28 results on '"Bradford S. Hamilton"'
Search Results
2. Challenges in tackling energy expenditure as obesity therapy: From preclinical models to clinical application
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Mona C. Löffler, Matthias J. Betz, Denis P. Blondin, Robert Augustin, Anand K. Sharma, Yu-Hua Tseng, Camilla Scheele, Heike Zimdahl, Michael Mark, Anita M. Hennige, Christian Wolfrum, Wolfgang Langhans, Bradford S. Hamilton, and Heike Neubauer more...
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Obesity ,Energy homeostasis ,Energy expenditure ,Methodology ,Clinical translatability ,Internal medicine ,RC31-1245 - Abstract
Background: A chronic imbalance of energy intake and energy expenditure results in excess fat storage. The obesity often caused by this overweight is detrimental to the health of millions of people. Understanding both sides of the energy balance equation and their counter-regulatory mechanisms is critical to the development of effective therapies to treat this epidemic. Scope of review: Behaviors surrounding ingestion have been reviewed extensively. This review focuses more specifically on energy expenditure regarding bodyweight control, with a particular emphasis on the organs and attractive metabolic processes known to reduce bodyweight. Moreover, previous and current attempts at anti-obesity strategies focusing on energy expenditure are highlighted. Precise measurements of energy expenditure, which consist of cellular, animal, and human models, as well as measurements of their translatability, are required to provide the most effective therapies. Major conclusions: A precise understanding of the components surrounding energy expenditure, including tailored approaches based on genetic, biomarker, or physical characteristics, must be integrated into future anti-obesity treatments. Further comprehensive investigations are required to define suitable treatments, especially because the complex nature of the human perspective remains poorly understood. more...
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- 2021
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Catalog
3. Publisher Correction: Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance
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Tina Schumann, Jörg König, Christian von Loeffelholz, Daniel F. Vatner, Dongyan Zhang, Rachel J. Perry, Michel Bernier, Jason Chami, Christine Henke, Anica Kurzbach, Nermeen N. El-Agroudy, Diana M. Willmes, Dominik Pesta, Rafael de Cabo, John F. O´Sullivan, Eric Simon, Gerald I. Shulman, Bradford S. Hamilton, and Andreas L. Birkenfeld more...
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Biology (General) ,QH301-705.5 - Published
- 2021
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4. Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance
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Christian von Loeffelholz, Dongyan Zhang, Daniel F. Vatner, Jason Chami, Rachel J. Perry, Bradford S. Hamilton, Tina Schumann, Diana M. Willmes, Anica Kurzbach, Eric Simon, Nermeen N. El-Agroudy, Christine Henke, Jörg König, Andreas L. Birkenfeld, Michel Bernier, Rafael de Cabo, Gerald I. Shulman, John F. O´Sullivan, and Dominik Pesta more...
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0301 basic medicine ,medicine.medical_specialty ,QH301-705.5 ,Medicine (miscellaneous) ,030209 endocrinology & metabolism ,Context (language use) ,Type 2 diabetes ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Animal disease models ,Diabetes mellitus ,Internal medicine ,medicine ,ddc:610 ,Biology (General) ,Chemistry ,Fatty liver ,AMPK ,medicine.disease ,Solute carrier family ,030104 developmental biology ,Endocrinology ,Knockout mouse ,General Agricultural and Biological Sciences ,Fat metabolism ,Non-alcoholic fatty liver disease - Abstract
Genome-wide association studies have identified SLC16A13 as a novel susceptibility gene for type 2 diabetes. The SLC16A13 gene encodes SLC16A13/MCT13, a member of the solute carrier 16 family of monocarboxylate transporters. Despite its potential importance to diabetes development, the physiological function of SLC16A13 is unknown. Here, we validate Slc16a13 as a lactate transporter expressed at the plasma membrane and report on the effect of Slc16a13 deletion in a mouse model. We show that loss of Slc16a13 increases mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased hepatic insulin sensitivity in high-fat diet fed Slc16a13 knockout mice. We propose a mechanism for improved hepatic insulin sensitivity in the context of Slc16a13 deficiency in which reduced intrahepatocellular lactate availability drives increased AMPK activation and increased mitochondrial respiration, while reducing hepatic lipid content. Slc16a13 deficiency thereby attenuates hepatic diacylglycerol-PKCε mediated insulin resistance in obese mice. Together, these data suggest that SLC16A13 is a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease., Schumann et al. demonstrate that the loss of a lactate transporter Slc16a13 increases mitochondrial respiration in the liver, which reduces hepatic lipid accumulation while increasing hepatic insulin sensitivity in mice fed a high-fat diet. This study suggests SLC16A13 as a potential target for the treatment of type 2 diabetes and non-alcoholic fatty liver disease. more...
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- 2021
5. Latent TGFβ-binding proteins regulate UCP1 expression and function via TGFβ2
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Pamela Fischer-Posovszky, Julian Roos, Ez-Zoubir Amri, Daniel Halbgebauer, Heike Neubauer, Daniel Tews, Jan-Bernd Funcke, Bradford S. Hamilton, Martin Wabitsch, Klaus-Michael Debatin, Eric Simon, Amri, Ez-Zoubir, Universitätsklinikum Ulm - University Hospital of Ulm, Boehringer Ingelheim Pharma GmbH & Co. KG, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA) more...
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Adipose Tissue, White ,Adipose tissue ,White adipose tissue ,Biology ,Transforming Growth Factor beta2 ,chemistry.chemical_compound ,TGF beta ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Adipocyte ,Brown adipose tissue ,TGF beta signaling pathway ,medicine ,Humans ,Obesity ,Progenitor cell ,Internal medicine ,Molecular Biology ,Cells, Cultured ,Uncoupling Protein 1 ,[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,Adipogenesis ,Cell Biology ,[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism ,RC31-1245 ,Cell biology ,medicine.anatomical_structure ,Latent TGF-beta Binding Proteins ,chemistry ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Original Article ,Browning ,CRISPR-Cas Systems ,Transforming growth factor - Abstract
Objective Activation of brown adipose tissue (BAT) in humans has been proposed as a new treatment approach for combating obesity and its associated diseases, as BAT participates in the regulation of energy homeostasis as well as glucose and lipid metabolism. Genetic contributors driving brown adipogenesis in humans have not been fully understood. Methods Profiling the gene expression of progenitor cells from subcutaneous and deep neck adipose tissue, we discovered new secreted factors with potential regulatory roles in white and brown adipogenesis. Among these, members of the latent transforming growth factor beta-binding protein (LTBP) family were highly expressed in brown compared to white adipocyte progenitor cells, suggesting that these proteins are capable of promoting brown adipogenesis. To investigate this potential, we used CRISPR/Cas9 to generate LTBP-deficient human preadipocytes. Results We demonstrate that LTBP2 and LTBP3 deficiency does not affect adipogenic differentiation, but diminishes UCP1 expression and function in the obtained mature adipocytes. We further show that these effects are dependent on TGFβ2 but not TGFβ1 signaling: TGFβ2 deficiency decreases adipocyte UCP1 expression, whereas TGFβ2 treatment increases it. The activity of the LTBP3–TGFβ2 axis that we delineate herein also significantly correlates with UCP1 expression in human white adipose tissue (WAT), suggesting an important role in regulating WAT browning as well. Conclusions These results provide evidence that LTBP3, via TGFβ2, plays an important role in promoting brown adipogenesis by modulating UCP1 expression and mitochondrial oxygen consumption., Highlights • Inhibition of LTBP2 and LTBP3 reduces secretion of TGFβ2. • Both knockout of LTBP2/3 or TGFβ2 inhibit UCP1 expression and mitochondrial respiration in human adipocytes. • Expression of TGFβ2 correlates with UCP1 expression in human adipose tissue. • Treatment with TGFβ2 rescues inhibition of UCP1 by LTBP knockout during adipogenesis. more...
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- 2021
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6. Anti-inflammatory properties of bone morphogenetic protein 4 in human adipocytes
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Martin Wabitsch, Monika Ehrhart-Bornstein, Triantafyllos Chavakis, Bradford S. Hamilton, Stefan R. Bornstein, Susanne Sales, and Elena Baraban
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0301 basic medicine ,medicine.medical_specialty ,Adipose Tissue, White ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Anti-Inflammatory Agents ,Medicine (miscellaneous) ,Adipose tissue ,Bone Morphogenetic Protein 4 ,Biology ,Bone morphogenetic protein ,03 medical and health sciences ,chemistry.chemical_compound ,Cell Movement ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Humans ,Obesity ,Inflammation ,Adipogenesis ,Nutrition and Dietetics ,Tumor Necrosis Factor-alpha ,Growth factor ,Bone morphogenetic protein 10 ,Cell Differentiation ,Bone morphogenetic protein 6 ,030104 developmental biology ,Endocrinology ,Cytokine ,Diabetes Mellitus, Type 2 ,chemistry ,Insulin Resistance ,Signal Transduction - Abstract
Background Obesity is characterized by increased adipocyte number and size as well as white adipose tissue (WAT) inflammation, which is fundamental for the development of insulin resistance and type-2 diabetes. These processes, regulated by various endocrine, paracrine and autocrine factors, are extensively studied with the hope to interfere and to inhibit weight gain and related complications in obese patients. Recent data suggest an important role of bone morphogenic protein 4 (BMP4) in the regulation of adipogenesis and development of obesity. BMP4 is a growth factor of the transforming growth factor-β superfamily. Initially, BMPs were identified as inducers of ectopic bone formation. It is now apparent, however, that these proteins have different pleiotropic developmental actions and including playing a role in white adipogenesis. Methods and results Here, we demonstrate that the expression of BMP4 in human WAT is negatively correlated to body mass index and to the expression of pro-inflammatory cytokines. In vitro, BMP4 expression in cultured human adipocytes is upregulated after induction of differentiation. Cells treated with exogenous BMP4 increased peroxisome proliferator-activated receptor γ (PPARγ) expression and significantly reduced the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α) and monocyte chemoattractant protein 1. TNF-α treatment of fully differentiated adipocytes resulted in downregulation of the expression of adipogenic genes and elevated expression of pro-inflammatory cytokines. Exogenous BMP4 addition significantly reduced the negative effect of TNF-α on the expression profile of adipocytes. Finally, treatment of human adipocytes with exogenous BMP4 reduced the adipocytes' chemoattractant potential and the migration of monocytes toward adipocyte-conditioned medium. Conclusions These results indicate that BMP4 is an important anti-inflammatory molecule, which may act through PPARγ and reduces TNF-α-mediated pro-inflammatory cytokine production in human adipocytes. Through its anti-inflammatory potential, BMP4 may serve as a protective factor for inflammation-related diseases such as insulin-tolerance or type-2 diabetes. more...
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- 2015
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7. Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes
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David A. Claremon, Herbert Nar, Yi Zhao, Deepak S. Lala, Paula Krosky, Gerard McGeehan, Frank Himmelsbach, Joan Guo, Shi Meng, Rong Guo, Linghang Zhuang, Annette Schuler-Metz, and Bradford S. Hamilton more...
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Male ,Models, Molecular ,medicine.medical_specialty ,Pyridones ,Drug Evaluation, Preclinical ,Adipose tissue ,Dehydrogenase ,Type 2 diabetes ,Pharmacology ,Biology ,Catalytic Domain ,Diabetes mellitus ,Internal medicine ,11-beta-Hydroxysteroid Dehydrogenase Type 1 ,Oxazines ,medicine ,Animals ,Humans ,Enzyme Inhibitors ,medicine.disease ,Small molecule ,Macaca fascicularis ,Endocrinology ,Diabetes Mellitus, Type 2 ,Cortisone ,Metabolic syndrome ,hormones, hormone substitutes, and hormone antagonists ,Intracellular ,medicine.drug - Abstract
To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585. more...
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- 2015
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8. Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor
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Bradford S. Hamilton, Frank Himmelsbach, Barbara A. Kruk, Joan Guo, Gerard McGeehan, Peter Lindblom, Rong Guo, Colin M. Tice, Brian M. McKeever, Linghang Zhuang, David A. Claremon, Judith A. Johnson, Katerina Leftheris, Lamont Howard, Salvacion Cacatian, Heike Schauerte, Annette Schuler-Metz, Richard Gregg, Reshma Panemangalore, Deepak S. Lala, Paula Krosky, Zhenrong Xu, Yuri Bukhtiyarov, Suresh B. Singh, Yuanjie Ye, Yi Zhao, Wei Zhao, and Shi Meng more...
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0301 basic medicine ,medicine.medical_specialty ,Pyridones ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,11β hsd1 ,Adipose tissue ,Administration, Oral ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,Cytochrome P-450 Enzyme System ,11β-hydroxysteroid dehydrogenase type 1 ,Oral administration ,In vivo ,Internal medicine ,Drug Discovery ,11-beta-Hydroxysteroid Dehydrogenase Type 1 ,Oxazines ,medicine ,Animals ,Molecular Biology ,IC50 ,Cells, Cultured ,Binding Sites ,biology ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Hydroxysteroid Dehydrogenases ,0104 chemical sciences ,Protein Structure, Tertiary ,Rats ,Molecular Docking Simulation ,Macaca fascicularis ,030104 developmental biology ,Endocrinology ,Adipose Tissue ,Pharmacodynamics ,biology.protein ,Molecular Medicine ,hormones, hormone substitutes, and hormone antagonists ,Half-Life - Abstract
A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011. more...
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- 2017
9. EGFL6 is increasingly expressed in human obesity and promotes proliferation of adipose tissue-derived stromal vascular cells
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Heike Neubauer, Wolfgang Rist, Bradford S. Hamilton, Rupert Oberauer, and Martin Lenter
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medicine.medical_specialty ,Stromal cell ,FGF21 ,Adipose tissue macrophages ,Clinical Biochemistry ,Adipose tissue ,Cell Separation ,Biology ,Paracrine signalling ,Tandem Mass Spectrometry ,Epidermal growth factor ,Internal medicine ,Weight Loss ,Cell Adhesion ,medicine ,Humans ,Obesity ,Molecular Biology ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,PRDM16 ,Membrane Glycoproteins ,Reverse Transcriptase Polymerase Chain Reaction ,Calcium-Binding Proteins ,3T3-L1 ,Cell Biology ,General Medicine ,Flow Cytometry ,Cell biology ,Endocrinology ,Adipose Tissue ,Culture Media, Conditioned ,Blood Vessels ,Electrophoresis, Polyacrylamide Gel ,Stromal Cells ,Cell Adhesion Molecules ,Chromatography, Liquid - Abstract
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 [(14)C]-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. more...
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- 2010
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10. Identification of potent agonists acting at an endogenous atypical β3-adrenoceptor state that modulate lipolysis in rodent fat cells
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Bradford S. Hamilton and Henri Doods
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Male ,Agonist ,medicine.drug_class ,Lipolysis ,Adipocytes, White ,Adrenergic beta-Antagonists ,Adipose tissue ,Biology ,Pharmacology ,Ligands ,Partial agonist ,Mice ,chemistry.chemical_compound ,Adipocyte ,Cyclic AMP ,medicine ,Animals ,Rats, Wistar ,Receptor ,Mice, Knockout ,Adrenergic beta-Agonists ,Small molecule ,In vitro ,Rats ,Cell biology ,Drug development ,chemistry ,Ethanolamines ,Receptors, Adrenergic, beta-3 ,Female ,Receptors, Adrenergic, beta-2 ,Receptors, Adrenergic, beta-1 - Abstract
Small molecules interacting with aminergic G-protein coupled receptors represent a number of very successful drugs. G-protein coupled receptors continue to be a significant group of targets for pharmaceutical intervention, and modifying their activity through small molecules is a major focus of drug development. Previously, these small molecules could be easily fit in models, as agonists, partial agonists or antagonists. More recently, however, these lines have been blurred as it is increasingly recognized that ligands can interact with receptors in various ways. Analysis of beta-adrenoceptors has revealed that several sites or states exist for the individual receptors. The putative atypical beta(4)-adrenoceptor identified on heart and adipose tissue is now recognized as a unique beta(1)-adrenoceptor state. Similarly, a unique beta(3)-adrenoceptor state has been identified using the aryloxypropanolamine CGP-12,177 and cloned receptor systems. Here we expand upon these observations, by describing an atypical state of the beta(3)-adrenoceptor that exists endogenously in adipose tissue. Furthermore, we describe novel arylethanolamine ligands that interact with this atypical state of the beta(3)-adrenoceptor with high affinity and provide additional tools to investigate the atypical beta(3)-adrenoceptor state to determine whether it can be influenced for therapeutic purposes. more...
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- 2008
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11. Influence of sub-chronic selective 11β-hydroxysteroid dehydrogenase 1 inhibition on the hypothalamic-pituitary-adrenal axis in female cynomolgus monkeys
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Annette Schuler-Metz, David A. Claremon, Deepak S. Lala, Paula Krosky, Bradford S. Hamilton, Corinna Schoelch, and Gerard McGeehan
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0301 basic medicine ,medicine.medical_specialty ,Hypothalamo-Hypophyseal System ,Time Factors ,Pyridones ,Pituitary-Adrenal System ,030209 endocrinology & metabolism ,Adrenocorticotropic hormone ,Biology ,Androgen Excess ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Dehydroepiandrosterone sulfate ,Internal medicine ,11-beta-Hydroxysteroid Dehydrogenase Type 1 ,Oxazines ,medicine ,Animals ,Enzyme Inhibitors ,Testosterone ,Pharmacology ,Macaca fascicularis ,030104 developmental biology ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Female ,Cortisone ,hormones, hormone substitutes, and hormone antagonists ,Glucocorticoid ,Hypothalamic–pituitary–adrenal axis ,medicine.drug ,Hormone - Abstract
Inhibition of local cortisol regeneration from circulating cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11β-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11β-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis. more...
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- 2015
12. Inhibition of fatty acid synthase prevents preadipocyte differentiation
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Jörg F. Rippmann, Moh Tadayyon, Bradford S. Hamilton, and Bernhard Schmid
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medicine.medical_specialty ,CD36 ,Cellular differentiation ,Biophysics ,Adipose tissue ,Biochemistry ,Mice ,chemistry.chemical_compound ,4-Butyrolactone ,3T3-L1 Cells ,Adipocyte ,Internal medicine ,Adipocytes ,medicine ,Animals ,Gene Silencing ,Molecular Biology ,Messenger RNA ,biology ,Cell Differentiation ,3T3-L1 ,Cell Biology ,Molecular biology ,Cerulenin ,Triclosan ,Fatty acid synthase ,Endocrinology ,chemistry ,biology.protein ,Fatty Acid Synthases - Abstract
Inhibition of fatty acid synthase (FAS) reduces food intake in rodents. As adipose tissue expresses FAS, we sought to investigate the effect of reduced FAS activity on adipocyte differentiation. FAS activity was suppressed either pharmacologically or by siRNA during differentiation of 3T3-L1 cells. Cerulenin (10 microM), triclosan (50 microM), and C75 (50 microM) reduced dramatically visible lipid droplet accumulation, while incorporation of [1-(14C)]acetate into lipids was reduced by 75%, 70%, and 90%, respectively. Additionally, the substances reduced FAS, CEBPalpha, and PPARgamma mRNA by up to 85% compared to that of control differentiated cells. Transient transfection with FAS siRNA suppressed FAS mRNA and FAS activity, and this was accompanied by reduction of CEBPalpha and PPARgamma mRNA levels, and complete prevention of lipid accumulation. CD36, a late marker of differentiation, was also reduced. Together, these results suggest that FAS generated signals may be essential to support preadipocyte differentiation. more...
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- 2005
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13. Hammerhead Ribozymes That Selectively Cleave the NPY Y1, Y4, and Y5 Receptor Full-Length RNA
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Bradford S. Hamilton, Heike A. Wieland, and Bernd Krist
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Male ,Pharmacology ,Y5 Receptor ,Base Sequence ,biology ,Molecular Sequence Data ,Ribozyme ,RNA ,Rats, Inbred Strains ,Rats ,Receptors, Neuropeptide Y ,Substrate Specificity ,Biochemistry ,Cleave ,Genetics ,biology.protein ,Animals ,Nucleic Acid Conformation ,RNA, Catalytic ,Sequence Alignment ,Ligase ribozyme - Abstract
The concept of exploiting the ribozyme catalytic center for cleaving a specific target RNA transcript was applied to the design of selective ribozymes for the rat Y1, Y4, and Y5 receptor subtypes. Ribozymes selective for the neuropeptide Y (NPY) receptor subtypes were designed and chemically modified. Recognition sites were selected both according to the extent of their sequence homology between the receptor subtypes and according to the localization within single-stranded regions accessible for hybridization. Stability of the ribozymes against nucleolytic activities was increased by introducing 2'-O-methylribonucleosides and 3'-terminal modifications, such as inverted ends or dideoxynucleosides. Ribozymes cleaving the full-length rat Y1, Y4 (1200 nt), and Y5 receptor mRNA (2200 nt) were identified. The specificity of the recognition sites and the subtype selectivity of the ribozyme-mediated cleavage was demonstrated. more...
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- 1998
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14. The Effect of Basic Fibroblast Growth Factor on the Reversion of Omental Adipocytes from Lean and Obese Patients
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Miriam Kidron, Bradford S. Hamilton, Mervyn Deitel, Daniel A. K. Roncari, and Anita Y.M. Kwan
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Messenger RNA ,medicine.medical_specialty ,Nutrition and Dietetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Basic fibroblast growth factor ,Reversion ,Adipose tissue ,medicine.disease ,Obesity ,chemistry.chemical_compound ,Cytosol ,Endocrinology ,chemistry ,Adipocyte ,Internal medicine ,medicine ,Surgery ,Specific activity ,business - Abstract
BACKGROUND: this study was designed to characterize some of the biochemical and molecular genetic changes during reversion of human fat cells. METHODS: mature adipocytes were isolated from greater omental fat tissue of eight lean and 14 massively obese persons by established methodology. RESULTS: at day 7 of adherence to Leighton tubes, there was appreciable depletion of triacylglycerol, as well as assumption of an elongated contour. Relatedly, there was an increase in the expression of Beta-actin mRNA and a significant decrease in the specific activity of cytosolic glycerophosphate dehydrogenase. The decrement in the specific activity of glycerophosphate dehydrogenase, after 7 days in culture, was significant at p < 0.001. Basic fibroblast growth factor at 10 ngml(1) accelerated significantly (p < 0.03) the decrease in the specific activity of glycerophosphate dehydrogenase in adipose cells from lean subjects. In contrast, basic fibroblast growth factor had no significant influence on cells from massively obese persons. CONCLUSION: such resistance may contribute to the intractability of massive obesity. more...
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- 1995
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15. Analysis of the transcriptome of differentiating and non-differentiating preadipocytes from rats and humans by next generation sequencing
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Bradford S. Hamilton, Fabian Birzele, Tobias Hildebrandt, Heike Neubauer, and Sybille Fässler
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Cellular differentiation ,Clinical Biochemistry ,Adipose tissue ,Biology ,Transcriptome ,chemistry.chemical_compound ,Mice ,Adipocyte ,3T3-L1 Cells ,Adipocytes ,Animals ,Humans ,Gene Regulatory Networks ,Progenitor cell ,Molecular Biology ,Genetics ,Adipogenesis ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cell Differentiation ,Cell Biology ,General Medicine ,Stromal vascular fraction ,Cell biology ,Extracellular Matrix ,Rats ,PPAR gamma ,chemistry ,Cell culture ,Transcription Factors - Abstract
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. more...
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- 2012
16. ChemInform Abstract: Discovery of BI 99179, a Potent and Selective Inhibitor of Type I Fatty Acid Synthase with Central Exposure
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Norbert Redemann, Joerg Kley, Juergen Mack, Bradford S. Hamilton, and Stefan Scheuerer
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Fatty acid synthase ,Biochemistry ,biology ,Chemotype ,Chemistry ,biology.protein ,General Medicine - Abstract
Based on a high-throughput screening, cyclopentanecarboxanilides (I) are identified as a new chemotype of non-covalent inhibitors of type 1 fatty acid synthase (FAS).
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- 2012
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17. Decreasing expression of a gene encoding a protein related to basic fibroblast growth factor during differentiation of human preadipocytes
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Bradford S. Hamilton, Daniel A. K. Roncari, Mervyn Deitel, and Krystyna Teichert-Kuliszewska
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Base Sequence ,Molecular Sequence Data ,Basic fibroblast growth factor ,Gene Expression ,A protein ,Cell Differentiation ,Glycerolphosphate Dehydrogenase ,Cell Biology ,Biology ,Fibroblast growth factor ,Polymerase Chain Reaction ,Biochemistry ,Molecular biology ,chemistry.chemical_compound ,chemistry ,Adipocyte ,Gene expression ,Adipocytes ,Humans ,Fibroblast Growth Factor 2 ,Obesity ,RNA, Messenger ,Molecular Biology ,Gene - Abstract
Pursuant to our findings that pituitary basic fibroblast growth factor (bFGF) stimulates the replication of preadipocytes and inhibits their differentiation, we have studied the changes in expression of a bFGF-related mRNA during differentiation. Human omental preadipocytes were grown in primary culture and induced to differentiate with chemically defined serum-free medium. The differentiation process was assessed by monitoring the rise of glycerophosphate dehydrogenase (GPDH) activity, while mRNA expression for a bFGF-related protein(s) and GPDH was examined by amplifying the respective target sequences by polymerase chain reaction. In the case of all cell strains, differentiated preadipocytes revealed much lower expression of bFGF-related mRNA than undifferentiated preadipocytes. Concurrently, the expression of the GPDH mRNA rose significantly. The finding that the expression of the bFGF-related protein is decreased appreciably during adipose differentiation is consonant with its proposed function to expand and maintain adipose cells in a relatively undifferentiated state.Key words: preadipocytes, differentiation, basic fibroblast growth factor, obesity, glycerophosphate dehydrogenase. more...
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- 1994
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18. Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure
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Joerg Kley, Bradford S. Hamilton, Stefan Scheuerer, Juergen Mack, and Norbert Redemann
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Proline ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Hypothalamus ,Molecular Conformation ,Administration, Oral ,Pharmaceutical Science ,Biochemistry ,Permeability ,Cell Line ,Substrate Specificity ,Inhibitory Concentration 50 ,Mice ,Structure-Activity Relationship ,In vivo ,Oral administration ,Drug Discovery ,Animals ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Structure–activity relationship ,Potency ,Molecular Targeted Therapy ,Enzyme Inhibitors ,Molecular Biology ,Benzoxazoles ,Dose-Response Relationship, Drug ,biology ,Chemistry ,Drug discovery ,Organic Chemistry ,Stereoisomerism ,High-Throughput Screening Assays ,Rats ,Fatty acid synthase ,Enzyme inhibitor ,Injections, Intravenous ,Microsomes, Liver ,biology.protein ,Molecular Medicine ,Caco-2 Cells ,Fatty Acid Synthases - Abstract
Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats. more...
- Published
- 2011
- Full Text
- View/download PDF
19. Accumulation of starch in Chlamydomonas reinhardtii flagellar mutants
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Daniel A. K. Roncari, Bradford S. Hamilton, and Kazuo Nakamura
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biology ,Bioenergetics ,Starch ,Chlamydomonas ,Mutant ,Wild type ,Chlamydomonas reinhardtii ,Cell Biology ,Flagellum ,biology.organism_classification ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,chemistry ,Flagella ,Mutation ,Animals ,Energy Metabolism ,Cytoskeleton ,Molecular Biology - Abstract
Paralyzed flagellar mutants pf-1, pf-2, pf-7, and pf-18 of the green alga Chlamydomonas reinhardtii (Dangeard) were shown to store a significantly greater amount of starch than the motile wild type 137c+. The increase in starch storage was significant relative to protein, chlorophyll, and cell number. Analysis of average cell size revealed that the paralyzed mutants were larger than the wild type. This increase in storage molecule accumulation supports an inverse relationship between chemical energy storage and energy utilization for biomechanical/motile cellular functions. Chlamydomonas reinhardtii provides a useful model for studies of the role of cytoskeletal activity in the energy relationship and balance of organisms.Key words: Chlamydomonas, cytoskeleton, paralyzed flagella, starch, bioenergetics. more...
- Published
- 1992
- Full Text
- View/download PDF
20. Characterization of the NPGP receptor and identification of a novel short mRNA isoform in human hypothalamus
- Author
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Henri Doods, Baerbel Laemmle, Bradford S. Hamilton, Marcus Schindler, Mario Beilmann, and Heike A. Wieland
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Receptors, Neuropeptide ,medicine.medical_specialty ,Physiology ,Clinical Biochemistry ,Molecular Sequence Data ,Hypothalamus ,Neuropeptide ,CHO Cells ,Biology ,Pregnancy Proteins ,Transfection ,Biochemistry ,Receptors, G-Protein-Coupled ,Cellular and Molecular Neuroscience ,Exon ,Radioligand Assay ,Endocrinology ,Orexin Receptors ,Internal medicine ,Cricetinae ,medicine ,Animals ,Humans ,Protein Isoforms ,Protein Splicing ,Tissue Distribution ,Neuropeptide FF ,Amino Acid Sequence ,RNA, Messenger ,Cloning, Molecular ,Receptor ,G protein-coupled receptor ,Orexins ,Sequence Homology, Amino Acid ,Alternative splicing ,Neuropeptides ,Intracellular Signaling Peptides and Proteins ,Exons ,Neuropeptide Y receptor ,Orexin ,Carrier Proteins ,Sequence Alignment - Abstract
Recently, an orphan G protein coupled receptor (GPCR) termed NPGPR was described. A shorter variant of this receptor lacking exon 1 was shown to have subnanomolar affinity for neuropeptide FF (NPFF), a pain modulatory peptide, and therefore was named NPFF 2 receptor. Here, we characterize the full-length cloned NPGPR and identify a novel short form lacking exon 2 with a differential pattern of mRNA abundance in several tissues and organs. The NPGPR is most similar to the recently cloned neuropeptide FF (NPFF) receptor which lacks exon 1, but also shows high homology to the orexin and neuropeptide Y (NPY) receptor families, two neuropeptides involved in food intake regulation. Therefore, we used binding studies to examine the interaction of NPFF, orexin and NPY with the NPGPR. [ 125 I] NPFF was displaced by NPFF with an IC 50 of 14.7±8.8 nM, whereas [ 125 I] Orexin B was displaced by Orexin B with an IC 50 of 415±195 nM. We conclude that orexins interact with the NPGPR and that the affinity of NPFF for NPGPR is approximately 100-fold lower than for the NPFF2 receptor. We postulate that NPGPR is a splice variant of the family of NPFF receptors and displays a binding profile different from the other members of the NPFF receptor family due to the presence of exon 1. In order to evaluate whether NPGPR levels are affected by the feeding status, we examined the mRNA level using real-time PCR in two feeding models, i.e. before and after diet-induced body weight increase as well as after chronic food restriction in rats. However, hypothalamic NPGPR mRNA was unchanged in both models. Therefore, our evidence does not support the hypothesis that NPGPR is involved in feeding regulation. more...
- Published
- 2003
21. Chronic application of MTII in a rat model of obesity results in sustained weight loss
- Author
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Henri Doods and Bradford S. Hamilton
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Blood Glucose ,Leptin ,Male ,Melanocortin agonist ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Rat model ,Medicine (miscellaneous) ,Cafeteria ,Eating ,Endocrinology ,Oxygen Consumption ,Weight loss ,Internal medicine ,Weight Loss ,medicine ,Animals ,Insulin ,Obesity ,Saline ,Triglycerides ,biology ,business.industry ,Public Health, Environmental and Occupational Health ,Calorimetry, Indirect ,biology.organism_classification ,medicine.disease ,Rats ,Disease Models, Animal ,alpha-MSH ,Female ,medicine.symptom ,business ,Food Science - Abstract
HAMILTON, BRADFORD S. AND HENRI N. DOODS.Chronic application of MTII in a rat model of obesity resultsin sustained weight loss. Obes Res. 2002;10:182–187.Objective: To examine the effects of a cafeteria diet and achronic treatment with melanocortin agonist (MTII) on ma-ture weight-stable female rats.Research Methods and Procedures: Ex-breeder Chbb:Thom rats (350 to 400 g) were divided into two groups:highly palatable food (HPF) and normal rat chow (RC).Both groups had ab libitum access to rat chow. The HPFgroup had access to chocolate bars, cookies, cheese, andnuts ( 20 g/d). After 21 days, the rats in each group werethen divided into control and treated groups. Mini-pumpsdelivering saline or MTII (1 mg/kg per day) for minimally28 days were implanted. Oxygen consumption was mea-sured for 17 days in a second group of rats implanted withmini-pumps containing MTII (1 mg/kg per day) or saline.Results: HPF rats ate less ( 50%) rat chow than RC rats.After 20 days, the HPF group had reached a plateau andweighed significantly more (p 0.005) than the RC group(411.7 9.3 g; n 17 vs. 365.1 9.4 g; n 16). HPF ratsand RC rats receiving MTII reduced their pellet intake andbody weight in the initial 2 weeks of treatment (day 14,RC-saline: 1.6 1.8 g; RC-MTII, 22.5 3.7 g; HPF-saline, 7.1 1.7 g; HPF-MTII, 30.7 4.8 g). Subse-quently, pellet intake returned to pre-implantation values,although body weights remained reduced in both HPF andRC groups. Oxygen consumption was increased in ratstreated with MTII.Discussion: This suggests that MTII initially reducedbody weight by limiting food intake; however, mainte-nance of weight is most likely due to increased energyexpenditure under conditions of normal and highly pal-atable diets in mature animals.Key words: melanocortin agonist, diet-induced obesity,pharmacotherapy, energy expenditure more...
- Published
- 2002
22. Magnetic resonance properties of ex vivo breast tissue at 1.5 T
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Bradford S. Hamilton, Simon J. Graham, Sola Ness, and Michael Bronskill
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Breast tissue ,Magnetic Resonance Spectroscopy ,Absorption spectroscopy ,medicine.diagnostic_test ,Chemistry ,Relaxation (NMR) ,Analytical chemistry ,Adipose tissue ,Water ,Magnetic resonance imaging ,Signal Processing, Computer-Assisted ,Magnetization ,Magnetics ,Nuclear magnetic resonance ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Female ,Magnetization transfer ,Breast ,Ex vivo - Abstract
The magnetic resonance absorption spectrum, T1 and T2 relaxation time distributions, and magnetization transfer properties of ex vivo breast tissue have been characterized at 1.5 T and 37 degrees C. The fraction of fibroglandular tissue within individual tissue samples (n = 31) was inferred from the tissue volumetric water content obtained by integration of resolvable broad-line fat and water resonances. The spectroscopically estimated water content was strongly correlated with that extracted enzymatically (Pearson correlation coefficient 0.98, P < < 0.01), which enabled the assignment of principal relaxation components for fibroglandular tissue (T2=0.04+/-0.01, T1=1.33+/-0.24 s), and for adipose tissue (T2=0.13+/-0.01, T1=0.23+/-0.01 s, and T2=0.38+/-0.03, T1=0.62+/-0.16 s). Th e relaxation components for fibroglandular tissue exhibited strong magnetization transfer, whereas those for adipose tissue showed little magnetization transfer effect. These results ultimately have applicability to the optimization of clinical magnetic resonance imaging and research investigations of the breast. more...
- Published
- 1997
23. Inherent Abnormalities of Fat Cells from Massively Obese Individuals
- Author
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Bradford S. Hamilton
- Subjects
medicine.medical_specialty ,Nutrition and Dietetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Adipose tissue ,White adipose tissue ,medicine.disease ,Obesity ,Obese Gene Product ,Pathogenesis ,Endocrinology ,Energy sensing ,Adipogenesis ,Relative resistance ,Internal medicine ,medicine ,Surgery ,business - Abstract
In vitro investigations into adipose cell dynamics have revealed intrinsic characteristics of massively obese individuals' cells that could contribute to a relatively intractable expanded fat mass. Morbidly corpulent peoples' preadipocytes replicate to a greater degree than those from lean individuals. Coupled with exaggerated differentiation this enhanced growth would result in a greater number of fat cells which would increase adipose tissue mass. The relative resistance to de-differentiation that adipocytes from the massively obese demonstrate would contribute to stability of an increased number of adipocytes further exacerbating the problem. The increased message of an energy sensing protein, the obese gene product, suggests that the morbidly obese are insensitive to its action. Together these attributes provide a strong argument for a significant genetic role in the pathogenesis of obesity. more...
- Published
- 1996
24. Increased obese mRNA expression in omental fat cells from massively obese humans
- Author
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Diana Paglia, Mervyn Deitel, Anita Y.M. Kwan, and Bradford S. Hamilton
- Subjects
Adult ,Leptin ,Male ,medicine.medical_specialty ,Adolescent ,Adipose tissue ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Body Mass Index ,Pathogenesis ,Mice ,Internal medicine ,medicine ,Animals ,Humans ,Obesity ,RNA, Messenger ,Aged ,Cell Size ,Regulation of gene expression ,Aged, 80 and over ,Mutation ,Proteins ,General Medicine ,Middle Aged ,medicine.disease ,Mice, Inbred C57BL ,Endocrinology ,Adipose Tissue ,Gene Expression Regulation ,Protein Biosynthesis ,Female ,Energy Metabolism ,Body mass index ,Omentum ,Ex vivo - Abstract
Obesity presents a significant challenge to the general health of affluent nations in terms of the number of people affected, the serious associated maladies and the lack of effective treatments. While common wisdom has held that obesity results from 'gluttony and sloth', a number of studies have indicated physiological causes of underlying the pathogenesis of obesity, with the degree of adiposity having a strong genetic component. Recently, the obese gene in the ob/ob mouse was cloned, along with its human homologue. The specific production of the obese protein by adipose tissue suggested that it may function in a feedback loop from fat tissue to the hypothalamus to control energy intake and/or energy expenditure, and that it may play a role in the pathogenesis of human obesity. In this study we report that obese mRNA expression is elevated in ex vivo omental adipocytes isolated from massively obese humans in the absence of an identifiable mutation. Therefore, we speculate that this increased expression may suggest that the massively obese are insensitive to the putative regulatory function(s) of the obese gene product. more...
- Published
- 1995
25. Obituary: Daniel A.K. Roncari, MD
- Author
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Bradford S. Hamilton and Mervyn Deitel
- Subjects
Nutrition and Dietetics ,business.industry ,Endocrinology, Diabetes and Metabolism ,Medicine ,Surgery ,Obituary ,business ,Classics - Published
- 1994
26. Cellular and Molecular Factors in Adipose Tissue Growth and Obesity
- Author
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Bradford S. Hamilton and Daniel A. K. Roncari
- Subjects
business.industry ,Basic fibroblast growth factor ,Adipose tissue ,Context (language use) ,medicine.disease ,Bioinformatics ,Obesity ,Type ii diabetes ,chemistry.chemical_compound ,chemistry ,Diabetes mellitus ,Medicine ,Effective treatment ,business - Abstract
One of the major challenges in biology and medicine is the unravelling of the fundamental abnormality imparting vulnerability to the development of obesity. The experimental approaches adopted to date have simply not provided the solution. It is pertinent, particularly in the context of this meeting, that obesity frequently triggers or aggravates non-insulin-dependent diabetes. Thus, prevention or effective treatment of obesity would also have a prophylactic or ameliorative effect on type II diabetes. This paper will review and provide new data about the proposed functions of heparin-binding (fibroblast) growth factors in relation to adipose cell dynamics and processes opposing adipose differentiation. more...
- Published
- 1993
- Full Text
- View/download PDF
27. Invited Commentary
- Author
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Bradford S. Hamilton
- Subjects
Nutrition and Dietetics ,Endocrinology, Diabetes and Metabolism ,Surgery - Published
- 1996
- Full Text
- View/download PDF
28. A new role for a fat actor
- Author
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Bradford S. Hamilton
- Subjects
Leptin ,medicine.medical_specialty ,media_common.quotation_subject ,Mice, Obese ,Fertility ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Fat mass ,Mice ,Pregnancy ,Internal medicine ,medicine ,Animals ,Homeostasis ,Humans ,Obesity ,media_common ,digestive, oral, and skin physiology ,Proteins ,General Medicine ,Recombinant Proteins ,Diet ,Endocrinology ,Adipose Tissue ,Female ,hormones, hormone substitutes, and hormone antagonists - Abstract
Supplementing the diet of ob/ob female mice with leptin not only reduces fat mass, but restores fertility.
- Published
- 1996
- Full Text
- View/download PDF
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