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      Developmental Programming of Obesity and Diabetes in Mouse, Monkey, and Man in 2018: Where Are We Headed?

      discussion
      Diabetes
      American Diabetes Association

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          Abstract

          Childhood obesity and its comorbidities continue to accelerate across the globe. Two-thirds of pregnant women are obese/overweight, as are 20% of preschoolers. Gestational diabetes mellitus (GDM) is escalating, affecting up to 1 in 5 pregnant women. The field of developmental origins of health and disease has begun to move beyond associations to potential causal mechanisms for developmental programming. Evidence across species compellingly demonstrates that maternal obesity, diabetes, and Western-style diets create a long-lasting signature on multiple systems, including infant stem cells, the early immune system, and gut microbiota. Such exposures accelerate adipogenesis, disrupt mitochondrial metabolism, and impair energy sensing, affecting neurodevelopment, liver, pancreas, and skeletal muscle. Attempts to prevent developmental programming have met with very limited success. A challenging level of complexity is involved in how the host genome, metabolome, and microbiome throughout pregnancy and lactation increase the offspring’s risk of metabolic diseases across the life span. Considerable gaps in knowledge include the timing of exposure(s) and permanence or plasticity of the response, encompassing effects from both maternal and paternal dysmetabolism. Basic, translational, and human intervention studies targeting pathways that connect diet, microbiota, and metabolism in mothers with obesity/GDM and their infants are a critical unmet need and present new challenges for disease prevention in the next generation.

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          Most cited references95

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          The maternal microbiota drives early postnatal innate immune development.

          Postnatal colonization of the body with microbes is assumed to be the main stimulus to postnatal immune development. By transiently colonizing pregnant female mice, we show that the maternal microbiota shapes the immune system of the offspring. Gestational colonization increases intestinal group 3 innate lymphoid cells and F4/80(+)CD11c(+) mononuclear cells in the pups. Maternal colonization reprograms intestinal transcriptional profiles of the offspring, including increased expression of genes encoding epithelial antibacterial peptides and metabolism of microbial molecules. Some of these effects are dependent on maternal antibodies that potentially retain microbial molecules and transmit them to the offspring during pregnancy and in milk. Pups born to mothers transiently colonized in pregnancy are better able to avoid inflammatory responses to microbial molecules and penetration of intestinal microbes.
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            Mesenchymal stem cells.

            Stem cells have two features: the ability to differentiate along different lineages and the ability of self-renewal. Two major types of stem cells have been described, namely, embryonic stem cells and adult stem cells. Embryonic stem cells (ESC) are obtained from the inner cell mass of the blastocyst and are associated with tumorigenesis, and the use of human ESCs involves ethical and legal considerations. The use of adult mesenchymal stem cells is less problematic with regard to these issues. Mesenchymal stem cells (MSCs) are stromal cells that have the ability to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as umbilical cord, endometrial polyps, menses blood, bone marrow, adipose tissue, etc. This is because the ease of harvest and quantity obtained make these sources most practical for experimental and possible clinical applications. Recently, MSCs have been found in new sources, such as menstrual blood and endometrium. There are likely more sources of MSCs waiting to be discovered, and MSCs may be a good candidate for future experimental or clinical applications. One of the major challenges is to elucidate the mechanisms of differentiation, mobilization, and homing of MSCs, which are highly complex. The multipotent properties of MSCs make them an attractive choice for possible development of clinical applications. Future studies should explore the role of MSCs in differentiation, transplantation, and immune response in various diseases.
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              Cellular mechanisms for insulin resistance in normal pregnancy and gestational diabetes.

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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                November 2018
                11 October 2018
                : 67
                : 11
                : 2137-2151
                Affiliations
                [1]Section of Neonatology, Department of Pediatrics; Department of Biochemistry & Molecular Genetics; Division of Endocrinology, Metabolism & Diabetes, Department of Medicine; and Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO
                Author notes
                Corresponding author: Jacob E. Friedman, jed.friedman@ 123456ucdenver.edu .
                Author information
                http://orcid.org/0000-0002-9283-9254
                Article
                0011
                10.2337/dbi17-0011
                6198344
                30348820
                6a56410d-a928-483f-b2c8-b44ace517031
                © 2018 by the American Diabetes Association.

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

                History
                : 19 March 2018
                : 21 August 2018
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 158, Pages: 15
                Funding
                Funded by: National Institutes of Health, DOI http://dx.doi.org/10.13039/100000002;
                Award ID: R24DK090964
                Award ID: P30DK048520
                Award ID: R01DK101659
                Award ID: 1UG3OD023248
                Award ID: R01HL109517
                Categories
                0310
                Perspectives in Diabetes

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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