States
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, Ann Arbor, United States
- *Correspondence: Ernesto Bernal-Mizrachi, ; Emilyn U. Alejandro,
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29
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Petkovic M, Sørensen AE, Leal EC, Carvalho E, Dalgaard LT. Mechanistic Actions of microRNAs in Diabetic Wound Healing. Cells 2020; 9:E2228. [PMID: 33023156 PMCID: PMC7601058 DOI: 10.3390/cells9102228] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 09/25/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
Wound healing is a complex biological process that is impaired under diabetes conditions. Chronic non-healing wounds in diabetes are some of the most expensive healthcare expenditures worldwide. Early diagnosis and efficacious treatment strategies are needed. microRNAs (miRNAs), a class of 18-25 nucleotide long RNAs, are important regulatory molecules involved in gene expression regulation and in the repression of translation, controlling protein expression in health and disease. Recently, miRNAs have emerged as critical players in impaired wound healing and could be targets for potential therapies for non-healing wounds. Here, we review and discuss the mechanistic background of miRNA actions in chronic wounds that can shed the light on their utilization as specific wound healing biomarkers.
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Affiliation(s)
- Marija Petkovic
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Anja Elaine Sørensen
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
| | - Ermelindo Carreira Leal
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
| | - Eugenia Carvalho
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; (E.C.L.); (E.C.)
- Institute for Interdisciplinary Research, University of Coimbra, 3030-789 Coimbra, Portugal
- Department of Geriatrics, University of Arkansas for Medical Sciences, and Arkansas Children’s Research Institute, Little Rock, AR 72205, USA
| | - Louise Torp Dalgaard
- Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark; (A.E.S.); (L.T.D.)
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