Thesis (Ph. D.)--University of North Carolina at Greensboro, 2006. / Advisor: Ron Morrison; submitted to the School of Human Environmental Sciences. Includes bibliographical references.

Fibroblast Growth Factor (FGF) 21 is a liver-derived endocrine factor with multiple metabolic effects on glucose and lipid homeostasis in animals. The adipose tissue has been proposed as a major target of FGF21, where it enhances glucose uptake and modulates lipolysis as well as thermogenesis. However, the molecular mechanisms underlying the pleiotropic effects of FGF21 in adipocytes and the physiological roles of FGF21 in regulating energy homeostasis remain poorly characterized. Therefore, the present study aimed to investigate: 1) the signal transduction pathway whereby FGF21 enhances glucose uptake in white adipocytes; 2) the role of FGF21 in lipolysis in both mouse and human white adipose tissues (WAT) and its underlying mechanisms involved; 3) the phenotypes of FGF21 knockout (KO) mice with respect to energy expenditure and adiposity under both standard chow and high fat diet. Key findings: 1. In vitro studies demonstrated that extracellular signal-regulated kinases (ERK1/2) play an obligatory role in mediating FGF21-induced upregulation of glucose transporter-1 (GLUT1) expression and hence elevation of glucose uptake in 3T3-L1 adipocytes. 2. Chromatin immunoprecipitation assay revealed that Serum Response Factor (SRF) and ETS-like protein-1 (Elk-1), the two transcription factors which are known as the downstream targets of ERK1/2, were recruited to the endogenous GLUT1 promoter in adipocytes. A conserved binding motif for these two transcription factors was also identified in the GLUT1 promoter responsive to FGF21 stimulation in 3T3-L1 adipocytes by site-directed mutagenesis and luciferase assay. 3. In WAT of diet-induced obese mice, FGF21-evoked downstream signaling events, including the phosphorylation of ERK1/2 and SRF/Elk-1, the upregulation of GLUT1, and the increased glucose uptake, were markedly blunted compared to lean controls, suggesting the existence of “FGF21 resistance” in obesity. 4. In vivo and ex vivo studies on fasted wild type and FGF21 KO mice demonstrated that FGF21 acutely suppressed basal and forskolin-stimulated lipolysis in WAT. 5. FGF21-inhibited lipolysis was mediated by Akt-dependent reduction of cyclic adenosine monophosphate (cAMP) levels in both mouse and human WAT. 6. FGF21 KO mice were resistant to diet- and aging-induced obesity, which was attributed to decreased fat mass. The increased lipolysis and fatty acid oxidation in FGF21 KO mice may explain in part the lean phenotype of FGF21 KO mice. Conclusions: These results collectively suggest FGF21 as a key modulator of glucose and lipid metabolism in WAT, by activation of ERK1/2 kinase and Akt respectively. FGF21 and its signaling components may represent potential targets for the future development of new strategies for treating obesity and its medical complications. / published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Introduction Globesity, the worldwide obesity epidemic, represents a major threat and public health burden. An uncontrolled expansion of the adipose tissue followed by a chronic low-grade inflammation leads to the dysfunction of the adipose organ resulting in obesity and its associated metabolic complications. Uncovering the mechanisms of adipogenesis, the development of adipocytes, therefore strikes as a key strategy in combating the disease. MicroRNAs (miRs), a class of small non-coding RNAs, have emerged in recent years as crucial modulators of diverse biological processes such as cell proliferation, differentiation, and signal transduction emphasizing their large potential as targets. Numerous miRs have been associated with the adipose tissue and metabolism and their dysregulation has repeatedly been linked to diseases including diabetes and obesity. This study aimed to investigate the role of miR-34a, an obesity-related miR, in the regulation of pre-adipocyte differentiation. Materials and Methods Mouse 3T3-L1 pre-adipocytes were employed as an in vitro system to study adipogenesis. Oil Red O staining served to evaluate the degree of adipogenesis and the over-expression of miR-34a in adipocytes was achieved by a lentiviral system. MiR and messenger RNA (mRNA) levels were analysed using TaqMan and SYBR Green-based quantitative real time PCR (qPCR) respectively. Results The expression of miR-34a was substantially down-regulated upon treatment of differentiation medium for two days and remained significantly low during the differentiation period compared with undifferentiated pre-adipocytes. Lentivirus-mediated over-expression of miR-34a successfully up-regulated miR-34a. Higher levels of miR-34a in turn mitigated adipogenesis as evidenced by blunted Oil Red O staining. This observation was found to be in good agreement with the qPCR analysis, which showed a down-regulation of several key adipogenic markers. Conclusion The down-regulation of miR-34a is required during pre-adipocyte differentiation for the efficient proceedings of the adipogenic programme. Further investigation is needed to evaluate the potential therapeutic implication of miR-34a-based treatment in managing obesity. / published_or_final_version / Medicine / Master / Master of Medical Sciences

No description available.

Dietary fatty acids are considered promoters of murine and human mammary tumors. The mechanism responsible is not known. Mammary adenocarcinomas in mice originate from preneoplastic cells (hyperplastic alveolar nodules (HAN)) which are derived from normal mammary epithelial cells. Diets rich in linoleic acid (18:2) have been associated with increased incidence of HAN and promotion of tumor growth. Diets rich in stearic acid (18:0) have been associated with decreased incidence of HAN and increased latency period for mammary tumor formation in mice.The effects of dietary 18:0 and 18:2 stages of murine mammary tumorigenesis were examined. The purpose of this study was to determine the effects of these dietary fatty acids on HAN production, mammary gland development, and fatty acid composition of mammary epithelial cells and adipocytes.Spontaneous mammary tumor producing strain A/ST mice were fed a high fat (15%) or low fat (5%) diet. High fat stock (ST) diet containing 1.5% 18:2 or a low fat corn oil (CO) diet containing 3% 18:2 were fed. Animals were sacrificed at 6 or 10 months of age. HAN, ductile and alveolar development were histologically determined in the left inguinal mammary gland. The contralateral gland was on the early diets rich in 18:2 (SF) or 18:0 (SA) were fed. A low*fat enzymatically dissociated and fatty acid compositions of adipocyte and epithelial cells were determined by GLC. Fatty acid profiles were examined for correlation to histologic findings.SA-fed mice had fewer HAN and less well developed mammary alveoli than the other dietary groups which exhibited moderate (ST) or high (CO, SF) HAN incidence. SF-fed mice had the earliest onset of any dietary group. CO-fed mice had later onset of HAN as compared to SF-fed mice but the HAN incidence was similarly high in both groups at 10 months of age.SA-fed mice were protected from development of expected numbers of HAN as compared to ST-fed mice. The reduction in HAN risk in this group was associated with reduced mammary alveolar development. Groups with high risk of HAN (SF and CO) exhibited increased amounts of 18:2 in their mammary epithelial cells and adipocytes. / Department of Biology

Thesis (M. Res.(Med.))--University of Hong Kong, 2007.

Thesis (Ph.D.)--George Mason University, 2008. / Vita: p. 221. Thesis director: Ancha Baranova. Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biosciences. Title from PDF t.p. (viewed Aug. 28, 2008). Includes bibliographical references (p. 168-220). Also issued in print.

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (leave 144-167). Also available in print.

Thesis (M.S.)--Rutgers University, 2008. / "Graduate Program in Nutritional Sciences." Includes bibliographical references (p. 53-58).

Thesis (M.Sc.)--York University, 2007. Graduate Programme in Science. / Typescript. Includes bibliographical references (leaves 72-82). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&res_dat=xri:pqdiss&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR31993