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Human Adipocytes: Proteomic Approaches
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Type 2 diabetes is characterized by increased levels of glucose in the blood originating from insulin resistance in insulin sensitive tissues and from reduced pancreatic insulin production. Around 400 million people in the world are diagnosed with type 2 diabetes and the correlation with obesity is strong. In addition to life style induction of obesity and type 2 diabetes, there are indications of genetic and epigenetic influences. This thesis has focused on the characterization of primary human adipocytes, who play a crucial role in the development of type 2 diabetes.

Histones are important proteins in chromatin dynamics and may be one of the factors behind epigenetic inheritance. In paper I, we characterized histone variants and posttranslational modifications in human adipocytes. Several of the specific posttranslational histone modifications we identified have been characterized in other cell types, but the majority was not previously known. Moreover, we identified a variant of histone H4 on protein level for the first time.

In paper II, we studied specific histone H3 methylations in the adipocytes. We found that overweight is correlated with a reduction of H3K4me2 while type 2 diabetes is associated with an increase of H3K4me3. This shows a genome-wide difference in important chromatin modifications that could help explain the epidemiologically shown association between epigenetics and metabolic health.

Caveolae is a plasma membrane structure involved in the initial and important steps of insulin signaling. In paper III we characterized the IQGAP1 interactome in human adipocytes and suggest that IQGAP1 is a link between caveolae and the cytoskeleton. Moreover, the amount of IQGAP1 is drastically lower in adipocytes from type 2 diabetic subjects compared with controls implying a potential role for IQGAP1 in insulin resistance.

In conclusion, this thesis provides new insights into the insulin signaling frameworks and the histone variants and modifications of human adipocytes.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2016. , 50 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1494
National Category
Endocrinology and Diabetes Cell Biology Cell and Molecular Biology Medical Genetics Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:liu:diva-125907DOI: 10.3384/diss.diva-125907ISBN: 978-91-7685-889-9 (print)OAI: oai:DiVA.org:liu-125907DiVA: diva2:909978
Public defence
2016-03-23, Berzeliussalen, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2016-03-08 Created: 2016-03-08 Last updated: 2016-04-04Bibliographically approved
List of papers
1. Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
Open this publication in new window or tab >>Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells
2011 (English)In: PLOS ONE, ISSN 1932-6203, Vol. 6, no 1Article in journal (Refereed) Published
Abstract [en]

Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 mu g of protein with histone content of 60%-70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments.

Place, publisher, year, edition, pages
Public Library of Science (PLoS), 2011
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-65933 (URN)10.1371/journal.pone.0015960 (DOI)000286512900014 ()
Note

Original Publication: Asa Jufvas, Peter Strålfors and Alexander Vener, Histone Variants and Their Post-Translational Modifications in Primary Human Fat Cells, 2011, PLOS ONE, (6), 1. http://dx.doi.org/10.1371/journal.pone.0015960 Licensee: Public Library of Science (PLoS) http://www.plos.org/

Available from: 2011-02-28 Created: 2011-02-28 Last updated: 2016-03-08
2. Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
Open this publication in new window or tab >>Global differences in specific histone H3 methylation are associated with overweight and type 2 diabetes.
Show others...
2013 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 5, no 1, 15Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Epidemiological evidence indicates yet unknown epigenetic mechanisms underlying a propensity for overweight and type 2 diabetes. We analyzed the extent of methylation at lysine 4 and lysine 9 of histone H3 in primary human adipocytes from 43 subjects using modification-specific antibodies.

RESULTS: The level of lysine 9 dimethylation was stable, while adipocytes from type 2 diabetic and non-diabetic overweight subjects exhibited about 40% lower levels of lysine 4 dimethylation compared with cells from normal-weight subjects. In contrast, trimethylation at lysine 4 was 40% higher in adipocytes from overweight diabetic subjects compared with normal-weight and overweight non-diabetic subjects. There was no association between level of modification and age of subjects.

CONCLUSIONS: The findings define genome-wide molecular modifications of histones in adipocytes that are directly associated with overweight and diabetes, and thus suggest a molecular basis for existing epidemiological evidence of epigenetic inheritance.

Place, publisher, year, edition, pages
BioMed Central, 2013
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-99450 (URN)10.1186/1868-7083-5-15 (DOI)000329455000001 ()24004477 (PubMedID)
Available from: 2013-10-18 Created: 2013-10-18 Last updated: 2017-12-06Bibliographically approved

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