Browsing by Author "Kimball, Scot R."

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    Intermittent Bolus Feeding Enhances Organ Growth More Than Continuous Feeding in a Neonatal Piglet Model
    El-Kadi, Samer Wassim; Boutry-Regard, Claire; Suryawan, Agus; Nguyen, Hanh V.; Kimball, Scot R.; Fiorotto, Marta L.; Davis, Teresa A. (2021-01)
    Background: Orogastric tube feeding is frequently prescribed for neonates who cannot ingest food normally. In a piglet model of the neonate, greater skeletal muscle growth is sustained by upregulation of translation initiation signaling when nutrition is delivered by intermittent bolus meals, rather than continuously. Objectives: The objective of this study was to determine the long-term effects of feeding frequency on organ growth and the mechanism by which feeding frequency modulates protein anabolism in these organs. Methods: Eighteen neonatal pigs were fed by gastrostomy tube the same amount of a sow milk replacer either by continuous infusion (CON) or on an intermittent bolus schedule (INT). After 21 d of feeding, the pigs were killed without interruption of feeding (CON; n = 6) or immediately before (INT-0; n = 6) or 60 min after (INT-60; n = 6) a meal, and fractional protein synthesis rates and activation indexes of signaling pathways that regulate translation initiation were measured in the heart, jejunum, ileum, kidneys, and liver. Results: Compared with continuous feeding, intermittent feeding stimulated the growth of the liver (+64%), jejunum (+48%), ileum (+40%), heart (+64%), and kidney (+56%). The increases in heart, kidney, jejunum, and ileum masses were proportional to whole body lean weight gain, but liver weight gain was greater in the INT-60 than the CON, and intermediate for the INT-0 group. For the liver and ileum, but not the heart, kidney, and jejunum, INT-60 compared with CON pigs had greater fractional protein synthesis rates (22% and 48%, respectively) and was accompanied by an increase in ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E binding protein 1 phosphorylation. Conclusions: These results suggest that intermittent bolus compared with continuous orogastric feeding enhances organ growth and that in the ileum and liver, intermittent feeding enhances protein synthesis by stimulating translation initiation.
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    Intermittent bolus feeding promotes greater lean growth than continuous feeding in a neonatal piglet model
    El-Kadi, Samer Wassim; Boutry, Claire; Suryawan, Agus; Gazzaneo, Maria C.; Orellana, Renan A.; Srivastava, Neeraj; Nguyen, Hanh V.; Kimball, Scot R.; Fiorotto, Marta L.; Davis, Teresa A. (2018-10)
    Background: Orogastric tube feeding is indicated in neonates with an impaired ability to ingest food normally and can be administered with an intermittent bolus or continuous feeding schedule. Objectives: The objectives were to 1) compare the long-term effect of continuous with intermittent feeding on growth using the newborn pig as a model, 2) determine whether feeding frequency alters lean tissue and fat mass gain, and 3) identify the signaling mechanisms by which protein deposition is controlled in skeletal muscle in response to feeding frequency. Design: Neonatal pigs were fed the same amount of a balanced formula by orogastric tube either as an intermittent bolus meal every 4 h (INT) or as a continuous infusion (CON). Body composition was assessed at the start and end of the study by dual-energy X-ray absorptiometry, and hormone and substrate profiles, muscle mass, protein synthesis, and indexes of nutrient and insulin signaling were measured after 21 d. Results: Body weight, lean mass, spine length, and skeletal muscle mass were greater in the INT group than in the CON group. Skeletal muscle fractional protein synthesis rates were greater in the INT group after a meal than in the CON group and were associated with higher circulating branched-chain amino acid and insulin concentrations. Skeletal muscle protein kinase B (PKB) and ribosomal protein S6 kinase phosphorylation and eukaryotic initiation factor (eIF) 4E-eIF4G complex formation were higher, whereas eIF2 alpha phosphorylation was lower in the INT group than in the CON group, indicating enhanced activation of insulin and amino acid signaling to translation initiation. Conclusions: These results suggest that when neonates are fed the same amounts of nutrients as intermittent meals rather than continuously there is greater lean growth. This response can be ascribed, in part, to the pulsatile pattern of amino acids, insulin, or both induced by INT, which enables the responsiveness of anabolic pathways to feeding to be sustained chronically in skeletal muscle.
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    PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice
    Stevens, Shaunaci A.; Aguiar, Maria K. Gonzalez; Toro, Allyson L.; Yerlikaya, Esma I.; Sunilkumar, Siddharth; VanCleave, Ashley M.; Pfleger, Jessica; Bradley, Elisa A.; Kimball, Scot R.; Dennis, Michael D. (American Physiological Society, 2022-11-16)
    Endoplasmic reticulum (ER) stress and inflammation are hallmarks of myocardial impairment. Here, we investigated the role of the stress response protein regulated in development and DNA damage 1 (REDD1) as a molecular link between ER stress and inflammation in cardiomyocytes. In mice fed a high-fat high-sucrose (HFHS, 42% kcal fat, 34% sucrose by weight) diet for 12 wk, REDD1 expression in the heart was increased in coordination with markers of ER stress and inflammation. In human AC16 cardiomyocytes exposed to either hyperglycemic conditions or the saturated fatty acid palmitate, REDD1 expression was increased coincident with ER stress and upregulated expression of the proinflammatory cytokines IL-1β, IL-6, and TNFα. In cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions, pharmacological inhibition of the ER kinase protein kinase RNA-like endoplasmic reticulum kinase (PERK) or knockdown of the transcription factor ATF4 prevented the increase in REDD1 expression. REDD1 deletion reduced proinflammatory cytokine expression in both cardiomyocytes exposed to hyperglycemic/hyperlipidemic conditions and in the hearts of obese mice. Overall, the findings support a model wherein HFHS diet contributes to the development of inflammation in cardiomyocytes by promoting REDD1 expression via activation of a PERK/ATF4 signaling axis.NEW & NOTEWORTHY Interplay between endoplasmic reticulum stress and inflammation contributes to cardiovascular disease progression. The studies here identify the stress response protein known as REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress with increased production of proinflammatory cytokines in the hearts of obese mice.