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dc.contributor.authorWang, Zhao
dc.identifier.citationSource: Dissertation Abstracts International, Volume: 68-08, Section: B, page: 5023.;Advisors: Philipp E. Scherer.
dc.description.abstractObesity is an epidemic with rising prevalence worldwide. Obesity poses a major risk for chronic diseases including hypertension, type II diabetes and cardiovascular disease. The uncontrolled expansion of adipose tissue is the key feature of obesity. In the past decade, the view of adipose tissue has undergone drastic change. Previously assumed to be merely an inert compartment for energy storage, it is now widely accepted that adipose tissue is a major endocrine organ. Adipokines secreted from adipocytes play critical roles in the initiation and progression of obesity-associated morbidities and mortalities. Adiponectin, a fat-derived hormone, is involved in insulin sensitization and whole body energy homeostasis. Dysregulation of adiponectin in the obese state is associated with insulin resistance, hypertension and cardiovascular disease. Adipocytes maintain tight control over circulating adiponectin levels, suggesting the existence of a complex, highly regulated biosynthetic pathway. However, the critical mediators of adiponectin maturation within the secretory pathway have not been elucidated. Previously, we found that a significant portion of de novo synthesized adiponectin is not secreted and retained in adipocytes. Here, we show that there is an abundant pool of properly folded adiponectin in the secretory pathway that is sequestered through thiol-mediated retention. Adiponectin is covalently bound to the chaperone ERp44 through disulfide bond within the lumen of endoplasmic reticulum (ER). An adiponectin mutant lacking cysteine 39 fails to stably interact with ERp44, demonstrating that this residue is the primary site mediating the covalent interaction. Another ER chaperone, Ero1-Lalpha, plays a critical role in the release of adiponectin from ERp44. Levels of both of these proteins are highly regulated in adipocytes and are influenced by the metabolic state of the cell. While less critical for the secretion of trimers, these chaperones play a major role in the assembly of higher order adiponectin complexes. Our data highlights the importance of post-translational events controlling the release of adiponectin from adipocytes. One mechanism of increasing circulating levels of adiponectin by PPARy agonists may be through selective upregulation of rate-limiting chaperones.;In the obese state, insulin resistance occurs in peripheral organs including skeletal muscle, adipose tissue and liver. To compensate for the desensitization of insulin signaling and to maintain glucose homeostasis, pancreatic beta cells increase the production and secretion of insulin. However, beta cell dysfunction emerges due to glucotoxicity and lipotoxicity and eventually leads to cell death when insulin resistance persists. Frank diabetes develops when insulin secretion cannot match the demand for sustaining euglycemia. To study the physiology and pathophysiology of beta cells during diabetes progression, several mouse models have been applied which have provided insights for the mechanisms of beta cell dysfunction and cell death. However, these animal models utilize acute, extreme, nonphysiological insults and some of them do not show significant beta cell recovery after injury. To evaluate beta cell dysfunction in a physiologically-relevant fashion, we created a novel mouse model for inducible and reversible ablation of pancreatic beta cells, the PANIC-ATTAC (pancreatic islet beta cell apoptosis through targeted activation of caspase 8). In this model, we efficiently induce beta cell apoptosis and concomitant hyperglycemia by administration of a chemical dimerizer which triggers apoptosis through caspase 8. Upon cessation of dimerizer treatment, the PANIC-ATTAC mice show significant beta cell recovery and restoration of euglycemia. We have used this mouse model to examine several anti-diabetic drugs including exendin-4, sitagliptin and a PPARgamma agonist. Additionally, during recovery, we find an increased population of Glut2 positive, insulin negative cells in the pancreas of PANIC-ATTAC mice which may represent a novel pool of potential beta cell precursors. The PANIC-ATTAC mouse model reveals many characteristic features that have not been described in existing models. The PANIC-ATTAC mouse model therefore has applications in many areas of diabetes research, allowing us to study survival mechanisms of beta cells during glucotoxic challenges, to identify beta cell precursors and to test the beneficial impact of pharmacological interventions.
dc.publisherProQuest Dissertations & Theses
dc.subjectMolecular biology.
dc.titlePhysiology and pathophysiology of adipocytes and pancreatic beta cells in obesity and diabetes mellitus

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