Browsing by Author "Anderson-Baucum, Emily"

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    Cellular metabolism constrains innate immune responses in early human ontogeny
    (Nature Research, 2018-11-16) Kan, Bernard; Michalski, Christina; Fu, Helen; Au, Hilda H.T.; Lee, Kelsey; Marchant, Elizabeth A.; Cheng, Maye F.; Anderson-Baucum, Emily; Aharoni-Simon, Michal; Tilley, Peter; Mirmira, Raghavendra G.; Ross, Colin J.; Luciani, Dan S.; Jan, Eric; Lavoie, Pascal M.; Medicine, School of Medicine
    Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.
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    Chronic high fat feeding restricts islet mRNA translation initiation independently of ER stress via DNA damage and p53 activation
    (Springer Nature, 2017-06-19) Hatanaka, Masayuki; Anderson-Baucum, Emily; Lakhter, Alexander; Kono, Tatsuyoshi; Maier, Bernhard; Tersey, Sarah A.; Tanizawa, Yukio; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Sims, Emily K.; Pediatrics, School of Medicine
    Under conditions of high fat diet (HFD) consumption, glucose dyshomeostasis develops when β-cells are unable to adapt to peripheral insulin demands. Few studies have interrogated the molecular mechanisms of β-cell dysfunction at the level of mRNA translation under such conditions. We sought to address this issue through polyribosome profile analysis of islets from mice fed 16-weeks of 42% HFD. HFD-islet analysis revealed clear trends toward global reductions in mRNA translation with a significant reduction in the polyribosome/monoribosome ratio for Pdx1 mRNA. Transcriptional and translational analyses revealed endoplasmic reticulum stress was not the etiology of our findings. HFD-islets demonstrated evidence of oxidative stress and DNA damage, as well as activation of p53. Experiments in MIN-6 β-cells revealed that treatment with doxorubicin to directly induce DNA damage mimicked our observed effects in islets. Islets from animals treated with pioglitazone concurrently with HFD demonstrated a reversal of effects observed from HFD alone. Finally, HFD-islets demonstrated reduced expression of multiple ribosome biogenesis genes and the key translation initiation factor eIF4E. We propose a heretofore unappreciated effect of chronic HFD on β-cells, wherein continued DNA damage owing to persistent oxidative stress results in p53 activation and a resultant inhibition of mRNA translation.
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    Deoxyhypusine Synthase Promotes a Pro-Inflammatory Macrophage Phenotype
    (Elsevier, 2021) Anderson-Baucum, Emily; Piñeros, Annie R.; Kulkarni, Abhishek; Webb-Robertson, Bobbie-Jo; Maier, Bernhard; Anderson, Ryan M.; Wu, Wenting; Tersey, Sarah A.; Mastracci, Teresa L.; Casimiro, Isabel; Scheuner, Donalyn; Metz, Thomas O.; Nakayasu, Ernesto S.; Evans-Molina, Carmella; Mirmira, Raghavendra G.; Biology, School of Science
    The metabolic inflammation (meta-inflammation) of obesity is characterized by proinflammatory macrophage infiltration into adipose tissue. Catalysis by deoxyhypusine synthase (DHPS) modifies the translation factor eIF5A to generate a hypusine (Hyp) residue. Hypusinated eIF5A (eIF5AHyp) controls the translation of mRNAs involved in inflammation, but its role in meta-inflammation has not been elucidated. Levels of eIF5AHyp were found to be increased in adipose tissue macrophages from obese mice and in murine macrophages activated to a proinflammatory M1-like state. Global proteomics and transcriptomics revealed that DHPS deficiency in macrophages altered the abundance of proteins involved in NF-κB signaling, likely through translational control of their respective mRNAs. DHPS deficiency in myeloid cells of obese mice suppressed M1 macrophage accumulation in adipose tissue and improved glucose tolerance. These findings indicate that DHPS promotes the post-transcriptional regulation of a subset of mRNAs governing inflammation and chemotaxis in macrophages and contributes to a proinflammatory M1-like phenotype.
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    Hypusine biosynthesis in β cells links polyamine metabolism to facultative cellular proliferation to maintain glucose homeostasis
    (American Association for the Advancement of Science, 2019-12-03) Levasseur, Esther M.; Yamada, Kentaro; Piñeros, Annie R.; Wu, Wenting; Syed, Farooq; Orr, Kara S.; Anderson-Baucum, Emily; Mastracci, Teresa L.; Maier, Bernhard; Mosley, Amber L.; Liu, Yunlong; Bernal-Mizrachi, Ernesto; Alonso, Laura C.; Scott, Donald; Garcia-Ocaña, Adolfo; Tersey, Sarah A.; Mirmira, Raghavendra G.; Pediatrics, School of Medicine
    Deoxyhypusine synthase (DHPS) utilizes the polyamine spermidine to catalyze the hypusine modification of the mRNA translation factor eIF5A and promotes oncogenesis through poorly-defined mechanisms. Because germline deletion of Dhps is embryonically lethal, its role in normal postnatal cellular function in vivo remains unknown. We generated a mouse model that enabled the inducible, postnatal deletion of Dhps specifically in postnatal islet β cells, which function to maintain glucose homeostasis. Removal of Dhps did not have an effect under normal physiologic conditions. However, upon development of insulin resistance, which induces β-cell proliferation, Dhps deletion caused alterations in proteins required for mRNA translation and protein secretion, reduced production of the cell cycle molecule cyclin D2, impaired β-cell proliferation, and induced overt diabetes. We found that hypusine biosynthesis was downstream of protein kinase C-ζ and was required for c-Myc-induced proliferation. Our studies reveal a requirement for DHPS in β cells to link polyamines to mRNA translation to effect facultative cellular proliferation and glucose homeostasis.
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    MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells
    (Springer, 2017-06) Sims, Emily K.; Lakhter, Alexander; Anderson-Baucum, Emily; Kono, Tatsuyoshi; Tong, Xin; Evans-Molina, Carmella; Pediatrics, School of Medicine
    AIMS/HYPOTHESIS: The role of beta cell microRNA (miR)-21 in the pathophysiology of type 1 diabetes has been controversial. Here, we sought to define the context of beta cell miR-21 upregulation in type 1 diabetes and the phenotype of beta cell miR-21 overexpression through target identification. METHODS: Islets were isolated from NOD mice and mice treated with multiple low doses of streptozotocin, as a mouse model of diabetes. INS-1 832/13 beta cells and human islets were treated with IL-1β, IFN-γ and TNF-α to mimic the milieu of early type 1 diabetes. Cells and islets were transfected with miR-21 mimics or inhibitors. Luciferase assays and polyribosomal profiling (PRP) were performed to define miR-21-target interactions. RESULTS: Beta cell miR-21 was increased in in vivo models of type 1 diabetes and cytokine-treated cells/islets. miR-21 overexpression decreased cell count and viability, and increased cleaved caspase 3 levels, suggesting increased cell death. In silico prediction tools identified the antiapoptotic mRNA BCL2 as a conserved miR-21 target. Consistent with this, miR-21 overexpression decreased BCL2 transcript and B cell lymphoma 2 (BCL2) protein production, while miR-21 inhibition increased BCL2 protein levels and reduced cleaved caspase 3 levels after cytokine treatment. miR-21-mediated cell death was abrogated in 828/33 cells, which constitutively overexpress Bcl2. Luciferase assays suggested a direct interaction between miR-21 and the BCL2 3' untranslated region. With miR-21 overexpression, PRP revealed a shift of the Bcl2 message towards monosome-associated fractions, indicating inhibition of Bcl2 translation. Finally, overexpression in dispersed human islets confirmed a reduction in BCL2 transcripts and increased cleaved caspase 3 production. CONCLUSIONS/INTERPRETATION: In contrast to the pro-survival role reported in other systems, our results demonstrate that miR-21 increases beta cell death via BCL2 transcript degradation and inhibition of BCL2 translation.
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    Smoking and the Risk of Type 2 Diabetes
    (Elsevier, 2017-06) Maddatu, Judith; Anderson-Baucum, Emily; Evans-Molina, Carmella; Department of Medicine, IU School of Medicine
    Despite accumulating evidence demonstrating strong epidemiologic and mechanistic associations between cigarette smoking, hyperglycemia, and the development of type 2 diabetes, tobacco abuse has not been uniformly recognized as a modifiable risk factor in diabetes prevention or screening strategies. In this review, we highlight population-based studies that have linked cigarette smoking with an increased risk of type 2 diabetes and summarize clinical and preclinical studies offering insight into mechanisms through which cigarette smoking and nicotine exposure impact body composition, insulin sensitivity, and pancreatic β cell function. Key questions for future studies are identified and strategies for smoking cessation as a means to decrease diabetes risk are discussed.