Heike Neubauer
Boehringer Ingelheim
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Featured researches published by Heike Neubauer.
Diabetes-metabolism Research and Reviews | 2009
Sebastian Kreuz; Corinna Schoelch; Leo Thomas; Wolfgang Rist; Jörg F. Rippmann; Heike Neubauer
Acetyl‐CoA carboxylases (ACC) 1 and 2 are central enzymes in lipid metabolism. To further investigate their relevance for the development of obesity and type 2 diabetes, expression of both ACC isoforms was analyzed in obese fa/fa Zucker fatty and Zucker diabetic fatty rats at different ages in comparison to Zucker lean controls.
Molecular and Cellular Biochemistry | 2010
Rupert Oberauer; Wolfgang Rist; Martin Lenter; Bradford S. Hamilton; Heike Neubauer
With increasing rates of obesity driving the incidence of type 2 diabetes and cardiovascular diseases to epidemic levels, understanding of the biology of adipose tissue expansion is a focus of current research. Identification and characterization of secreted proteins of the adipose tissue could provide further insights into the function of adipose tissue and might help to therapeutically influence the development of obesity and associated metabolic disorders. In the present study, we identified human epidermal growth factor-like domain multiple-6 (EGFL6) as an adipose tissue-secreted protein. EGFL6 expression in human subcutaneous adipose tissue significantly increased with obesity and decreased after weight loss. Further, expression and secretion of EGFL6 increased with in vitro differentiation of human preadipocytes, suggesting that mature adipocytes are the main source of EGFL6. Containing epidermal growth factor (EGF)-like repeats, an Arg-Gly-Asp (RGD) integrin binding motif and a mephrin, A5 protein and receptor protein-tyrosine phosphatase mu (MAM) domain, EGFL6 was suggested to be an extra-cellular matrix protein. Recombinant human EGFL6 protein mediated cell adhesion of human adipose tissue-derived stromal vascular cells (AD-SVC) in an RGD-dependent manner. FACS analyses revealed specific binding of the protein to the cell surface of AD-SVC with the binding being predominantly mediated by the EGF-like repeats. Recombinant EGFL6 enhanced proliferation of human AD-SVC as measured by MTS assay and [14C]-thymidine incorporation. These results indicate that human EGFL6 is a paracrine/autocrine growth factor of adipose tissue up-regulated in obesity and potentially involved in the process of adipose tissue expansion and the development of obesity.
Science Signaling | 2017
Aliki Perdikari; Elisabeth Kulenkampff; Carla Rudigier; Heike Neubauer; Gerd Luippold; Norbert Redemann; Christian Wolfrum
Multiple kinases are potential targets to enhance the development and function of brown fat. Finding the kinases that power brown fat Obesity and its associated health risks are a critical and growing problem. Unlike white adipocytes, which store energy, brown adipocytes dissipate energy in the form of heat. Expansion or activation of brown fat has been proposed as a strategy to combat obesity. Using high-throughput analysis that combined RNA interference with pharmacological inhibitors, Perdikari et al. identified kinases that affected brown adipocyte proliferation, differentiation, or formation (when these cells acquire the ability to dissipate energy as heat). Of the 190 brown fat–regulating kinases, they investigated in detail the role of AMPK in promoting the formation of brown adipocytes. Their results highlight kinases that could be therapeutically targeted to enhance the development and function of brown fat. Brown adipose tissue (BAT) is responsible for thermogenesis that is not associated with shivering through the process of converting chemical energy into heat through uncoupling protein 1 (UCP1) in the mitochondria. Thus, expanding or activating BAT could be a potential tool against obesity. To analyze the effect of kinase signaling on brown adipocyte formation, a process that describes the acquisition of the ability to dissipate energy as heat, we performed lentiviral-mediated short hairpin knockdown or used pharmacological inhibitors in a high-content and high-throughput in vitro image-based screen. We identified 190 kinases that either stimulated or inhibited brown adipocyte proliferation, differentiation, or formation. Among these kinases, we found that 5′ AMP–activated protein kinase (AMPK) promoted the formation of brown adipocytes abundant inUCP1. Together, our results provide insight into the kinases, particularly AMPK, that regulate brown adipocyte formation.
PLOS ONE | 2014
Silke Uhrig-Schmidt; Matthias Geiger; Gerd Luippold; Gerald Birk; Detlev Mennerich; Heike Neubauer; Dirk Grimm; Christian Wolfrum; Sebastian Kreuz
In recent years, the increasing prevalence of obesity and obesity-related co-morbidities fostered intensive research in the field of adipose tissue biology. To further unravel molecular mechanisms of adipose tissue function, genetic tools enabling functional studies in vitro and in vivo are essential. While the use of transgenic animals is well established, attempts using viral and non-viral vectors to genetically modify adipocytes in vivo are rare. Therefore, we here characterized recombinant Adeno-associated virus (rAAV) vectors regarding their potency as gene transfer vehicles for adipose tissue. Our results demonstrate that a single dose of systemically applied rAAV8-CMV-eGFP can give rise to remarkable transgene expression in murine adipose tissues. Upon transcriptional targeting of the rAAV8 vector to adipocytes using a 2.2 kb fragment of the murine adiponectin (mAP2.2) promoter, eGFP expression was significantly decreased in off-target tissues while efficient transduction was maintained in subcutaneous and visceral fat depots. Moreover, rAAV8-mAP2.2-mediated expression of perilipin A – a lipid-droplet-associated protein – resulted in significant changes in metabolic parameters only three weeks post vector administration. Taken together, our findings indicate that rAAV vector technology is applicable as a flexible tool to genetically modify adipocytes for functional proof-of-concept studies and the assessment of putative therapeutic targets in vivo.
Molecular metabolism | 2015
Nigel Beaton; Carla Rudigier; Hansjörg Moest; Sebastian Müller; Nadja Mrosek; Eva Röder; Gottfried Rudofsky; Thomas Rülicke; Jozef Ukropec; Barbara Ukropcova; Robert Augustin; Heike Neubauer; Christian Wolfrum
Objective Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. Methods We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Results Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Conclusions Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans.
Molecular and Cellular Biochemistry | 2012
Fabian Birzele; Sybille Fässler; Heike Neubauer; Tobias Hildebrandt; Bradford S. Hamilton
Alongside cell lines such as 3T3-L1 cells, primary cell culture models of adipogenesis have helped in developing an understanding of the process of adipocyte recruitment and maintenance, which may lead to therapeutic advances to treat the growing epidemic of obesity. Recently, it has been demonstrated that fat cell progenitors (DFAT) established through ceiling culture of adipocytes retain an enhanced ability to undergo adipocyte differentiation compared to preadipocytes isolated from the stromal vascular fraction of adipose tissue. Clonal expansion of rat DFAT cells identified differentiation capable and incapable cell strains. To understand the mechanisms underlying these differences, comparison of their transcriptomes by next generation sequencing was performed. Two hundred seventy-eight genes with a significant fold change of 1.4 were detected as being consistently deregulated between differentiating and non-differentiating strains. Bioinformatic network analyses identified components of the extra-cellular matrix and PPARγ as important genes in this process, suggesting crosstalk between ECM and transcription factors influences differentiation. Analyses of the transcriptomes of human DFAT cells in early and late passage (non-differentiating) confirmed the importance of these pathways in maintaining an adipogenic potential.
Cell Reports | 2018
Aliki Perdikari; German Leparc; Miroslav Balaz; Nuno D. Pires; Martin E. Lidell; Wenfei Sun; Francesc Fernandez-Albert; Sebastian Müller; Nassila Akchiche; Hua Dong; Lucia Balazova; Lennart Opitz; Eva Röder; Holger Klein; Patrik Stefanicka; Lukas Varga; Pirjo Nuutila; Kirsi A. Virtanen; Tarja Niemi; Markku Taittonen; Gottfried Rudofsky; Jozef Ukropec; Sven Enerbäck; Elia Stupka; Heike Neubauer; Christian Wolfrum
Recruitment and activation of thermogenic adipocytes have received increasing attention as a strategy to improve systemic metabolic control. The analysis of brown and brite adipocytes is complicated by the complexity of adipose tissue biopsies. Here, we provide an in-depth analysis of pure brown, brite, and white adipocyte transcriptomes. By combining mouse and human transcriptome data, we identify a gene signature that can classify brown and white adipocytes in mice and men. Using a machine-learning-based cell deconvolution approach, we develop an algorithm proficient in calculating the brown adipocyte content in complex human and mouse biopsies. Applying this algorithm, we can show in a human weight loss study that brown adipose tissue (BAT) content is associated with energy expenditure and the propensity to lose weight. This online available tool can be used for in-depth characterization of complex adipose tissue samples and may support the development of therapeutic strategies to increase energy expenditure in humans.
Cell Reports | 2016
Salvatore Modica; Leon G. Straub; Miroslav Balaz; Wenfei Sun; Lukas Varga; Patrik Stefanicka; Milan Profant; Eric Simon; Heike Neubauer; Barbara Ukropcova; Jozef Ukropec; Christian Wolfrum
Diabetologia | 2012
S. Glund; C. Schoelch; Leo Thomas; H. G. Niessen; D. Stiller; G. J. Roth; Heike Neubauer
Archive | 2012
Gerald Juergen Roth; Martin Fleck; Niklas Heine; Joerg Kley; Thorsten Lehmann-Lintz; Heike Neubauer; Bernd Nosse