hrp0086p1-p445 | Fat Metabolism and Obesity P1 | ESPE2016

The Impact of Activating PIK3CA Mutations and PTEN Haploinsufficiency on Human Adipocyte Phenotype and Biology

Kassner Franziska , Handel Norman , Leipert Jenny , Sauer Tina , Wilhelm Franziska , Landgraf Kathrin , Kiess Wieland , Korner Antje , Garten Antje

Background: The phosphatase and tensin homolog (PTEN)/phosphatidylinositol-3-kinase (PI3K)/AKT signaling pathway is central for cell cycle control, differentiation, migration, and metabolism. Unrestricted growth of adipose tissue in particular is frequently seen in humans with germline PTEN and mosaic activating PIK3CA mutations, respectively.Objective and hypotheses: We assume that adipocytes from affected tissue show hyperproliferation and modified dif...

hrp0092rfc4.4 | Fat Metabolism and Obesity Session | ESPE2019

The Novel Phosphatidylinositol-3-Kinase (PI3K) Inhibitor Alpelisib Effectively Inhibits Growth of PTEN Haploinsufficient Lipoma Cells

Kirstein Anna , Augustin Adrien , Kiess Wieland , Garten Antje

Background and Aim: Germline mutations in the tumor suppressor gene PTEN cause PTEN Hamartoma Tumor Syndrome (PHTS). Pediatric patients frequently develop lipomas. PTEN antagonizes the growth promoting PI3K/AKT/mTOR pathway. There is no current treatment option except surgery. Treatment attempts with the mTORC1 inhibitor Rapamycin could not reverse lipoma growth. Recently, lipomas associated with a related syndrome caused by mosaic activating PI3K mutations (P...

hrp0092p1-30 | Diabetes and Insulin | ESPE2019

Effects of Glypican-4 Protein on INS1E Cell Viability and Insulin Signalling

Buhl Joseph , Garten Antje , Richter Sandy , Kiess Wieland , Penke Melanie

Background: Glypican-4 is a heparan sulphate proteoglycan. In addition to a membrane-bound glypican-4, a soluble form exists. Human and rodent adipose tissue were identified as source of circulating glypican-4. Glypican-4 serum levels are associated with obesity and insulin resistance, as in type 2 diabetes (T2D). Because of its positive effect on insulin sensitivity, glypican-4 might play a role in the development of obesity, insulin resistance, and T2D. We a...

hrp0094fc2.4 | Fat, Metabolism and Obesity | ESPE2021

PTEN germline mutations lead to adipose tissue overgrowth mediated via FOXO1 and SREBP1.

Kirstein Anna , Kehr Stephanie , Nebe Michele , Kiess Wieland , Garten Antje ,

Background and Aim: Pediatric patients with germline mutations in the tumor suppressor gene PTEN (PTEN hamartoma tumor syndrome, PHTS) frequently develop lipomas. PTEN antagonizes phosphoinositide 3-kinase (PI3K) signaling, which can induce adipogenesis upon activation through insulin. The PI3K downstream target AKT can deactivate FOXO1 via phosphorylation, initiating the expression of the lipogenesis activating transcription factor SREBP1. To study t...

hrp0095p1-263 | Fat, Metabolism and Obesity | ESPE2022

Small integral membrane protein 10 like 1 (SMIM10L1) affects adipogenesis and apoptosis in adipose progenitor cells.

Kirstein Anna , Nebe Michèle , Richter Sandy , Kiess Wieland , Garten Antje

Background: Pediatric patients with germline pathogenic variants in the tumor suppressor gene PTEN frequently develop cancer and adipose tissue overgrowth in the form of lipomas. While the canonical function of the phosphatase PTEN is to antagonize the growth promoting PI3K pathway, non-canonical PTEN functions e.g. in the nucleus are less well described. To uncover the mechanisms leading to lipoma formation related to PTEN mutations, we previously performed R...

hrp0089fc6.3 | Fat, Metabolism and obesity | ESPE2018

Role of PTEN in the Proliferation and Differentiation of Preadipocytes

Kirstein Anna , Kassner Franziska , Schmid Gordian L. , Handel Norman , Penke Melanie , Kiess Wieland , Garten Antje

Background/aim: The PTEN hamartoma tumor syndrome (PHTS) is an overgrowth syndrome caused mainly by germline mutations in the tumor suppressor PTEN. Patients are predisposed for the development of malignant and benign tumors. Children and adolescents with PHTS frequently develop single or multiple lipomas. PTEN antagonizes the phosphatidylinositide3-kinase/AKT/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway, which promotes proliferation and differentiation in ...

hrp0089p2-p170 | Fat, Metabolism and Obesity P2 | ESPE2018

Development of Resistance to Sorafenib, a Multikinase Inhibitor, in Hepatocellular Carcinoma is Mediated by SIRT

Garten Antje , Grohmann Theresa , Barnikol-Oettler Anja , Kluckova Katharina , Lavery Gareth , Kiess Wieland , Penke Melanie

Background/aim: Sorafenib® is a multi-kinase inhibitor and one of the few systemic treatment options for patients with advanced hepatocellular carcinomas (HCCs). Resistance to Sorafenib® develops frequently and could be mediated by the NAD dependent deacetylase sirtuin (SIRT) 1, a master regulator of cellular energy metabolism and stress responses. We aimed to find out if Sorafenib® treatment depends on changes in cellular NAD le...

hrp0086p2-p708 | Endocrinology and Multisystemic Diseases P2 | ESPE2016

Inhibition of NAMPT Increases the Sensitivity of Leukemia Cells for Etoposide

Gorski Theresa , Petzold-Quinque Stefanie , Richter Sandy , Schuster Susanne , Penke Melanie , Kiess Wieland , Garten Antje

Background: Cancer cells have a high NAD turnover rate due to their increased cell proliferation and DNA repair. Nicotinamide phosphoribosyltransferase (NAMPT) is the key enzyme of the NAD salvage pathway, a regulator of the intracellular NAD pool and of the activity of Sirtuins (SIRTs), a class of NAD-dependent deacetylases.Objective and hypotheses: Cancer cells are highly dependent on NAD and are expected to be more susceptible to an inhibition of NAD ...

hrp0082lbp-d3-1007 | (1) | ESPE2014

Hepatic NAD Metabolism is Dysregulated by an Excessive Supply of Lipids

Kiess Wieland , Penke Melanie , Treebak Jonas T , Schuster Susanne , Gorski Theresa , Garten Antje

Background: Animal and human studies have shown that nicotinamide phosphoribosyltransferase (NAMPT), the key enzyme of mammalian NAD biosynthesis from nicotinamide, is modified in non-alcoholic fatty liver disease. Here, we investigated the effect of a high fat diet on hepatic NAD metabolism in mice.Objective and hypotheses: A dysregulation of NAD metabolism is a pathogenic factor for the development of steatohepatitis (NASH).Metho...

hrp0084fc5.1 | Endocrine Oncology/Turner | ESPE2015

Resveratrol Potentiates Growth Inhibitory Effects of Rapamycin in PTEN-deficient Lipoma Cells by Suppressing p70S6 Kinase Activity

Leipert Jenny , Kassner Franziska , Schuster Susanne , Handel Norman , Korner Antje , Kiess Wieland , Garten Antje

Background: Patients with PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome and germ line mutations in PTEN frequently develop lipomatosis, for which there is no standard treatment. Rapamycin was shown to reduce the growth of lipoma cells with heterozygous PTEN deficiency in vitro, but concomitantly induced an up regulation of AKT phosphorylation.Objective and hypotheses: Since it was shown that resveratrol stabilizes PTEN,...