36 results on '"Belgardt BF"'
Search Results
2. The Tp53 network regulates pancreatic beta cell survival
- Author
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Müller, N, additional, Wessel, C, additional, Grieß, K, additional, Polanski, C, additional, and Belgardt, BF, additional
- Published
- 2018
- Full Text
- View/download PDF
3. The role of ceramide synthases in pancreatic beta cell demise
- Author
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Grieß, K, additional, Polanski, C, additional, Markgraf, D, additional, Lammert, E, additional, Roden, M, additional, Stark, H, additional, Brüning, J, additional, and Belgardt, BF, additional
- Published
- 2018
- Full Text
- View/download PDF
4. Sfrp5 erhöht die glukosestimulierte, aber nicht die basale Insulinsekretion in INS-1E Zellen der Ratte
- Author
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Carstensen-Kirberg, M, additional, Röhrig, K, additional, Niersmann, C, additional, Ouwens, M, additional, Belgardt, BF, additional, Roden, M, additional, and Herder, C, additional
- Published
- 2017
- Full Text
- View/download PDF
5. Enhanced PIP3 signaling in POMC neurons causes diet-sensitive obesity as the consequence of neuronal silencing via KATP channel activation
- Author
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Plum, L, primary, Ma, X, additional, Hampel, B, additional, Münzberg, H, additional, Shanabrough, M, additional, Rother, E, additional, Koch, L, additional, Janoschek, R, additional, Alber, J, additional, Belgardt, BF, additional, Krone, W, additional, Horvath, TL, additional, Ashcroft, FM, additional, and Brüning, JC, additional
- Published
- 2006
- Full Text
- View/download PDF
6. Post mortem analysis of hepatic volume and lipid content by magnetic resonance imaging and spectroscopy in fixed murine neonates.
- Author
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Jonuscheit M, Uhlemeyer C, Korzekwa B, Schouwink M, Öner-Sieben S, Ensenauer R, Roden M, Belgardt BF, and Schrauwen-Hinderling VB
- Subjects
- Animals, Mice, Inbred C57BL, Lipids analysis, Mice, Organ Size, Magnetic Resonance Spectroscopy, Female, Reproducibility of Results, Tissue Fixation, Autopsy, Male, Liver diagnostic imaging, Liver metabolism, Magnetic Resonance Imaging methods, Animals, Newborn
- Abstract
Maternal obesity and hyperglycemia are linked to an elevated risk for obesity, diabetes, and steatotic liver disease in the adult offspring. To establish and validate a noninvasive workflow for perinatal metabolic phenotyping, fixed neonates of common mouse strains were analyzed postmortem via magnetic resonance imaging (MRI)/magnetic resonance spectroscopy (MRS) to assess liver volume and hepatic lipid (HL) content. The key advantage of nondestructive MRI/MRS analysis is the possibility of further tissue analyses, such as immunohistochemistry, RNA extraction, and even proteomics, maximizing the data that can be gained per individual and therefore facilitating comprehensive correlation analyses. This study employed an MRI and
1 H-MRS workflow to measure liver volume and HL content in 65 paraformaldehyde-fixed murine neonates at 11.7 T. Liver volume was obtained using semiautomatic segmentation of MRI acquired by a RARE sequence with 0.5-mm slice thickness. HL content was measured by a STEAM sequence, applied with and without water suppression. T1 and T2 relaxation times of lipids and water were measured for respective correction of signal intensity. The HL content, given as CH2 /(CH2 + H2 O), was calculated, and the intrasession repeatability of the method was tested. The established workflow yielded robust results with a variation of ~3% in repeated measurements for HL content determination. HL content measurements were further validated by correlation analysis with biochemically assessed triglyceride contents (R2 = 0.795) that were measured in littermates. In addition, image quality also allowed quantification of subcutaneous adipose tissue and stomach diameter. The highest HL content was measured in C57Bl/6N (4.2%) and the largest liver volume and stomach diameter in CBA (53.1 mm3 and 6.73 mm) and NMRI (51.4 mm3 and 5.96 mm) neonates, which also had the most subcutaneous adipose tissue. The observed effects were independent of sex and litter size. In conclusion, we have successfully tested and validated a robust MRI/MRS workflow that allows assessment of morphology and HL content and further enables paraformaldehyde-fixed tissue-compatible subsequent analyses in murine neonates., (© 2024 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)- Published
- 2024
- Full Text
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7. Semaphorin-3A regulates liver sinusoidal endothelial cell porosity and promotes hepatic steatosis.
- Author
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Eberhard D, Balkenhol S, Köster A, Follert P, Upschulte E, Ostermann P, Kirschner P, Uhlemeyer C, Charnay I, Preuss C, Trenkamp S, Belgardt BF, Dickscheid T, Esposito I, Roden M, and Lammert E
- Subjects
- Animals, Humans, Neuropilin-1 metabolism, Neuropilin-1 genetics, Obesity metabolism, Obesity pathology, Obesity genetics, Cofilin 1 metabolism, Cofilin 1 genetics, Disease Models, Animal, Male, Phosphorylation, Cells, Cultured, Mice, Mice, Knockout, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 2 pathology, Diabetes Mellitus, Type 2 genetics, Diet, High-Fat adverse effects, Endothelial Cells metabolism, Endothelial Cells pathology, Liver metabolism, Liver pathology, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Non-alcoholic Fatty Liver Disease genetics, Semaphorin-3A metabolism, Semaphorin-3A genetics, Signal Transduction, Mice, Inbred C57BL
- Abstract
Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, increases worldwide and associates with type 2 diabetes and other cardiometabolic diseases. Here we demonstrate that Sema3a is elevated in liver sinusoidal endothelial cells of animal models for obesity, type 2 diabetes and MASLD. In primary human liver sinusoidal endothelial cells, saturated fatty acids induce expression of SEMA3A, and loss of a single allele is sufficient to reduce hepatic fat content in diet-induced obese mice. We show that semaphorin-3A regulates the number of fenestrae through a signaling cascade that involves neuropilin-1 and phosphorylation of cofilin-1 by LIM domain kinase 1. Finally, inducible vascular deletion of Sema3a in adult diet-induced obese mice reduces hepatic fat content and elevates very low-density lipoprotein secretion. Thus, we identified a molecular pathway linking hyperlipidemia to microvascular defenestration and early development of MASLD., (© 2024. The Author(s).)
- Published
- 2024
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8. Pancreatic islet protection at the expense of secretory function involves serine-linked mitochondrial one-carbon metabolism.
- Author
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Pelligra A, Mrugala J, Griess K, Kirschner P, Nortmann O, Bartosinska B, Köster A, Krupenko NI, Gebel D, Westhoff P, Steckel B, Eberhard D, Herebian D, Belgardt BF, Schrader J, Weber APM, Krupenko SA, and Lammert E
- Published
- 2023
- Full Text
- View/download PDF
9. MIC26 and MIC27 are bona fide subunits of the MICOS complex in mitochondria and do not exist as glycosylated apolipoproteins.
- Author
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Lubeck M, Derkum NH, Naha R, Strohm R, Driessen MD, Belgardt BF, Roden M, Stühler K, Anand R, Reichert AS, and Kondadi AK
- Subjects
- Humans, Glycosylation, Mitochondrial Proteins metabolism, Mitochondria metabolism, Apolipoproteins metabolism, Membrane Proteins genetics, Diabetes Mellitus pathology
- Abstract
Impairments of mitochondrial functions are linked to human ageing and pathologies such as cancer, cardiomyopathy, neurodegeneration and diabetes. Specifically, aberrations in ultrastructure of mitochondrial inner membrane (IM) and factors regulating them are linked to diabetes. The development of diabetes is connected to the 'Mitochondrial Contact Site and Cristae Organising System' (MICOS) complex which is a large membrane protein complex defining the IM architecture. MIC26 and MIC27 are homologous apolipoproteins of the MICOS complex. MIC26 has been reported as a 22 kDa mitochondrial and a 55 kDa glycosylated and secreted protein. The molecular and functional relationship between these MIC26 isoforms has not been investigated. In order to understand their molecular roles, we depleted MIC26 using siRNA and further generated MIC26 and MIC27 knockouts (KOs) in four different human cell lines. In these KOs, we used four anti-MIC26 antibodies and consistently detected the loss of mitochondrial MIC26 (22 kDa) and MIC27 (30 kDa) but not the loss of intracellular or secreted 55 kDa protein. Thus, the protein assigned earlier as 55 kDa MIC26 is nonspecific. We further excluded the presence of a glycosylated, high-molecular weight MIC27 protein. Next, we probed GFP- and myc-tagged variants of MIC26 with antibodies against GFP and myc respectively. Again, only the mitochondrial versions of these tagged proteins were detected but not the corresponding high-molecular weight MIC26, suggesting that MIC26 is indeed not post-translationally modified. Mutagenesis of predicted glycosylation sites in MIC26 also did not affect the detection of the 55 kDa protein band. Mass spectrometry of a band excised from an SDS gel around 55 kDa could not confirm the presence of any peptides derived from MIC26. Taken together, we conclude that both MIC26 and MIC27 are exclusively localized in mitochondria and that the observed phenotypes reported previously are exclusively due to their mitochondrial function., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lubeck et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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- View/download PDF
10. E96V Mutation in the Kdelr3 Gene Is Associated with Type 2 Diabetes Susceptibility in Obese NZO Mice.
- Author
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Altenhofen D, Khuong JM, Kuhn T, Lebek S, Görigk S, Kaiser K, Binsch C, Griess K, Knebel B, Belgardt BF, Cames S, Eickelschulte S, Stermann T, Rasche A, Herwig R, Weiss J, Vogel H, Schürmann A, Chadt A, and Al-Hasani H
- Subjects
- Animals, Mice, Insulin metabolism, Insulin-Secreting Cells metabolism, Mice, Inbred C3H, Mice, Obese, Diabetes Mellitus, Type 2 genetics, Obesity genetics, Genetic Predisposition to Disease, Receptors, Peptide genetics
- Abstract
Type 2 diabetes (T2D) represents a multifactorial metabolic disease with a strong genetic predisposition. Despite elaborate efforts in identifying the genetic variants determining individual susceptibility towards T2D, the majority of genetic factors driving disease development remain poorly understood. With the aim to identify novel T2D risk genes we previously generated an N2 outcross population using the two inbred mouse strains New Zealand obese (NZO) and C3HeB/FeJ (C3H). A linkage study performed in this population led to the identification of the novel T2D-associated quantitative trait locus (QTL) Nbg15 (NZO blood glucose on chromosome 15, Logarithm of odds (LOD) 6.6). In this study we used a combined approach of positional cloning, gene expression analyses and in silico predictions of DNA polymorphism on gene/protein function to dissect the genetic variants linking Nbg15 to the development of T2D. Moreover, we have generated congenic strains that associated the distal sublocus of Nbg15 to mechanisms altering pancreatic beta cell function. In this sublocus, Cbx6 , Fam135b and Kdelr3 were nominated as potential causative genes associated with the Nbg15 driven effects. Moreover, a putative mutation in the Kdelr3 gene from NZO was identified, negatively influencing adaptive responses associated with pancreatic beta cell death and induction of endoplasmic reticulum stress. Importantly, knockdown of Kdelr3 in cultured Min6 beta cells altered insulin granules maturation and pro-insulin levels, pointing towards a crucial role of this gene in islets function and T2D susceptibility.
- Published
- 2023
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11. Sphingolipid subtypes differentially control proinsulin processing and systemic glucose homeostasis.
- Author
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Griess K, Rieck M, Müller N, Karsai G, Hartwig S, Pelligra A, Hardt R, Schlegel C, Kuboth J, Uhlemeyer C, Trenkamp S, Jeruschke K, Weiss J, Peifer-Weiss L, Xu W, Cames S, Yi X, Cnop M, Beller M, Stark H, Kondadi AK, Reichert AS, Markgraf D, Wammers M, Häussinger D, Kuss O, Lehr S, Eizirik D, Lickert H, Lammert E, Roden M, Winter D, Al-Hasani H, Höglinger D, Hornemann T, Brüning JC, and Belgardt BF
- Subjects
- Humans, Proinsulin genetics, Proinsulin metabolism, Sphingolipids metabolism, Insulin metabolism, Homeostasis, Carrier Proteins metabolism, Glucose metabolism, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 metabolism, Diabetes Mellitus, Type 1 metabolism, Insulin-Secreting Cells metabolism
- Abstract
Impaired proinsulin-to-insulin processing in pancreatic β-cells is a key defective step in both type 1 diabetes and type 2 diabetes (T2D) (refs.
1 , 2 ), but the mechanisms involved remain to be defined. Altered metabolism of sphingolipids (SLs) has been linked to development of obesity, type 1 diabetes and T2D (refs.3-8 ); nonetheless, the role of specific SL species in β-cell function and demise is unclear. Here we define the lipid signature of T2D-associated β-cell failure, including an imbalance of specific very-long-chain SLs and long-chain SLs. β-cell-specific ablation of CerS2, the enzyme necessary for generation of very-long-chain SLs, selectively reduces insulin content, impairs insulin secretion and disturbs systemic glucose tolerance in multiple complementary models. In contrast, ablation of long-chain-SL-synthesizing enzymes has no effect on insulin content. By quantitatively defining the SL-protein interactome, we reveal that CerS2 ablation affects SL binding to several endoplasmic reticulum-Golgi transport proteins, including Tmed2, which we define as an endogenous regulator of the essential proinsulin processing enzyme Pcsk1. Our study uncovers roles for specific SL subtypes and SL-binding proteins in β-cell function and T2D-associated β-cell failure., (© 2022. The Author(s).)- Published
- 2023
- Full Text
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12. Selective ablation of P53 in pancreatic beta cells fails to ameliorate glucose metabolism in genetic, dietary and pharmacological models of diabetes mellitus.
- Author
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Uhlemeyer C, Müller N, Rieck M, Kuboth J, Schlegel C, Grieß K, Dorweiler TF, Heiduschka S, Eckel J, Roden M, Lammert E, Stoffel M, and Belgardt BF
- Subjects
- Humans, Mice, Animals, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Insulin metabolism, Glucose metabolism, Insulin-Secreting Cells metabolism, Diabetes Mellitus, Type 2 metabolism
- Abstract
Objective: Beta cell dysfunction and death are critical steps in the development of both type 1 and type 2 diabetes (T1D and T2D), but the underlying mechanisms are incompletely understood. Activation of the essential tumor suppressor and transcription factor P53 (also known as TP53 and Trp53 in mice) was linked to beta cell death in vitro and has been reported in several diabetes mouse models and beta cells of humans with T2D. In this article, we set out to determine the beta cell specific role of P53 in beta cell dysfunction, cell death and development of diabetes in vivo., Methods: We generated beta cell specific P53 knockout (P53
BKO ) mice and used complementary genetic, dietary and pharmacological models of glucose intolerance, beta cell dysfunction and diabetes development to evaluate the functional role of P53 selectively in beta cells. We further analyzed the effect of P53 ablation on beta cell survival in isolated pancreatic islets exposed to diabetogenic stress inducers ex vivo by flow cytometry., Results: Beta cell specific ablation of P53/Trp53 failed to ameliorate glucose tolerance, insulin secretion or to increase beta cell numbers in genetic, dietary and pharmacological models of diabetes. Additionally, loss of P53 in beta cells did not protect against streptozotocin (STZ) induced hyperglycemia and beta cell death, although STZ-induced activation of classical pro-apoptotic P53 target genes was significantly reduced in P53BKO mice. In contrast, Olaparib mediated PARP1 inhibition protected against acute ex vivo STZ-induced beta cell death and islet destruction., Conclusions: Our study reveals that ablation of P53 specifically in beta cells is unexpectedly unable to attenuate beta cell failure and death in vivo and ex vivo. While during development and progression of diabetes, P53 and P53-regulated pathways are activated, our study suggests that P53 signaling is not essential for loss of beta cells or beta cell dysfunction. P53 in other cell types and organs may predominantly regulate systemic glucose homeostasis., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)- Published
- 2023
- Full Text
- View/download PDF
13. Positive allosteric γ-aminobutyric acid type A receptor modulation prevents lipotoxicity-induced injury in hepatocytes in vitro.
- Author
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Rohbeck E, Hasse B, Koopmans G, Romero A, Belgardt BF, Roden M, Eckel J, and Romacho T
- Subjects
- Apoptosis, Calcium metabolism, Caspase 3 metabolism, HEK293 Cells, Hepatocytes, Humans, NF-kappa B metabolism, NF-kappa B pharmacology, Palmitates metabolism, Palmitates pharmacology, Picrotoxin metabolism, Picrotoxin pharmacology, Poly(ADP-ribose) Polymerase Inhibitors metabolism, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, gamma-Aminobutyric Acid metabolism, gamma-Aminobutyric Acid pharmacology, Receptors, GABA metabolism, Receptors, GABA-A genetics, Receptors, GABA-A metabolism
- Abstract
Aim: To determine if a novel positive allosteric modulator of the γ-aminobutyric acid type A (GABA
A ) receptor, the thioacrylamide-derivative HK4, which does not penetrate the blood-brain barrier, protects human hepatocytes against lipotoxicity-induced injury., Materials and Methods: Allosteric modulation of the GABAA receptor by HK4 was determined by patch clamp in HEK-293 cells, calcium influx in INS-1E cells and by using the specific GABAA channel blockers picrotoxin and tert-butylbicyclophosphorothionate (TBPS) in HepG2 cells. Apoptosis was analysed using caspase 3/7, terminal deoxynucleotidyl transferase-dUTP nick end labelling (TUNEL) and array assays in HepG2 cells and/or human primary hepatocytes. Phosphorylation of STAT3 and the NF-κB subunit p65, protein disulphide isomerase (PDI) and poly-ADP-ribose polymerase-1 (PARP-1) was detected by Western blotting., Results: Patch clamping, calcium influx measurements and apoptosis assays with the non-competitive GABAA channel blockers picrotoxin and TBPS proved HK4 as a selective positive allosteric modulator of the GABAA receptor. In HepG2 cells, which expressed the main GABAA receptor subunits, HK4 prevented palmitate-induced apoptosis. This protective effect was mediated by downregulation of caspase 3/7 activity and was additionally verified by TUNEL assay. HK4 effectively prevented palmitate-induced apoptosis in human primary hepatocytes. HK4 reduced STAT3 and NF-κB phosphorylation, reduced cleaved PARP-1 expression and upregulated the endoplasmic reticulum (ER) chaperone PDI., Conclusions: HK4 reduced lipotoxic-induced apoptosis by preventing inflammation, DNA damage and ER stress. We propose that the effect of HK4 is mediated by STAT3 and NF-κB. It is suggested that thioacrylamide compounds represent an innovative pharmacological tool to treat or prevent non-alcoholic steatohepatitis as first-in-class drugs., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)- Published
- 2022
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14. Interaction between magnesium and methylglyoxal in diabetic polyneuropathy and neuronal models.
- Author
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Strom A, Strassburger K, Schmuck M, Shevalye H, Davidson E, Zivehe F, Bönhof G, Reimer R, Belgardt BF, Fleming T, Biermann B, Burkart V, Müssig K, Szendroedi J, Yorek MA, Fritsche E, Nawroth PP, Roden M, and Ziegler D
- Subjects
- Animals, Cross-Sectional Studies, Diabetes Mellitus metabolism, Diabetic Neuropathies etiology, Energy Metabolism, Female, Glycation End Products, Advanced metabolism, Humans, Male, Mice, Middle Aged, Mitochondria metabolism, Neurons metabolism, Polyneuropathies physiopathology, Sensorimotor Cortex metabolism, Magnesium metabolism, Polyneuropathies metabolism, Pyruvaldehyde metabolism
- Abstract
Objective: The lack of effective treatments against diabetic sensorimotor polyneuropathy demands the search for new strategies to combat or prevent the condition. Because reduced magnesium and increased methylglyoxal levels have been implicated in the development of both type 2 diabetes and neuropathic pain, we aimed to assess the putative interplay of both molecules with diabetic sensorimotor polyneuropathy., Methods: In a cross-sectional study, serum magnesium and plasma methylglyoxal levels were measured in recently diagnosed type 2 diabetes patients with (n = 51) and without (n = 184) diabetic sensorimotor polyneuropathy from the German Diabetes Study baseline cohort. Peripheral nerve function was assessed using nerve conduction velocity and quantitative sensory testing. Human neuroblastoma cells (SH-SY5Y) and mouse dorsal root ganglia cells were used to characterize the neurotoxic effect of methylglyoxal and/or neuroprotective effect of magnesium., Results: Here, we demonstrate that serum magnesium concentration was reduced in recently diagnosed type 2 diabetes patients with diabetic sensorimotor polyneuropathy and inversely associated with plasma methylglyoxal concentration. Magnesium, methylglyoxal, and, importantly, their interaction were strongly interrelated with methylglyoxal-dependent nerve dysfunction and were predictive of changes in nerve function. Magnesium supplementation prevented methylglyoxal neurotoxicity in differentiated SH-SY5Y neuron-like cells due to reduction of intracellular methylglyoxal formation, while supplementation with the divalent cations zinc and manganese had no effect on methylglyoxal neurotoxicity. Furthermore, the downregulation of mitochondrial activity in mouse dorsal root ganglia cells and consequently the enrichment of triosephosphates, the primary source of methylglyoxal, resulted in neurite degeneration, which was completely prevented through magnesium supplementation., Conclusions: These multifaceted findings reveal a novel putative pathophysiological pathway of hypomagnesemia-induced carbonyl stress leading to neuronal damage and merit further investigations not only for diabetic sensorimotor polyneuropathy but also other neurodegenerative diseases associated with magnesium deficiency and impaired energy metabolism., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)
- Published
- 2021
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15. ATM and P53 differentially regulate pancreatic beta cell survival in Ins1E cells.
- Author
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Uhlemeyer C, Müller N, Grieß K, Wessel C, Schlegel C, Kuboth J, and Belgardt BF
- Subjects
- Animals, Apoptosis drug effects, Apoptosis genetics, Ataxia Telangiectasia Mutated Proteins antagonists & inhibitors, Ataxia Telangiectasia Mutated Proteins genetics, Cell Line, Cell Survival drug effects, DNA Damage drug effects, Diabetes Mellitus pathology, Endoplasmic Reticulum Stress drug effects, Endoplasmic Reticulum Stress genetics, Gene Knockdown Techniques, Humans, Insulin-Secreting Cells drug effects, Protease Inhibitors pharmacology, Protein Processing, Post-Translational drug effects, RNA, Small Interfering metabolism, Rats, Streptozocin toxicity, Tunicamycin toxicity, Ataxia Telangiectasia Mutated Proteins metabolism, Cell Survival genetics, Insulin-Secreting Cells pathology, Signal Transduction genetics, Tumor Suppressor Protein p53 metabolism
- Abstract
Pancreatic beta cell death is a hallmark of type 1 and 2 diabetes (T1D/T2D), but the underlying molecular mechanisms are incompletely understood. Key proteins of the DNA damage response (DDR), including tumor protein P53 (P53, also known as TP53 or TRP53 in rodents) and Ataxia Telangiectasia Mutated (ATM), a kinase known to act upstream of P53, have been associated with T2D. Here we test and compare the effect of ATM and P53 ablation on beta cell survival in the rat beta cell line Ins1E. We demonstrate that ATM and P53 differentially regulate beta cell apoptosis induced upon fundamentally different types of diabetogenic beta cell stress, including DNA damage, inflammation, lipotoxicity and endoplasmic reticulum (ER) stress. DNA damage induced apoptosis by treatment with the commonly used diabetogenic agent streptozotocin (STZ) is regulated by both ATM and P53. We show that ATM is a key STZ induced activator of P53 and that amelioration of STZ induced cell death by inhibition of ATM mainly depends on P53. While both P53 and ATM control lipotoxic beta cell apoptosis, ATM but not P53 fails to alter inflammatory beta cell death. In contrast, tunicamycin induced (ER stress associated) apoptosis is further increased by ATM knockdown or inhibition, but not by P53 knockdown. Our results reveal differential roles for P53 and ATM in beta cell survival in vitro in the context of four key pathophysiological types of diabetogenic beta cell stress, and indicate that ATM can use P53 independent signaling pathways to modify beta cell survival, dependent on the cellular insult., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
- Full Text
- View/download PDF
16. Sfrp5 increases glucose-stimulated insulin secretion in the rat pancreatic beta cell line INS-1E.
- Author
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Carstensen-Kirberg M, Röhrig K, Niersmann C, Ouwens DM, Belgardt BF, Roden M, and Herder C
- Subjects
- Animals, Blood Glucose metabolism, Cell Line, Cell Proliferation, Cell Survival, Cyclin B1 metabolism, MAP Kinase Kinase 4 metabolism, Phosphorylation, RNA, Messenger metabolism, Rats, Signal Transduction, Wnt Proteins metabolism, Wnt Signaling Pathway, Adipokines metabolism, Glucose metabolism, Insulin metabolism, Insulin Secretion, Insulin-Secreting Cells drug effects
- Abstract
Previous studies reported that secreted frizzled-related protein-5 (Sfrp5) decreases beta cell proliferation and increases fasting insulin levels, but studies on direct effects of Sfrp5 on insulin secretion and its underlying mechanisms are missing. This study examined effects of Sfrp5 on (i) beta cell viability and proliferation, (ii) basal and glucose-stimulated insulin secretion and (iii) canonical and non-canonical Wnt signalling pathways. We incubated rat INS-1E cells with 0.1, 1 or 5 μg/ml recombinant Sfrp5 for 24h. We measured basal and glucose-stimulated insulin secretion at glucose concentrations of 2.5 and 20 mmol/l. Phosphorylated and total protein content as well as mRNA levels of markers of cell proliferation, canonical and non-canonical Wnt signalling pathways were examined using Western blotting and real-time PCR. Differences between treatments were analysed by repeated measurement one-way ANOVA or Friedman's test followed by correction for multiple testing using the Benjamini-Hochberg procedure. At 5 μg/ml, Sfrp5 reduced mRNA levels of cyclin-B1 by 25% (p<0.05). At 1 and 5 μg/ml, Sfrp5 increased glucose-stimulated insulin secretion by 24% and by 34% (both p<0.05), respectively, but had no impact on basal insulin secretion. Sfrp5 reduced the phosphorylation of the splicing forms p46 and p54 of JNK by 39% (p<0.01) and 49% (p<0.05), respectively. In conclusion, Sfrp5 reduced markers of cell proliferation, but increased in parallel dose-dependently glucose-stimulated insulin secretion in INS-1E cells. This effect is likely mediated by reduced JNK activity, an important component of the non-canonical Wnt signalling pathway., Competing Interests: Christian Herder is Academic Editor with PLoS ONE. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2019
- Full Text
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17. Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer.
- Author
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Ostermann AL, Wunderlich CM, Schneiders L, Vogt MC, Woeste MA, Belgardt BF, Niessen CM, Martiny B, Schauss AC, Frommolt P, Nikolaev A, Hövelmeyer N, Sears RC, Koch PJ, Günzel D, Brüning JC, and Wunderlich FT
- Subjects
- Animals, Colonic Neoplasms metabolism, Diet, High-Fat, Gene Expression Regulation physiology, Humans, Insulin physiology, Intestinal Mucosa cytology, Mice, Mice, Inbred C57BL, Signal Transduction, Colonic Neoplasms prevention & control, Forkhead Box Protein O1 metabolism, Insulin metabolism, Insulin-Like Growth Factor I metabolism, Intestinal Mucosa metabolism
- Abstract
Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.
- Published
- 2019
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18. Exploring biological and social networks to better understand and treat diabetes mellitus: Comment on "Network science of biological systems at different scales: A review" by Gosak et al.
- Author
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Belgardt BF, Jarasch A, and Lammert E
- Subjects
- Humans, Social Support, Diabetes Mellitus, Type 2, Social Networking
- Published
- 2018
- Full Text
- View/download PDF
19. DYRK1A: A Promising Drug Target for Islet Transplant-Based Diabetes Therapies.
- Author
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Belgardt BF and Lammert E
- Subjects
- Humans, Transplants, Diabetes Mellitus, Type 1, Islets of Langerhans Transplantation
- Published
- 2016
- Full Text
- View/download PDF
20. The microRNA-200 family regulates pancreatic beta cell survival in type 2 diabetes.
- Author
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Belgardt BF, Ahmed K, Spranger M, Latreille M, Denzler R, Kondratiuk N, von Meyenn F, Villena FN, Herrmanns K, Bosco D, Kerr-Conte J, Pattou F, Rülicke T, and Stoffel M
- Subjects
- Animals, Apoptosis genetics, Cell Survival genetics, Diabetes Mellitus, Type 2 pathology, Gene Expression Regulation, HSP40 Heat-Shock Proteins biosynthesis, Humans, Insulin metabolism, Insulin-Secreting Cells pathology, Mice, Mice, Inbred NOD, MicroRNAs metabolism, Signal Transduction, X-Linked Inhibitor of Apoptosis Protein biosynthesis, Diabetes Mellitus, Type 2 genetics, Insulin-Secreting Cells metabolism, MicroRNAs genetics
- Abstract
Pancreatic beta cell death is a hallmark of type 1 (T1D) and type 2 (T2D) diabetes, but the molecular mechanisms underlying this aspect of diabetic pathology are poorly understood. Here we report that expression of the microRNA (miR)-200 family is strongly induced in islets of diabetic mice and that beta cell-specific overexpression of miR-200 in mice is sufficient to induce beta cell apoptosis and lethal T2D. Conversely, mir-200 ablation in mice reduces beta cell apoptosis and ameliorates T2D. We show that miR-200 negatively regulates a conserved anti-apoptotic and stress-resistance network that includes the essential beta cell chaperone Dnajc3 (also known as p58IPK) and the caspase inhibitor Xiap. We also observed that mir-200 dosage positively controls activation of the tumor suppressor Trp53 and thereby creates a pro-apoptotic gene-expression signature found in islets of diabetic mice. Consequently, miR-200-induced T2D is suppressed by interfering with the signaling of Trp53 and Bax, a proapoptotic member of the B cell lymphoma 2 protein family. Our results reveal a crucial role for the miR-200 family in beta cell survival and the pathophysiology of diabetes.
- Published
- 2015
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21. Distinct Roles for JNK and IKK Activation in Agouti-Related Peptide Neurons in the Development of Obesity and Insulin Resistance.
- Author
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Tsaousidou E, Paeger L, Belgardt BF, Pal M, Wunderlich CM, Brönneke H, Collienne U, Hampel B, Wunderlich FT, Schmidt-Supprian M, Kloppenburg P, and Brüning JC
- Subjects
- Action Potentials drug effects, Adiposity drug effects, Animals, Body Weight drug effects, Enzyme Activation drug effects, Glucose metabolism, Homeostasis drug effects, Insulin metabolism, Leptin pharmacology, MAP Kinase Signaling System drug effects, Male, Mice, Inbred C57BL, Mutant Proteins metabolism, Neurons drug effects, Agouti-Related Protein metabolism, I-kappa B Kinase metabolism, Insulin Resistance, JNK Mitogen-Activated Protein Kinases metabolism, Neurons enzymology, Obesity enzymology
- Abstract
Activation of c-Jun N-terminal kinase 1 (JNK1)- and inhibitor of nuclear factor kappa-B kinase 2 (IKK2)-dependent signaling plays a crucial role in the development of obesity-associated insulin and leptin resistance not only in peripheral tissues but also in the CNS. Here, we demonstrate that constitutive JNK activation in agouti-related peptide (AgRP)-expressing neurons of the hypothalamus is sufficient to induce weight gain and adiposity in mice as a consequence of hyperphagia. JNK activation increases spontaneous action potential firing of AgRP cells and causes both neuronal and systemic leptin resistance. Similarly, activation of IKK2 signaling in AgRP neurons also increases firing of these cells but fails to cause obesity and leptin resistance. In contrast to JNK activation, IKK2 activation blunts insulin signaling in AgRP neurons and impairs systemic glucose homeostasis. Collectively, these experiments reveal both overlapping and nonredundant effects of JNK- and IKK-dependent signaling in AgRP neurons, which cooperate in the manifestation of the metabolic syndrome., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
22. SIK2 regulates insulin secretion.
- Author
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Belgardt BF and Stoffel M
- Subjects
- Animals, Female, Male, Insulin-Secreting Cells physiology, Phosphotransferases metabolism, Protein Serine-Threonine Kinases metabolism, Ubiquitin-Protein Ligases metabolism
- Abstract
Correct regulation of insulin secretion by the pancreas is crucial for organismal function and survival. The AMPK-related kinase SIK2 (salt-inducible kinase 2) is now shown to be stabilized in pancreatic β-cells following glucose stimulation, leading to improved systemic glucose homeostasis by regulating cellular calcium flux and insulin secretion.
- Published
- 2014
- Full Text
- View/download PDF
23. The fat mass and obesity associated gene (Fto) regulates activity of the dopaminergic midbrain circuitry.
- Author
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Hess ME, Hess S, Meyer KD, Verhagen LA, Koch L, Brönneke HS, Dietrich MO, Jordan SD, Saletore Y, Elemento O, Belgardt BF, Franz T, Horvath TL, Rüther U, Jaffrey SR, Kloppenburg P, and Brüning JC
- Subjects
- Adenine metabolism, Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Animals, Cocaine pharmacology, Corpus Striatum physiology, Dopaminergic Neurons physiology, Exploratory Behavior drug effects, Exploratory Behavior physiology, Female, G Protein-Coupled Inwardly-Rectifying Potassium Channels physiology, Locomotion drug effects, Locomotion physiology, Male, Methylation, Methyltransferases metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mixed Function Oxygenases deficiency, Mixed Function Oxygenases genetics, Oxo-Acid-Lyases deficiency, Oxo-Acid-Lyases genetics, Phenotype, Quinpirole pharmacology, RNA Processing, Post-Transcriptional, RNA, Messenger metabolism, Receptors, Dopamine D2 deficiency, Receptors, Dopamine D2 physiology, Receptors, Dopamine D3 physiology, Reward, Signal Transduction drug effects, Dopamine physiology, Dopaminergic Neurons enzymology, Mesencephalon physiology, Mixed Function Oxygenases physiology, Oxo-Acid-Lyases physiology
- Abstract
Dopaminergic (DA) signaling governs the control of complex behaviors, and its deregulation has been implicated in a wide range of diseases. Here we demonstrate that inactivation of the Fto gene, encoding a nucleic acid demethylase, impairs dopamine receptor type 2 (D2R) and type 3 (D3R) (collectively, 'D2-like receptor')-dependent control of neuronal activity and behavioral responses. Conventional and DA neuron-specific Fto knockout mice show attenuated activation of G protein-coupled inwardly-rectifying potassium (GIRK) channel conductance by cocaine and quinpirole. Impaired D2-like receptor-mediated autoinhibition results in attenuated quinpirole-mediated reduction of locomotion and an enhanced sensitivity to the locomotor- and reward-stimulatory actions of cocaine. Analysis of global N(6)-methyladenosine (m(6)A) modification of mRNAs using methylated RNA immunoprecipitation coupled with next-generation sequencing in the midbrain and striatum of Fto-deficient mice revealed increased adenosine methylation in a subset of mRNAs important for neuronal signaling, including many in the DA signaling pathway. Several proteins encoded by these mRNAs had altered expression levels. Collectively, FTO regulates the demethylation of specific mRNAs in vivo, and this activity relates to the control of DA transmission.
- Published
- 2013
- Full Text
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24. Acute selective ablation of rat insulin promoter-expressing (RIPHER) neurons defines their orexigenic nature.
- Author
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Rother E, Belgardt BF, Tsaousidou E, Hampel B, Waisman A, Myers MG Jr, and Brüning JC
- Subjects
- Animals, Arcuate Nucleus of Hypothalamus cytology, Feeding Behavior, Glucose Tolerance Test, Mice, Paraventricular Hypothalamic Nucleus cytology, Rats, Real-Time Polymerase Chain Reaction, Weight Loss, Arcuate Nucleus of Hypothalamus metabolism, Insulin genetics, Neurons metabolism, Paraventricular Hypothalamic Nucleus metabolism, Promoter Regions, Genetic
- Abstract
Rat insulin promoter (RIP)-expressing neurons in the hypothalamus control body weight and energy homeostasis. However, genetic approaches to study the role of these neurons have been limited by the fact that RIP expression is predominantly found in pancreatic β-cells, which impedes selective targeting of neurons. To define the function of hypothalamic RIP-expressing neurons, we set out to acutely and selectively eliminate them via diphtheria toxin-mediated ablation. Therefore, the diphtheria toxin receptor transgene was specifically expressed upon RIP-specific Cre recombination using a RIP-Cre line first described by Herrera (RIP(HER)-Cre) [Herrera PL (2000) Development 127:2317-2322]. Using proopiomelanocortin-expressing cells located in the arcuate nucleus of the hypothalamus and in the pituitary gland as a model, we established a unique protocol of intracerebroventricular application of diphtheria toxin to efficiently ablate hypothalamic cells with no concomitant effect on pituitary proopiomelanocortin-expressing corticotrophs in the mouse. Using this approach to ablate RIP(HER) neurons in the brain, but not in the pancreas, resulted in decreased food intake and loss of body weight and fat mass. In addition, ablation of RIP(HER) neurons caused increased c-Fos immunoreactivity of neurons in the paraventricular nucleus (PVN) of the hypothalamus. Moreover, transsynaptic tracing of RIP(HER) neurons revealed labeling of neurons located in the PVN and dorsomedial hypothalamic nucleus. Thus, our experiments indicate that RIP(HER) neurons inhibit anorexigenic neurons in the PVN, revealing a basic orexigenic nature of these cells.
- Published
- 2012
- Full Text
- View/download PDF
25. Dwarfism in mice lacking collagen-binding integrins α2β1 and α11β1 is caused by severely diminished IGF-1 levels.
- Author
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Blumbach K, Niehoff A, Belgardt BF, Ehlen HW, Schmitz M, Hallinger R, Schulz JN, Brüning JC, Krieg T, Schubert M, Gullberg D, and Eckes B
- Subjects
- Animals, Bone Density genetics, Bone and Bones cytology, Bone and Bones physiology, Collagen metabolism, Extracellular Matrix physiology, Female, Growth Hormone metabolism, Growth Hormone-Releasing Hormone metabolism, Homeostasis physiology, Liver physiology, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Osteoblasts physiology, Signal Transduction physiology, Dwarfism genetics, Dwarfism metabolism, Insulin-Like Growth Factor I metabolism, Integrin alpha2beta1 genetics, Integrins genetics, Receptors, Collagen genetics
- Abstract
Mice with a combined deficiency in the α2β1 and α11β1 integrins lack the major receptors for collagen I. These mutants are born with inconspicuous differences in size but develop dwarfism within the first 4 weeks of life. Dwarfism correlates with shorter, less mineralized and functionally weaker bones that do not result from growth plate abnormalities or osteoblast dysfunction. Besides skeletal dwarfism, internal organs are correspondingly smaller, indicating proportional dwarfism and suggesting a systemic cause for the overall size reduction. In accordance with a critical role of insulin-like growth factor (IGF)-1 in growth control and bone mineralization, circulating IGF-1 levels in the sera of mice lacking either α2β1 or α11β1 or both integrins were sharply reduced by 39%, 64%, or 81% of normal levels, respectively. Low hepatic IGF-1 production resulted from diminished growth hormone-releasing hormone expression in the hypothalamus and, subsequently, reduced growth hormone expression in the pituitary glands of these mice. These findings point out a novel role of collagen-binding integrin receptors in the control of growth hormone/IGF-1-dependent biological activities. Thus, coupling hormone secretion to extracellular matrix signaling via integrins represents a novel concept in the control of endocrine homeostasis.
- Published
- 2012
- Full Text
- View/download PDF
26. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons.
- Author
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Klöckener T, Hess S, Belgardt BF, Paeger L, Verhagen LA, Husch A, Sohn JW, Hampel B, Dhillon H, Zigman JM, Lowell BB, Williams KW, Elmquist JK, Horvath TL, Kloppenburg P, and Brüning JC
- Subjects
- Action Potentials drug effects, Action Potentials genetics, Age Factors, Animals, Animals, Newborn, Blood Glucose drug effects, Body Weight drug effects, Calorimetry methods, Dose-Response Relationship, Drug, Eating drug effects, Eating physiology, Enzyme Inhibitors pharmacology, Enzyme-Linked Immunosorbent Assay methods, Female, Gene Expression Regulation drug effects, Glucose Tolerance Test, Green Fluorescent Proteins genetics, Hypoglycemic Agents pharmacology, In Vitro Techniques, Injections, Intraventricular methods, Insulin pharmacology, Leptin administration & dosage, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neurons metabolism, Patch-Clamp Techniques, RNA, Messenger metabolism, Signal Transduction drug effects, Signal Transduction genetics, Steroidogenic Factor 1 genetics, Steroidogenic Factor 1 metabolism, Time Factors, Tolbutamide pharmacology, Ventromedial Hypothalamic Nucleus cytology, Dietary Fats adverse effects, Neurons drug effects, Obesity chemically induced, Obesity pathology, Phosphatidylinositol 3-Kinases metabolism, Receptor, Insulin metabolism, Ventromedial Hypothalamic Nucleus pathology
- Abstract
Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.
- Published
- 2011
- Full Text
- View/download PDF
27. Mutant huntingtin causes metabolic imbalance by disruption of hypothalamic neurocircuits.
- Author
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Hult S, Soylu R, Björklund T, Belgardt BF, Mauer J, Brüning JC, Kirik D, and Petersén Å
- Subjects
- Adenoviridae genetics, Adenoviridae metabolism, Animals, Female, Gene Expression Regulation, Huntingtin Protein, Huntington Disease metabolism, Huntington Disease pathology, Hypothalamus physiopathology, Insulin Resistance, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Leptin metabolism, Male, Mice, Mice, Transgenic, Mutation, Nerve Tissue Proteins genetics, Neuropeptides genetics, Neuropeptides metabolism, Nuclear Proteins genetics, Orexins, Phenotype, Hypothalamus metabolism, Nerve Tissue Proteins metabolism, Nuclear Proteins metabolism
- Abstract
In Huntington's disease (HD), the mutant huntingtin protein is ubiquitously expressed. The disease was considered to be limited to the basal ganglia, but recent studies have suggested a more widespread pathology involving hypothalamic dysfunction. Here we tested the hypothesis that expression of mutant huntingtin in the hypothalamus causes metabolic abnormalities. First, we showed that bacterial artificial chromosome-mediated transgenic HD (BACHD) mice developed impaired glucose metabolism and pronounced insulin and leptin resistance. Selective hypothalamic expression of a short fragment of mutant huntingtin using adeno-associated viral vectors was sufficient to recapitulate these metabolic disturbances. Finally, selective hypothalamic inactivation of the mutant gene prevented the development of the metabolic phenotype in BACHD mice. Our findings establish a causal link between mutant huntingtin expression in the hypothalamus and metabolic dysfunction, and indicate that metabolic parameters are powerful readouts to assess therapies aimed at correcting dysfunction in HD by silencing huntingtin expression in the brain., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
28. CNS leptin and insulin action in the control of energy homeostasis.
- Author
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Belgardt BF and Brüning JC
- Subjects
- Animals, Appetite Regulation drug effects, Appetite Regulation genetics, Appetite Regulation physiology, Central Nervous System drug effects, Energy Intake drug effects, Energy Intake genetics, Energy Intake physiology, Energy Metabolism drug effects, Energy Metabolism genetics, Homeostasis drug effects, Homeostasis genetics, Humans, Insulin metabolism, Insulin pharmacology, Leptin genetics, Leptin physiology, Models, Biological, Central Nervous System metabolism, Energy Metabolism physiology, Homeostasis physiology, Insulin physiology, Leptin metabolism
- Abstract
The obesity and diabetes pandemics have made it an urgent necessity to define the central nervous system (CNS) pathways controlling body weight, energy expenditure, and fuel metabolism. The pancreatic hormone insulin and the adipose tissue-derived leptin are known to act on diverse neuronal circuits in the CNS to maintain body weight and metabolism in a variety of species, including humans. Because these homeostatic circuits are disrupted during the development of obesity, the pathomechanisms leading to CNS leptin and insulin resistance are a focal point of research. In this review, we summarize the recent findings concerning the mechanisms and novel neuronal mediators of both insulin and leptin action in the CNS., (© 2010 New York Academy of Sciences.)
- Published
- 2010
- Full Text
- View/download PDF
29. Novel roles for JNK1 in metabolism.
- Author
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Belgardt BF, Mauer J, and Brüning JC
- Subjects
- Animals, Central Nervous System physiology, Glucose metabolism, Glucose Intolerance physiopathology, Glucose Intolerance prevention & control, Humans, Insulin physiology, Insulin Resistance physiology, Mice, Mice, Knockout, Models, Animal, Obesity physiopathology, Obesity prevention & control, Signal Transduction physiology, Energy Metabolism physiology, Lipid Metabolism physiology, Metabolic Syndrome physiopathology, Mitogen-Activated Protein Kinase 8 physiology
- Abstract
Activation of stress-kinase signaling has recently been recognized as an important pathophysiological mechanism in the development of diet-induced obesity, type 2 diabetes mellitus and other aging-related pathologies. Here, c-Jun N-terminal Kinase (JNK) 1 knockout mice have been shown to exhibit protection from diet-induced obesity, glucose intolerance, and insulin resistance. Nonetheless, the tissue-specific role of JNK1-activation in the development of the metabolic syndrome has been poorly defined so far. Recently, it was demonstrated that JNK1 signaling plays a crucial role in the central nervous system (CNS) and in the pituitary to control systemic glucose and lipid metabolism partially through regulation of hormones involved in growth and energy expenditure.
- Published
- 2010
- Full Text
- View/download PDF
30. Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism.
- Author
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Belgardt BF, Mauer J, Wunderlich FT, Ernst MB, Pal M, Spohn G, Brönneke HS, Brodesser S, Hampel B, Schauss AC, and Brüning JC
- Subjects
- Adiposity physiology, Animals, Body Weight physiology, Dietary Fats administration & dosage, Growth Hormone metabolism, Hypothalamo-Hypophyseal System metabolism, Insulin metabolism, Insulin Resistance physiology, Intermediate Filament Proteins metabolism, Mice, Mice, Obese, Mice, Transgenic, Mitogen-Activated Protein Kinase 8 deficiency, Mitogen-Activated Protein Kinase 8 genetics, Nerve Tissue Proteins metabolism, Nestin, Signal Transduction, Thyroid Gland metabolism, Glucose metabolism, Hypothalamus metabolism, Mitogen-Activated Protein Kinase 8 metabolism, Pituitary Gland metabolism
- Abstract
c-Jun N-terminal kinase (JNK) 1-dependent signaling plays a crucial role in the development of obesity-associated insulin resistance. Here we demonstrate that JNK activation not only occurs in peripheral tissues, but also in the hypothalamus and pituitary of obese mice. To resolve the importance of JNK1 signaling in the hypothalamic/pituitary circuitry, we have generated mice with a conditional inactivation of JNK1 in nestin-expressing cells (JNK1(DeltaNES) mice). JNK1(DeltaNES) mice exhibit improved insulin sensitivity both in the CNS and in peripheral tissues, improved glucose metabolism, as well as protection from hepatic steatosis and adipose tissue dysfunction upon high-fat feeding. Moreover, JNK1(DeltaNES) mice also show reduced somatic growth in the presence of reduced circulating growth hormone (GH) and insulin-like growth factor 1 (IGF1) concentrations, as well as increased thyroid axis activity. Collectively, these experiments reveal an unexpected, critical role for hypothalamic/pituitary JNK1 signaling in the coordination of metabolic/endocrine homeostasis.
- Published
- 2010
- Full Text
- View/download PDF
31. Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance.
- Author
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Bailly-Maitre B, Belgardt BF, Jordan SD, Coornaert B, von Freyend MJ, Kleinridders A, Mauer J, Cuddy M, Kress CL, Willmes D, Essig M, Hampel B, Protzer U, Reed JC, and Brüning JC
- Subjects
- Animals, Endoplasmic Reticulum pathology, Genetic Therapy methods, Gluconeogenesis drug effects, Glucose metabolism, Hyperglycemia therapy, Liver metabolism, Membrane Proteins administration & dosage, Membrane Proteins therapeutic use, Mice, Mice, Obese, Unfolded Protein Response, Endoribonucleases antagonists & inhibitors, Glucose Intolerance therapy, Insulin Resistance, Membrane Proteins pharmacology, Obesity complications, Protein Serine-Threonine Kinases antagonists & inhibitors
- Abstract
The unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response is a physiological process enabling cells to cope with altered protein synthesis demands. However, under conditions of obesity, prolonged activation of the UPR has been shown to have deteriorating effects on different metabolic pathways. Here we identify Bax inhibitor-1 (BI-1), an evolutionary conserved ER-membrane protein, as a novel modulator of the obesity-associated alteration of the UPR. BI-1 partially inhibits the UPR by interacting with IRE1alpha and inhibiting IRE1alpha endonuclease activity as seen on the splicing of the transcription factor Xbp-1. Because we observed a down-regulation of BI-1 expression in liver and muscle of genetically obese ob/ob and db/db mice as well as in mice with diet-induced obesity in vivo, we investigated the effect of restoring BI-1 expression on metabolic processes in these mice. Importantly, BI-1 overexpression by adenoviral gene transfer dramatically improved glucose metabolism in both standard diet-fed mice as well as in mice with diet-induced obesity and, critically, reversed hyperglycemia in db/db mice. This improvement in whole body glucose metabolism and insulin sensitivity was due to dramatically reduced gluconeogenesis as shown by reduction of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression. Taken together, these results identify BI-1 as a critical regulator of ER stress responses in the development of obesity-associated insulin resistance and provide proof of concept evidence that gene transfer-mediated elevations in hepatic BI-1 may represent a promising approach for the treatment of type 2 diabetes.
- Published
- 2010
- Full Text
- View/download PDF
32. Hormone and glucose signalling in POMC and AgRP neurons.
- Author
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Belgardt BF, Okamura T, and Brüning JC
- Subjects
- Agouti-Related Protein biosynthesis, Agouti-Related Protein metabolism, Animals, Energy Metabolism physiology, Homeostasis physiology, Humans, Insulin physiology, Leptin physiology, Neurons metabolism, Pro-Opiomelanocortin biosynthesis, Pro-Opiomelanocortin metabolism, Agouti-Related Protein physiology, Blood Glucose physiology, Neurons physiology, Pro-Opiomelanocortin physiology, Signal Transduction physiology
- Abstract
In the wake of the obesity pandemic, increased research efforts are under way to define how peripheral hormones and metabolites regulate energy homeostasis. The melanocortin system, comprising anorexigenic proopiomelanocortin (POMC) expressing neurons and orexigenic agouti-related protein (AgRP)/neuropeptide Y (NPY) coexpressing neurons in the arcuate nucleus of the hypothalamus are crucial for normal energy homeostasis both in rodents and humans. They are regulated by peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids and fatty acids. Although much progress has been made, recent reports continue to underline how restricted our understanding of POMC and AgRP/NPY neuron regulation by these signals is. Importantly, ATP-dependent potassium (K(ATP)) channels are regulated both by ATP (from glucose metabolism) and by leptin and insulin, and directly control electrical excitability of both POMC and AgRP neurons. Thus, this review attempts to offer an integrative overview about how peripheral signals, particularly leptin, insulin and glucose, converge on a molecular level in POMC and AgRP neurons of the arcuate nucleus of the hypothalamus to control energy homeostasis.
- Published
- 2009
- Full Text
- View/download PDF
33. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity.
- Author
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Kleinridders A, Schenten D, Könner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, and Brüning JC
- Subjects
- Animals, Dietary Fats metabolism, Eating, Energy Metabolism, Enzyme Activation, Female, Glucose metabolism, Homeostasis, Humans, I-kappa B Kinase metabolism, Insulin metabolism, Insulin Resistance, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity physiology, Myeloid Differentiation Factor 88 genetics, Weight Gain, Central Nervous System metabolism, Diet, Leptin metabolism, Myeloid Differentiation Factor 88 metabolism, Obesity metabolism, Palmitic Acid metabolism, Signal Transduction physiology
- Abstract
Obesity-associated activation of inflammatory pathways represents a key step in the development of insulin resistance in peripheral organs, partially via activation of TLR4 signaling by fatty acids. Here, we demonstrate that palmitate acting in the central nervous system (CNS) inhibits leptin-induced anorexia and Stat3 activation. To determine the functional significance of TLR signaling in the CNS in the development of leptin resistance and diet-induced obesity in vivo, we have characterized mice deficient for the TLR adaptor molecule MyD88 in the CNS (MyD88(DeltaCNS)). Compared to control mice, MyD88(DeltaCNS) mice are protected from high-fat diet (HFD)-induced weight gain, from the development of HFD-induced leptin resistance, and from the induction of leptin resistance by acute central application of palmitate. Moreover, CNS-restricted MyD88 deletion protects from HFD- and icv palmitate-induced impairment of peripheral glucose metabolism. Thus, we define neuronal MyD88-dependent signaling as a key regulator of diet-induced leptin and insulin resistance in vivo.
- Published
- 2009
- Full Text
- View/download PDF
34. PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response.
- Author
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Belgardt BF, Husch A, Rother E, Ernst MB, Wunderlich FT, Hampel B, Klöckener T, Alessi D, Kloppenburg P, and Brüning JC
- Subjects
- 3-Phosphoinositide-Dependent Protein Kinases, Animals, Body Weight drug effects, Corticosterone metabolism, Corticosterone pharmacology, Female, Forkhead Box Protein O1, Forkhead Transcription Factors antagonists & inhibitors, Forkhead Transcription Factors genetics, Gene Deletion, Gene Expression Regulation, Hyperphagia genetics, Hypothalamus cytology, Hypothalamus metabolism, Insulin metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pituitary Gland metabolism, Pro-Opiomelanocortin deficiency, Pro-Opiomelanocortin genetics, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Energy Metabolism, Forkhead Transcription Factors metabolism, Pro-Opiomelanocortin metabolism, Protein Serine-Threonine Kinases deficiency, Stress, Physiological
- Abstract
Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(DeltaPOMC) mice). PDK1(DeltaPOMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(DeltaPOMC) mice exhibit progressive, severe hypocortisolism caused by loss of POMC-expressing corticotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POMC cells is sufficient to ameliorate positive energy balance in PDK1(DeltaPOMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.
- Published
- 2008
- Full Text
- View/download PDF
35. Enhanced PIP3 signaling in POMC neurons causes KATP channel activation and leads to diet-sensitive obesity.
- Author
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Plum L, Ma X, Hampel B, Balthasar N, Coppari R, Münzberg H, Shanabrough M, Burdakov D, Rother E, Janoschek R, Alber J, Belgardt BF, Koch L, Seibler J, Schwenk F, Fekete C, Suzuki A, Mak TW, Krone W, Horvath TL, Ashcroft FM, and Brüning JC
- Subjects
- Animals, Chromones metabolism, Diet, Eating drug effects, Female, Hypoglycemic Agents pharmacology, Hypothalamus cytology, Hypothalamus metabolism, Insulin metabolism, Leptin metabolism, Male, Membrane Potentials drug effects, Mice, Mice, Knockout, Morpholines metabolism, Neurons cytology, Neurons drug effects, PTEN Phosphohydrolase genetics, Phosphatidylinositol 3-Kinases metabolism, Phosphoinositide-3 Kinase Inhibitors, Tolbutamide pharmacology, Neurons metabolism, Obesity, PTEN Phosphohydrolase metabolism, Phosphatidylinositol Phosphates metabolism, Potassium Channels metabolism, Pro-Opiomelanocortin metabolism, Second Messenger Systems physiology
- Abstract
Leptin and insulin have been identified as fuel sensors acting in part through their hypothalamic receptors to inhibit food intake and stimulate energy expenditure. As their intracellular signaling converges at the PI3K pathway, we directly addressed the role of phosphatidylinositol3,4,5-trisphosphate-mediated (PIP3-mediated) signals in hypothalamic proopiomelanocortin (POMC) neurons by inactivating the gene for the PIP3 phosphatase Pten specifically in this cell type. Here we show that POMC-specific disruption of Pten resulted in hyperphagia and sexually dimorphic diet-sensitive obesity. Although leptin potently stimulated Stat3 phosphorylation in POMC neurons of POMC cell-restricted Pten knockout (PPKO) mice, it failed to significantly inhibit food intake in vivo. POMC neurons of PPKO mice showed a marked hyperpolarization and a reduction in basal firing rate due to increased ATP-sensitive potassium (KATP) channel activity. Leptin was not able to elicit electrical activity in PPKO POMC neurons, but application of the PI3K inhibitor LY294002 and the KATP blocker tolbutamide restored electrical activity and leptin-evoked firing of POMC neurons in these mice. Moreover, icv administration of tolbutamide abolished hyperphagia in PPKO mice. These data indicate that PIP3-mediated signals are critical regulators of the melanocortin system via modulation of KATP channels.
- Published
- 2006
- Full Text
- View/download PDF
36. Central insulin action in energy and glucose homeostasis.
- Author
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Plum L, Belgardt BF, and Brüning JC
- Subjects
- Animals, Humans, Hypothalamus cytology, Hypothalamus metabolism, Leptin metabolism, Neuronal Plasticity physiology, Neurons metabolism, Phosphatidylinositol 3-Kinases metabolism, Signal Transduction physiology, Energy Metabolism, Glucose metabolism, Homeostasis, Insulin metabolism
- Abstract
Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level.
- Published
- 2006
- Full Text
- View/download PDF
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