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Polyunsaturated fatty acid synthesis and type 2 diabetes complications

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dc.contributor.advisor Jump, Donald B.
dc.creator Tripathy, Sasmita
dc.date.accessioned 2012-07-30T20:04:27Z
dc.date.available 2013-10-24T19:58:53Z
dc.date.copyright 2012-07-11
dc.date.issued 2012-07-11
dc.identifier.uri http://hdl.handle.net/1957/31666
dc.description Graduation date: 2013 en_US
dc.description Access restricted to the OSU Community at author's request from July 27, 2012 - July 27, 2013
dc.description.abstract Type 2 diabetes mellitus (T2DM) is a disease of multi-complications affecting more than 20 million US adults. Hyperglycemia is the classic clinical feature of diabetes, and uncontrolled hyperglycemia leads to deadly health complications. Thus, control of blood glucose represents a major goal for diabetics. Human and rodent studies revealed another clinical feature; diabetics have low tissue and plasma levels of polyunsaturated fatty acids (PUFAs), an effect often attributed by impaired endogenous PUFA synthesis. In this context, rodent studies have revealed a possible link between PUFA synthesis and high fat diet induced obesity and diabetes. These studies have shown that obese and diabetic mice have low hepatic expression and activity of fatty acid elongase-5 (Elovl5), a key enzyme involved in the PUFA synthesis pathway. Over-expression of Elovl5 in livers of chow fed C57BL/6J mice decreased fasting blood glucose and increased hepatic glycogen contents. Therefore, my hypothesis for the current work is that elevated hepatic Elovl5 activity or improved hepatic PUFA synthesis will improve systemic and hepatic carbohydrate metabolism in a mouse model of diet induced obesity and diabetes. Using a recombinant adenovirus approach, we over-expressed Elovl5 in livers of high fat diets (60% calories derived from fat as lard, Research Diets) induced obese-diabetic mice. Elevated hepatic Elovl5 activity increased hepatic and plasma C₂₀₋₂₂ PUFA contents, reduced homeostatic model assessment for insulin resistance (HOMA-IR), improved glucose tolerance and lowered fasting blood glucose to euglycemic levels in obese-diabetic mice. The mechanism for insulin mimetic effect of Elovl5 on hepatic glucose metabolism was correlated with increased phosphorylation of Akt-S⁴⁷³, FoxO1-S²⁵⁶ and PP2Acat-Y³⁰⁷, decreased nuclear content of FoxO1, and decreased expression of Pck1 and G6Pase; important enzymes involved in gluconeogenesis (GNG) and glucose production. Phospho-FoxO1 is excluded from nuclei, ubiquitinated and degraded by the proteasome. Loss of nuclear FoxO1, due to its increased phosphorylation, leads to the reduction in the expression of key genes involved in gluconeogenesis, i.e., Pck1 and G6Pase. Using obese-diabetic mice liver extracts and HepG2 cells, I established that Elovl5 uses two mechanisms to control hepatic GNG. The first mechanism involves Elovl5 mediated increased Akt2-S⁴⁷³ and FoxO1-S²⁵⁶ phosphorylation via mTORC2-rictor pathway. The second mechanism involves Elovl5 mediated attenuation of de-phosphorylation of FoxO1 via PP2A inhibition. Together, these mechanisms increase FoxO1 phosphorylation status in livers of fasted obese-diabetic mice, lower hepatic FoxO1 nuclear abundance and FoxO1 capacity to sustain transcription of GNG genes and inhibit GNG and restore blood glucose levels in fasted obese-diabetic mice. Results of these studies showed Elovl5 corrected high fat diet induced hyperglycemia in C57BL/6J mice, identified the molecular mechanism of Elovl5 control of GNG and explained how Elovl5 or PUFA synthesis controls GNG. Therefore, these findings will be eventually helpful in developing a therapeutic target to combat hyperglycemia. en_US
dc.language.iso en_US en_US
dc.subject Elovl5 en_US
dc.subject Hyperglycemia en_US
dc.subject FoxO1 en_US
dc.subject Gluconeogenesis en_US
dc.subject Rictor en_US
dc.subject.lcsh Diabetes -- Complications en_US
dc.subject.lcsh Hyperglycemia en_US
dc.subject.lcsh Unsaturated fatty acids -- Synthesis en_US
dc.subject.lcsh Gluconeogenesis -- Regulation en_US
dc.title Polyunsaturated fatty acid synthesis and type 2 diabetes complications en_US
dc.type Thesis/Dissertation en_US
dc.degree.name Doctor of Philosophy (Ph. D.) in Nutrition en_US
dc.degree.level Doctoral en_US
dc.degree.discipline Health and Human Sciences en_US
dc.degree.grantor Oregon State University en_US
dc.contributor.committeemember Traber, Maret G.
dc.contributor.committeemember Ho, Emily
dc.contributor.committeemember Iwaniec, Urszula
dc.contributor.committeemember Hall, Jean A.
dc.description.peerreview no en_us
dc.description.embargo 2013-07-27
dc.description.embargopolicy OSU Users en

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