Analysis of genetic susceptibility to type II diabetes in mice

Analysis of genetic susceptibility to type II diabetes in mice

Bibliographic Details
Main Author: Yazbek, Soha Nabil
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2010
Subjects:
Genetics
CSS
Obesity
Type II Diabetes
Parental effect
SLC35B4
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1277326732
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case12773267322021-08-03T05:33:51Z Analysis of genetic susceptibility to type II diabetes in mice Yazbek, Soha Nabil Genetics Genetics CSS Obesity Type II Diabetes Parental effect SLC35B4 The prevalence of type 2 diabetes (T2D) is increasing as obesity increases worldwide and insulin resistance (IR) remains the most important factor in its development. The resulting hyperglycemia leads to complications including retinopathy, stroke and amputations. Life style changes and treatments have not been successful in elevating the progression of IR into diabetes nor preventing co-morbidities with cardiovascular involvement. Despite compelling evidence that susceptibility to obesity and T2D is highly heritable and considerable progress with gene identification, most susceptibility genes continue to elude discovery. We used mouse models of diet-induced metabolic disease to facilitate gene discovery and better characterize the underlying genetic architecture of T2D. Analysis of the C57BL/6JA/J panel of Chromosome substitution strains (CSS) identified 8 chromosomes with at least 1 QTL affecting glucose homeostasis. First, we analyzed global gene expression patterns in 6C1 and 6C2 congenic strains of CSS-6 defining Obrq2, a QTL for body weight, and measures of IR. Pathway analysis of global gene expression patterns in liver identified expression level differences between 6C1 and 6C2 in pathways related to mitochondrial oxidative phosphorylation (OxPhos). The OxPhos expression differences were subtle but evident in each complex of the electron transport chain. This data suggests the importance of hepatic mitochondrial function in the development of obesity and insulin resistance. Next, we developed two consecutive subcongenic panels for Obrq2. Through genetic and phenotypic analysis of congenic, subcongenic and subsubcongenic strains, we uncovered a complex genetic architecture for metabolic traits associated with T2D. Multiple closely linked QTLs demonstrated strong effects with considerable phenotypic heterogeneity. Analysis of one of them, Obrq2a1, identified the solute receptor Slc35b4 as a potential regulator of obesity and insulin resistance. Slc35b4 mRNA expression level differences in liver were associated with the phenotype. Finally, we provided first evidence for a non-imprinting transgenrational paternal effect on body weight and food intake using crosses between obesity resistant congenic strain 6C2d and obesity sensitive strain B6. The phenotype was transmitted through the paternal lineage for at least 3 generations, but was lost if passed through the female lineages. 2010 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1277326732 http://rave.ohiolink.edu/etdc/view?acc_num=case1277326732 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Genetics
Genetics
CSS
Obesity
Type II Diabetes
Parental effect
SLC35B4
spellingShingle Genetics
Genetics
CSS
Obesity
Type II Diabetes
Parental effect
SLC35B4
Yazbek, Soha Nabil
Analysis of genetic susceptibility to type II diabetes in mice
author Yazbek, Soha Nabil
author_facet Yazbek, Soha Nabil
author_sort Yazbek, Soha Nabil
title Analysis of genetic susceptibility to type II diabetes in mice
title_short Analysis of genetic susceptibility to type II diabetes in mice
title_full Analysis of genetic susceptibility to type II diabetes in mice
title_fullStr Analysis of genetic susceptibility to type II diabetes in mice
title_full_unstemmed Analysis of genetic susceptibility to type II diabetes in mice
title_sort analysis of genetic susceptibility to type ii diabetes in mice
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2010
url http://rave.ohiolink.edu/etdc/view?acc_num=case1277326732
work_keys_str_mv AT yazbeksohanabil analysisofgeneticsusceptibilitytotypeiidiabetesinmice
_version_ 1719421755574976512

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