Uwe Knippschild

Publications (54) View all

• Article: De novo lipogenesis in human fat and liver is linked to ChREBP-β and metabolic health.

  Leah Eissing, Thomas Scherer, Klaus Tödter, Uwe Knippschild, Jan Willem Greve, Wim A Buurman, Hans O Pinnschmidt, Sander S Rensen, Anna M Wolf, Alexander Bartelt, Joerg Heeren, Christoph Buettner, Ludger Scheja
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  ABSTRACT: Clinical interest in de novo lipogenesis has been sparked by recent studies in rodents demonstrating that de novo lipogenesis specifically in white adipose tissue produces the insulin-sensitizing fatty acid palmitoleate. By contrast, hepatic lipogenesis is thought to contribute to metabolic disease. How de novo lipogenesis in white adipose tissue versus liver is altered in human obesity and insulin resistance is poorly understood. Here we show that lipogenic enzymes and the glucose transporter-4 are markedly decreased in white adipose tissue of insulin-resistant obese individuals compared with non-obese controls. By contrast, lipogenic enzymes are substantially upregulated in the liver of obese subjects. Bariatric weight loss restored de novo lipogenesis and glucose transporter-4 gene expression in white adipose tissue. Notably, lipogenic gene expression in both white adipose tissue and liver was strongly linked to the expression of carbohydrate-responsive element-binding protein-β and to metabolic risk markers. Thus, de novo lipogenesis predicts metabolic health in humans in a tissue-specific manner and is likely regulated by glucose-dependent carbohydrate-responsive element-binding protein activation.
  Nature Communications 02/2013; 4:1528. · 7.40 Impact Factor
• Article: Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b.

  Jan-Wilhelm Kornfeld, Catherina Baitzel, A Christine Könner, Hayley T Nicholls, Merly C Vogt, Karolin Herrmanns, Ludger Scheja, Cécile Haumaitre, Anna M Wolf, Uwe Knippschild, Jost Seibler, Silvia Cereghini, Joerg Heeren, Markus Stoffel, Jens C Brüning
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  ABSTRACT: Insulin resistance represents a hallmark during the development of type 2 diabetes mellitus and in the pathogenesis of obesity-associated disturbances of glucose and lipid metabolism. MicroRNA (miRNA)-dependent post-transcriptional gene silencing has been recognized recently to control gene expression in disease development and progression, including that of insulin-resistant type 2 diabetes. The deregulation of miRNAs miR-143 (ref. 4), miR-181 (ref. 5), and miR-103 and miR-107 (ref. 6) alters hepatic insulin sensitivity. Here we report that the expression of miR-802 is increased in the liver of two obese mouse models and obese human subjects. Inducible transgenic overexpression of miR-802 in mice causes impaired glucose tolerance and attenuates insulin sensitivity, whereas reduction of miR-802 expression improves glucose tolerance and insulin action. We identify Hnf1b (also known as Tcf2) as a target of miR-802-dependent silencing, and show that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signalling and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr(db/db) mice. Thus, this study defines a critical role for deregulated expression of miR-802 in the development of obesity-associated impairment of glucose metabolism through targeting of Hnf1b, and assigns Hnf1b an unexpected role in the control of hepatic insulin sensitivity.
  Nature 02/2013; 494(7435):111-5. · 36.28 Impact Factor
• Article: Changed adipocytokine concentrations in colorectal tumor patients and morbidly obese patients compared to healthy controls.

  Andreas Hillenbrand, Juliane Fassler, Nadine Huber, Pengfei Xu, Doris Henne-Bruns, Markus Templin, Hubert Schrezenmeier, Anna Maria Wolf, Uwe Knippschild
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  ABSTRACT: BACKGROUND: Obesity has been associated with increased incidence of colorectal cancer. Adipose tissue dysfunction accompanied with alterations in the release of adipocytokines has been proposed to contribute to cancer pathogenesis and progression. The aim of this study was to analyze plasma concentrations of several adipose tissue expressed hormones in colorectal cancer patients (CRC) and morbidly obese (MO) patients and to compare these concentrations to clinicopathological parameters. METHODS: Plasma concentrations of adiponectin, resistin, leptin, active plasminogen activator inhibitor (PAI)-1, monocyte chemotactic protein (MCP)-1, interleukin (IL)-1 alpha, and tumor necrosis factor (TNF)-alpha were determined in 67 patients operated on for CRC (31 rectal cancers, 36 colon cancers), 37 patients operated on for morbid obesity and 60 healthy blood donors (BD). RESULTS: Compared to BD, leptin concentrations were lowered in CRC patients whereas those of MO patients were elevated. Adiponectin concentrations were only lowered in MO patients. Concentrations of MCP-1, PAI-1, and IL-1 alpha were elevated in both CRC and MO patients, while resistin and TNF-alpha were similarly expressed in MO and CRC patients compared to BD. Resistin concentrations positively correlated with tumor staging (p<0.002) and grading (p=0.015) of rectal tumor patients. CONCLUSIONS: The results suggest that both MO and CRC have low-grade inflammation as part of their etiology.
  BMC Cancer 11/2012; 12(1):545. · 3.01 Impact Factor
• Source

  Available from: Manfred Weiss

  Dataset: HillenbrandA WeissM 2012 Intern J Inflamm Rev Adipokine Sepsis 972368

  Andreas Hillenbrand, Manfred Weiss, Uwe Knippschild, Anna Maria Wolf, Markus Huber-Lang
• Article: Inhibition of Pancreatic Cancer Cell Growth In Vivo Using a Tetracycline-Inducible Cyclin D1 Antisense Expression System.

  Jian Cheng Wang, Matthias Thiere, Doris Henne-Bruns, Uwe Knippschild, Marko Kornmann
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  ABSTRACT: OBJECTIVES: Cyclin D1 is important for pancreatic cancer growth. Our aim was to determine the effects of cyclin D1 inhibition on the growth of established pancreatic tumors. METHODS: PANC-1 cells harboring cyclin D1 antisense cDNA in a tetracycline-inducible vector system were prepared. The effects of cyclin D1 inhibition after tumor development were characterized in a mouse model. RESULTS: In vitro removal of tetracycline induced cyclin D1 antisense cDNA expression and inhibited cyclin D1 expression and cyclin D1-associated kinase activity as well as anchorage-dependent and -independent growth. After establishment of xenograft tumors in the presence of tetracycline (2 mg/mL) in the drinking water, animals were assigned to either control (tetracycline remained in the drinking water) or to the group without tetracycline for which tetracycline was removed from the drinking water. Tumor growth was significantly inhibited after removal of tetracycline. Microscopic analysis revealed that the area of central necrosis was significantly increased in the group without tetracycline paralleled by a reduction of the vital peripheral area of proliferating cells. CONCLUSIONS: Our results confirmed that cyclin D1 plays an important role in the growth of pancreatic cancer cells and may be an attractive molecular target for the treatment of human pancreatic cancer.
  Pancreas 06/2012; · 2.39 Impact Factor