Thesis (doctoral)--Lund University, 1997. / Added t.p. with thesis statement inserted.

Thesis (M.A.)--University of North Carolina at Chapel Hill, 2004. / Includes bibliographical references (leaves 33-36).

In Drosophila, eight insulin-like peptides (DILP1-8) are produced and secreted in different locations. They regulate many aspects of development and physiology, such as organism growth, metabolic homeostasis, reproduction, stress resistance and life span. DILP2, 3 and 5 are mainly produced by a cluster of median neurosecretory cells in the brain known as insulin producing cells (IPCs). Here we showed that IPCs are under tight regulation of two G-protein coupled receptors (GPCRs), serotonin receptor 5-HT1A and octopamine receptor OAMB. Genetic manipulations of these two receptors in IPCs affected transcription levels of DILPs, hence altered feeding, carbohydrate levels, and resistance to stress (Paper I and II). Moreover, we showed that the insulin receptor (dInR) is strongly expressed in leucokininergic neurons (LK neurons), and selectively regulates growth of around 300 neuropeptidergic neurons expressing the bHLH transcription factor DIMMED. Overexpression of dInR in DIMM-positive neurons led to substantial neuronal growth, including cell body size, golgi apparatus and nuclear size, while knockdown of dInR had the opposite effect (Paper III). Manipulations of components in the insulin signaling pathway in LK neurons resulted in the similar cell size phenotypes. Furthermore, dInR regulated size scaling of DIMM-postive neurons is nutrient-dependent and partially requires the presence of DIMM (Paper III). Finally, we investigated the roles of DILPs (2, 3, 5 and 7) and LK neurons in regulation of feeding and diuresis at the adult stage (Paper IV).  In summary, we have identified two more regulators for IPC activity and demonstrated developmental roles of  DILPs and dInR in regulating neuronal size. Moreover, DILPs regulate water homeostasis together with a diuretic hormone leucokinin and as a consequence affects feeding behavior. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 3: In press. Paper 4: Manuscript.</p>

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / 2031-01-01

Molecular analysis of the cross talk between Angiotensin II (Ang II) and insulin signaling systems reveal that they are multifaceted and occur at cellular level and intracellular level. Experiments were carried out to evaluate the crosstalk between the Ang II receptors-AT1 and AT2 and the Insulin Receptor (IR) to understand the changes in the signaling pathway that could lead to the transition from hypertension to insulin resistance. Transient expression of rat AT2 in CHO cells induced co-immunoprecipitation of the AT2R with IRâ and inhibition of IRâ tyrosine phosphorylation. An AT2-peptide carrying the amino acids 226-363 (that spans 3rd intracellular loop (ICL) and C-terminal cytoplasmic domain) was sufficient for AT2- IRâ interaction in a yeast two-hybrid assay. An orthovanadate-insensitive AT2- IRâ association was also observed in human breast cancer cell line MCF-7. Interestingly, while AT2- IRâ complex formation was insensitive to pertussis toxin (PTX), AT2-mediated inhibition of IRâ phosphorylation was partially sensitive to PTX treatment in MCF-7. To address the mechanism behind the transition of an early hypertensive heart to an insulin resistant status, we investigated the changes that occur at post translational level in the IR and its downstream signaling molecules that modulate insulin signaling. Early hypertension was induced in 10-week old SD rats by 2% NaCl diet in combination with Ang II infusion. Enhanced serine phosphorylation of the IRâ suggestive of dysfunctional insulin signaling was observed in cardiac tissues as a result of the treatment. In addition, an enhanced association of both AT1R and AT2R with IRâ was observed in the heart tissue lysates from hypertensive rat heart. To evaluate the tissue effects of Ang II, we compared the transcriptome of hypertensive rat hearts to the controls. Analysis suggests that the Ang II induces multiple responses in heart tissue that result in changes to the gene expression pattern intended to promote insulin sensitivity and insulin resistance. Taken together our results suggest that exogenous Ang II and moderately high salt diet promote metabolic abnormalities in heart tissue that result in sequestration of IR and modulation of IR signaling, and significant changes in gene expression profile in the hypertensive heart.

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Metabolic syndrome includes several metabolic and hormonal disorders, such as abdominal obesity, insulin resistance, and lower blood ghrelin. Women with breastfeeding history exhibit a reduced risk for metabolic syndrome in later life. The purpose of aim 1 was to determine the incidence of metabolic syndrome in low income, overweight/obese women in early postpartum and to assess its relationship to lactation status. It has been found that the incidence of metabolic syndrome is much higher in formula feeding women than that of the breastfeeding ones (44.3% vs. 22.4%, p < 0.01). The breastfeeding mothers had reduced triglycerides (109.07 mg/dl vs. 143.10 mg/dl, p < 001) and elevated serum high-density lipoprotein (HDL)-cholesterol (58.59 mg/dl vs. 51.76 mg/dl, p < 0.01). The goal of aim 2 was to explore associations between ghrelin, metabolic syndrome and infant feeding methods in low income, overweight/obese women in early postpartum. In our study, the breastfeeding mothers in early postpartum had higher plasma ghrelin, as compared to those who formula fed (584.73 pg/ml vs. 450.77 pg/ml, p < 0.01). Additionally, it is found that plasma ghrelin was negatively associated with incidence and numbers of risk factors for metabolic syndrome, before and after controlling for body mass index (BMI). After adjusting for ghrelin in logistic regression analyses, significant relationships between lactation status and metabolic syndrome disappeared. Thus, the protective function of breastfeeding against metabolic syndrome in overweight/obese women in early postpartum may related to the plasma ghrelin values. The purpose of aim 3 was to detect the influence of weight loss on insulin resistance and plasma adiponectin, zinc (Zn), manganese (Mn) and copper (Cu) in low income, overweight/obese women in early postpartum. After an eight-week weight loss intervention, plasma levels of adiponectin, Zn and Mn were significantly enhanced, and plasma concentrations of insulin (7.53±0.56 vs. 6.23±0.49, p <0.01) and insulin resistance (1.84±0.15 vs. 1.44±0.12, p <0.01) were reduced. The increase of adiponectin, Zn and Mn was positively associated with weight reduction. However, the plasma Cu was not significantly affected. The relationships between weight loss and reduced insulin resistance disappeared after adjusting the increases of adiponectin, Zn and Mn during weight loss. Thus, weight loss had beneficial effects on insulin resistance, plasma values of adiponectin Zn and Mn. It is plausible that the influence of weight loss on insulin resistance may be associated with improvements of plasma of adiponectin, Zn and Mn. Collectively, the results of this study demonstrate the important benefits of breastfeeding on prevention of metabolic syndrome in overweight/obese women in early postpartum. This study also emphasizes the influence of ghrelin on risk factors of metabolic syndrome and lactation status. / text

Pyruvate carboxylase (PC), converting pyruvate to oxaloacetate (OAA), is a critical contributor to anaplerosis in pancreatic β-cell, the process that can replenish the intermediates in Krebs cycle. The level of PC is markedly high in pancreatic β-cell, about 7-fold higher than that in α-cell. PC activity is reduced in the islets of animals with type 2 diabetes. Moreover, the rate of pyruvate carboxylation catalyzed by PC is well correlated with glucose-stimulated insulin secretion (GSIS), further supporting the important role of PC in insulin secretion. Tumor protein p53 or p53, best known for its role as a tumor suppressor, has been studied extensively for its broad influence and complex regulation. p53 suppresses tumor progression by responding to a wide variety of intrinsic and extrinsic cellular stress signals. Recent studies have revealed novel roles of p53 in response to metabolic stress, such as oxidative or nutrient stress. MDM2 is the major E3 ubiquitin ligases to control p53 activity negatively. p53 and MDM2 form a negative-feedback loop, where p53 stimulates the expression of MDM2, in turn MDM2 inhibits not only the stability but also the transcriptional activity of p53. In the previous study, mice lacking Mdm2 specifically in pancreatic β-cells have been generated, and display impaired insulin secretion and glucose metabolism. Further study has suggested that the impaired insulin secretion is caused by downregulation of pyruvate carboxylase (PC). To explore the interaction of PC with MDM2-p53 pathway in regulating insulin secretion, we inserted human PC DNA into a shuttle vector pShuttle-CMV to generate a recombinant adenovirus containing human PC gene, that is then used to restore the level of PC in Mdm2 KO islet. The recovery of insulin secretion confirmed that the downregulation of PC leads to β-cell dysfunction. Given that MDM2 is the main E3 ubiquitin protein ligase to restrain p53 activity, abnormal high level of p53 is suggested to suppress the activity of PC in Mdm2 β-cell KO mice. The putative p53 response element is found in a sequence of PC intron gene, indicating that PC can be a downstream target of p53. Using pGL3 Luciferase Reporter Vector, it is verified that p53 suppresses the activity of PC by directly targeting PC. / published_or_final_version / Medicine / Master / Master of Medical Sciences

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