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  1. Article ; Online: Concomitant western diet and chronic-binge alcohol dysregulate hepatic metabolism.

    Delfin Gerard Buyco / Joseph L Dempsey / Eleonora Scorletti / Sookyoung Jeon / Chelsea Lin / Julia Harkin / Susovon Bayen / Emma E Furth / Jasmin Martin / Monique Delima / Royce Hooks / Jaimarie Sostre-Colón / Sina A Gharib / Paul M Titchenell / Rotonya M Carr

    PLoS ONE, Vol 18, Iss 5, p e

    2023  Volume 0281954

    Abstract: Background and aims There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises ...

    Abstract Background and aims There is significant overlap between non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) with regards to risk factors and disease progression. However, the mechanism by which fatty liver disease arises from concomitant obesity and overconsumption of alcohol (syndrome of metabolic and alcohol-associated fatty liver disease; SMAFLD), is not fully understood. Methods Male C57BL6/J mice were fed chow diet (Chow) or high-fructose, high-fat, high-cholesterol diet (FFC) for 4 weeks, then administered either saline or ethanol (EtOH, 5% in drinking water) for another 12 weeks. The EtOH treatment also consisted of a weekly 2.5 g EtOH/kg body weight gavage. Markers for lipid regulation, oxidative stress, inflammation, and fibrosis were measured by RT-qPCR, RNA-seq, Western blot, and metabolomics. Results Combined FFC-EtOH induced more body weight gain, glucose intolerance, steatosis, and hepatomegaly compared to Chow, EtOH, or FFC. Glucose intolerance by FFC-EtOH was associated with decreased hepatic protein kinase B (AKT) protein expression and increased gluconeogenic gene expression. FFC-EtOH increased hepatic triglyceride and ceramide levels, plasma leptin levels, hepatic Perilipin 2 protein expression, and decreased lipolytic gene expression. FFC and FFC-EtOH also increased AMP-activated protein kinase (AMPK) activation. Finally, FFC-EtOH enriched the hepatic transcriptome for genes involved in immune response and lipid metabolism. Conclusions In our model of early SMAFLD, we observed that the combination of an obesogenic diet and alcohol caused more weight gain, promoted glucose intolerance, and contributed to steatosis by dysregulating leptin/AMPK signaling. Our model demonstrates that the combination of an obesogenic diet with a chronic-binge pattern alcohol intake is worse than either insult alone.
    Keywords Medicine ; R ; Science ; Q
    Subject code 610
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Global-run on sequencing identifies Gm11967 as an Akt-dependent long noncoding RNA involved in insulin sensitivity

    Dominic Santoleri / Hee-Woong Lim / Matthew J. Emmett / Julian Stoute / Matthew J. Gavin / Jaimarie Sostre-Colón / Kahealani Uehara / Jaclyn E. Welles / Kathy Fange Liu / Mitchell A. Lazar / Paul M. Titchenell

    iScience, Vol 25, Iss 6, Pp 104410- (2022)

    2022  

    Abstract: Summary: The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and ... ...

    Abstract Summary: The insulin responsive Akt and FoxO1 signaling axis is a key regulator of the hepatic transcriptional response to nutrient intake. Here, we used global run-on sequencing (GRO-seq) to measure the nascent transcriptional response to fasting and refeeding as well as define the specific role of hepatic Akt and FoxO1 signaling in mediating this response. We identified 599 feeding-regulated transcripts, as well as over 6,000 eRNAs, and mapped their dependency on Akt and FoxO1 signaling. Further, we identified several feeding-regulated lncRNAs, including the lncRNA Gm11967, whose expression was dependent upon the liver Akt-FoxO1 axis. Restoring Gm11967 expression in mice lacking liver Akt improved insulin sensitivity and induced glucokinase protein expression, indicating that Akt-dependent control of Gm11967 contributes to the translational control of glucokinase. More broadly, we have generated a unique genome-wide dataset that defines the feeding and Akt/FoxO1-dependent transcriptional changes in response to nutrient availability.
    Keywords Physiology ; Molecular Physiology ; Omics ; Transcriptomics ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2022-06-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia

    Anna E. Garcia Whitlock / Jamarie Sostre-Colón / Matthew Gavin / Niels D. Martin / Joseph A. Baur / Carrie A. Sims / Paul M. Titchenell

    Molecular Metabolism, Vol 51, Iss , Pp 101246- (2021)

    2021  

    Abstract: Objective: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. ... ...

    Abstract Objective: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. Methods: We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. Results: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. Conclusions: This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute ...
    Keywords Stress-induced hyperglycemia ; Insulin resistance ; Lipolysis ; FOXO ; AKT ; Internal medicine ; RC31-1245
    Subject code 571
    Language English
    Publishing date 2021-09-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Shared PPARα/γ Target Genes Regulate Brown Adipocyte Thermogenic Function

    Yachen Shen / Yvonne Su / Francisco J. Silva / Angela H. Weller / Jaimarie Sostre-Colón / Paul M. Titchenell / David J. Steger / Patrick Seale / Raymond E. Soccio

    Cell Reports, Vol 30, Iss 9, Pp 3079-3091.e

    2020  Volume 5

    Abstract: Summary: Brown adipose tissue (BAT) generates heat to maintain body temperature and suppress obesity. Agonists for nuclear receptors PPARα and PPARγ both affect brown adipocyte function, yet the interplay between these factors in BAT is uncertain. Here, ... ...

    Abstract Summary: Brown adipose tissue (BAT) generates heat to maintain body temperature and suppress obesity. Agonists for nuclear receptors PPARα and PPARγ both affect brown adipocyte function, yet the interplay between these factors in BAT is uncertain. Here, we report that PPARα shares most genomic binding sites with PPARγ, and these common binding sites are more related to BAT function than PPARγ-selective sites without PPARα. Integrating PPARα and PPARγ genomic occupancy with cold-responsive BAT transcriptomes identifies a subset of 16 genes with potential relevance to BAT function. Among these, we focused on the lysosomal protease cathepsin Z (CTSZ) and showed it is necessary for mitochondrial respiration in both mouse and human brown adipocytes. Thus, CTSZ is a shared PPARα/γ target gene in BAT and a regulator of brown adipocyte thermogenic function. : Brown adipocytes uniquely express high levels of PPARα and PPARγ, yet the interplay between these two nuclear receptors was unknown. Shen et al. show PPARα co-occupies regulatory DNA with PPARγ. Shared target genes of both, including the candidate CTSZ, reveal brown fat function better than PPARγ targets alone. Keywords: brown adipocytes, PPARα, PPARγ, rosiglitazone, fenofibrate, CTSZ, thermogenesis
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Early B Cell Factor Activity Controls Developmental and Adaptive Thermogenic Gene Programming in Adipocytes

    Anthony R. Angueira / Suzanne N. Shapira / Jeff Ishibashi / Samay Sampat / Jaimarie Sostre-Colón / Matthew J. Emmett / Paul M. Titchenell / Mitchell A. Lazar / Hee-Woong Lim / Patrick Seale

    Cell Reports, Vol 30, Iss 9, Pp 2869-2878.e

    2020  Volume 4

    Abstract: Summary: Brown adipose tissue (BAT) activity protects animals against hypothermia and represents a potential therapeutic target to combat obesity. The transcription factor early B cell factor-2 (EBF2) promotes brown adipocyte differentiation, but its ... ...

    Abstract Summary: Brown adipose tissue (BAT) activity protects animals against hypothermia and represents a potential therapeutic target to combat obesity. The transcription factor early B cell factor-2 (EBF2) promotes brown adipocyte differentiation, but its roles in maintaining brown adipocyte fate and in stimulating BAT recruitment during cold exposure were unknown. We find that the deletion of Ebf2 in adipocytes of mice ablates BAT character and function, resulting in cold intolerance. Unexpectedly, prolonged exposure to cold restores the thermogenic profile and function of Ebf2 mutant BAT. Enhancer profiling and genetic assays identified EBF1 as a candidate regulator of the cold response in BAT. Adipocyte-specific deletion of both Ebf1 and Ebf2 abolishes BAT recruitment during chronic cold exposure. Mechanistically, EBF1 and EBF2 promote thermogenic gene transcription through increasing the expression and activity of ERRα and PGC1α. Together, these studies demonstrate that EBF proteins specify the developmental fate and control the adaptive cold response of brown adipocytes. : Angueira et al. show that early B cell factors (EBFs) control both basal and cold-induced thermogenic activity in brown adipocytes. EBF2 is required to maintain BAT fate under basal conditions, ensuring a capacity for thermogenesis upon cold challenge. BAT recruitment during chronic cold exposure requires EBF1 or EBF2 activity. Keywords: brown adipocyte, UCP1, EBF1, EBF2, thermogenesis, brown fat, ERR, cold exposure, PGC1
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-03-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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  6. Article ; Online: The Polycomb protein, Bmi1, regulates insulin sensitivity

    Corey E. Cannon / Paul M. Titchenell / David N. Groff / Abdelfattah El Ouaamari / Rohit N. Kulkarni / Morris J. Birnbaum / Doris A. Stoffers

    Molecular Metabolism, Vol 3, Iss 8, Pp 794-

    2014  Volume 802

    Abstract: Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. ...

    Abstract Objective: The Polycomb Repressive Complexes (PRC) 1 and 2 function to epigenetically repress target genes. The PRC1 component, Bmi1, plays a crucial role in maintenance of glucose homeostasis and beta cell mass through repression of the Ink4a/Arf locus. Here we have explored the role of Bmi1 in regulating glucose homeostasis in the adult animal, which had not been previously reported due to poor postnatal survival of Bmi1−/− mice. Methods: The metabolic phenotype of Bmi1+/− mice was characterized, both in vivo and ex vivo. Glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps were performed. The insulin signaling pathway was assessed at the protein and transcript level. Results: Here we report a negative correlation between Bmi1 levels and insulin sensitivity in two models of insulin resistance, aging and liver-specific insulin receptor deficiency. Further, heterozygous loss of Bmi1 results in increased insulin sensitivity in adult mice, with no impact on body weight or composition. Hyperinsulinemic-euglycemic clamp reveals increased suppression of hepatic glucose production and increased glucose disposal rate, indicating elevated glucose uptake to peripheral tissues, in Bmi1+/− mice. Enhancement of insulin signaling, specifically an increase in Akt phosphorylation, in liver and, to a lesser extent, in muscle appears to contribute to this phenotype. Conclusions: Together, these data define a new role for Bmi1 in regulating insulin sensitivity via enhancement of Akt phosphorylation.
    Keywords Polycomb Repressive Complex ; Hepatic glucose production ; Insulin signaling ; Muscle glucose uptake ; Internal medicine ; RC31-1245
    Language English
    Publishing date 2014-11-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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