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      Hypergravity disruption of homeorhetic adaptations to lactation in rat dams include changes in circadian clocks

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          Summary

          Altered gravity load induced by spaceflight (microgravity) and centrifugation (hypergravity) is associated with changes in circadian, metabolic, and reproductive systems. Exposure to 2-g hypergravity (HG) during pregnancy and lactation decreased rate of mammary metabolic activity and increased pup mortality. We hypothesize HG disrupted maternal homeorhetic responses to pregnancy and lactation are due to changes in maternal metabolism, hormone concentrations, and maternal behavior related to gravity induced alterations in circadian clocks. Effect of HG exposure on mammary, liver and adipose tissue metabolism, plasma hormones and maternal behavior were analyzed in rat dams from mid-pregnancy (Gestational day [G]11) through early lactation (Postnatal day [P]3); comparisons were made across five time-points: G20, G21, P0 (labor and delivery), P1 and P3. Blood, mammary, liver, and adipose tissue were collected for analyzing plasma hormones, glucose oxidation to CO 2 and incorporation into lipids, or gene expression. Maternal behavioral phenotyping was conducted using time-lapse videographic analyses. Dam and fetal-pup body mass were significantly reduced in HG in all age groups. HG did not affect labor and delivery; however, HG pups experienced a greater rate of mortality. PRL, corticosterone, and insulin levels and receptor genes were altered by HG. Mammary, liver and adipose tissue metabolism and expression of genes that regulate lipid metabolism were altered by HG exposure. Exposure to HG significantly changed expression of core clock genes in mammary and liver and circadian rhythms of maternal behavior. Gravity load alterations in dam's circadian system may have impacted homeorhetic adaptations needed for a successful lactation.

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          Most cited references68

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          The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation.

          The ability to ensure continuous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-alpha, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess.
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            Circadian clocks: regulators of endocrine and metabolic rhythms.

            Daily and seasonal rhythms in the endocrine system are co-ordinated by a hypothalamic pacemaker, the suprachiasmatic nuclei (SCN) that is synchronised to solar time by direct retinal afferents. Individual SCN neurons are circadian clocks, their intrinsic oscillator consisting of a series of interlinked autoregulatory transcriptional/post-translational feedback loops incorporating Period (Per) and Cryptochrome (Cry) genes. Mutations that alter the rate of transcription of Per and Cry genes or the stability of Per and Cry proteins affect clock speed. Molecular timekeeping in SCN neurons is synchronised and sustained by interneuronal neuropeptidergic signals. A molecular clock mechanism comparable to that of the SCN is present in most major organ systems. These tissue clocks are synchronised by endocrine, autonomic and behavioural cues that are dependent on the SCN, and in turn they drive the circadian expression of local transcriptomes, thereby co-ordinating circadian metabolism and physiology. Rhythmic glucocorticoid signalling is a prominent mediator of SCN output and internal synchroniser. The role of local SCN-synchronised clocks in controlling vital processes, including xenobiotic detoxification, cell division and nutrient metabolism, is essential to health, and disturbances to circadian timing arising from modern working schedules are becoming recognised as an increasingly relevant factor in major systemic illness. Moreover, the newly identified molecular components of circadian control systems provide novel avenues for therapeutic intervention.
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              Adaptations of glucose metabolism during pregnancy and lactation.

              Increased glucose requirements of the gravid uterus during late pregnancy and even greater requirements of the lactating mammary glands necessitate major adjustments in glucose production and utilization in maternal liver, adipose tissue, skeletal muscle, and other tissues. In ruminants, which at all times rely principally on hepatic gluconeogenesis for their glucose supply, hepatic glucose synthesis during late pregnancy and early lactation is increased to accommodate uterine or mammary demands even when the supply of dietary substrate is inadequate. At the same time, glucose utilization by adipose tissue and muscle is reduced. In pregnant animals, these responses are exaggerated by moderate undernutrition and are mediated by reduced tissue sensitivity and responsiveness to insulin, associated with decreased tissue expression of the insulin-responsive facilitative glucose transporter, GLUT4. Peripheral tissue responses to insulin remain severely attenuated during early lactation but recover as the animal progresses through mid lactation. Specific homeorhetic effectors of decreased insulin-mediated glucose metabolism during late pregnancy have yet to be conclusively identified. In contrast, somatotropin is almost certainly a predominant homeorhetic influence during lactation because its exogenous administration causes specific changes in glucose metabolism (and many other functions) of various nonmammary tissues which faithfully mimic normal adaptations to early lactation.
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                Author and article information

                Journal
                Biol Open
                Biol Open
                biolopen
                bio
                Biology Open
                The Company of Biologists (Bidder Building, 140 Cowley Road, Cambridge, CB4 0DL, UK )
                2046-6390
                15 June 2012
                30 April 2012
                : 1
                : 6
                : 570-581
                Affiliations
                [1 ]Department of Animal Science, Purdue University , West Lafayette, IN 47907, USA
                [2 ]Department of Animal Science, University of Vermont , Burlington, VT 05405, USA
                [3 ]NASA/Ames Research Center , Moffett Field, CA 94035-1000, USA
                [4 ]Department of Obstetrics and Gynecology, Wake Forest University School of Medicine , Winston-Salem, NC 27101, USA
                Author notes
                [* ]Author for correspondence ( theresa-casey@ 123456purdue.edu )
                [‡]

                These authors contributed equally to this project

                Article
                BIO2012687
                10.1242/bio.2012687
                3509447
                23213450
                c47cacd1-efc3-4c05-be51-483da307831e
                © 2012. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License ( http://creativecommons.org/licenses/by-nc-sa/3.0/).

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                Categories
                Research Article

                Life sciences
                circadian,hypergravity,lactation,homeorhesis,mammary,pregnancy
                Life sciences
                circadian, hypergravity, lactation, homeorhesis, mammary, pregnancy

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