Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 176-182). Also available on the Internet.

Thesis (Ph. D.)--University of Missouri-Columbia, 2000. / Typescript. Vita. Includes bibliographical references (leaves 176-182). Also available on the Internet.

published_or_final_version / Surgery / Master / Master of Research in Medicine

Breast cancer is the most common malignant cancer in western countries. It can be classified into various types/stages according to patient age, tumor size, histological grade or hormone receptor status. Obesity is a well-known risk factor of breast tumor. Studies have shown that overweight or obese postmenopausal women have a threefold higher risk to develop breast cancer in comparison to their lean or normal counterparts. There are many mechanisms that can link obesity with breast cancer and one of the major contributors is adipokines. The main focus of this study is adiponectin. Many cellular and animal studies have illustrated the inhibitory action of adiponectin on breast cancer cell proliferation. In this study, the effect of complete loss of adiponectin expression on breast cancer development in Mouse Mammary Tumor Virus-polyomavirus middle T antigen(MMTV-PyVT)mice [PyVT(+/-)]will be investigated. Mice with [ADN(+/+)]or without [ADN(-/-)] adiponectin gene were used for comparison. It was found that PyVT(+/-)ADN(-/-)mice had earlier tumor onset time and larger tumor volume than PyVT(+/-)ADN(+/+) mice. Histological analysis has demonstrated that increased and more dispersed metastasis existed in lung tissue of PyVT(+/-)ADN(-/-)mice in comparing with PyVT(+/-)ADN(+/+)mice. The aggressiveness of adiponectin deficient tumor was preserved after implantation into immune-deficient mice. Gene expression and protein expression studies of PyVT tumor have indicated a different expression level and pattern of two important molecules: P63 and YY1. In conclusion, tumor developed under microenvironment of adiponectin deficient will give rise to a more aggressive tumor. This tumor consistsof modified genotypes and phenotypes that are permanent and can be preserved after re-implantation into immuno-compromised mice. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Background and objectives: A lot of studies proved that adipocyte fatty acid binding protein (A-FABP), an adipokine mainly expressed in adipocytes and macrophages, is the key link between obesity and inflammation which is suggested to be a therapeutic target for obesity-related diseases. Loss-of-function study was employed by using A-FABP knockout (KO) mice generated by our group to investigate role of A-FABP in high fat high cholesterol (HFHC) diet-induced obesity. Key findings: 1. Our study confirmed that HFHC diet-induced A-FABP KO mice have a significantly increased body weight when compared to the wild-type (WT) control mice. 2. Higher adiposity was the major reason for the A-FABP KO mice to be heavier than the WT controls under HFHC diet induction. 3. The marked increase of the weight of subcutaneous fat and peri-renal fat contributed to the higher adiposity of the HFHC-diet induced A-FABP KO mice when compared to the WT controls. 4. The HFHC-diet induced A-FABP KO mice significantly consumed less oxygen and produced less carbon dioxide suggesting the reduced energy expenditure but had higher weekly energy intake when compared with the WT controls, leading to higher adiposity. 5. The A-FABP KO mice were protected against HFHC diet induced glucose intolerance, insulin resistance, hyperglycemia and hyperinsulinemia when compared with the WT controls. There was also a better insulin secretion in response to glucose stimulation in A-FABP KO mice under prolonged HFHC diet induction when compared with the WT controls. 6. The A-FABP KO mice were protected against the development of hypercholesterolemia and hypertriglycemia when compared the WT controls under HFHC diet induction. However, there was no significant difference in the fasting serum free fatty acids (FFA) level among A-FABP WT and KO mice fed with standard chow (STC) or HFHC diet. 7. A-FABP KO mice were protected against isolated systolic hypertension (ISH) under HFHC diet induction. 8. The A-FABP KO mice were protected against HFHC diet-induced liver injury as indicated by a lower serum ALT level suggesting a better liver function when compared with the WT controls. 9. Under HFHC diet induction, M1 macrophage polarization was dominant in fat tissues of A-FABP WT mice but M2 macrophage polarization was dominant in fat tissues of A-FABP KO mice, suggesting an improved inflammatory status in the adipose tissue of the A-FABP KO mice when compared with the WT controls. This may also be the reason for why HFHC diet-induced A-FABP KO mice have an increased body weight but are metabolically healthier compared to their WT controls. Conclusions: A-FABP KO mice had a significant higher body weight and higher adiposity due to the reduced energy expenditure and increased weekly food intake as indicated in the metabolic cage study and the reason for metabolic healthier is due to the alleviated HFHC diet induced M1 macrophage polarization in various adipose tissues suggesting an improved inflammatory status in A-FABP KO mice comparing to the WT controls. / published_or_final_version / Medicine / Master / Master of Philosophy

Not available / text

No description available.

Both white and brown adipose tissues exhibit extensive vascularity. Increased angiogenesis in brown adipose tissue (BAT) is crucial for brown fat activation and thermogenesis in animals during cold acclimation. BAT can be similarly activated by food intake to generate heat through cellular respiration, in a process known as diet induced thermogenesis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates both pathological and physiological angiogenesis and can stimulate cell proliferation, migration, survival and vessel permeability. However, VEGF has also been shown to affect an increasing number of non-vascular cells such as skeletal muscle and kidney podocytes. The expression and function of VEGF in white and brown adipocytes are not fully understood. We have previously shown that the expression of VEGF is concomitantly regulated with skeletal muscle differentiation. Here we show that VEGF is expressed in BAT and all major white adipose depots in mice. VEGF expression was increased during white and brown adipocyte differentiation and was regulated in cultured brown adipocytes by the \(PPAR\gamma\) agonist troglitazone and by \(PGC1\alpha\) in BAT in vivo. Systemic VEGF neutralization led to brown adipocyte apoptosis in vivo, loss of mitochondrial cristae and increased mitophagy and was associated with increased inflammation and fibrosis. VEGFR2 was expressed in both brown preadipocytes and adipocytes. Blockade of VEGF signaling using anti-VEGFR2 antibody DC101 increased brown adipocyte apoptosis in vitro. VEGF also functioned as a mitogen and survival factor for brown preadipocytes. VEGF 164 and VEGF 188, isoforms that can bind heparan sulfate proteoglycans, comprise >98% of total VEGF in BAT, subcutaneous and perigonadal fat depots. Embryos that lacked VEGF 164 and 188 displayed abnormal BAT development with fewer brown adipocytes, lower levels of mitochondrial uncoupling protein 1 and Cox IV. These results indicate a direct role for VEGF signaling in brown adipocytes and preadipocytes and suggest the importance of heparan sulfate binding VEGF isoforms in BAT development. Elucidation of the role of VEGF signaling in adipocytes is vital to understanding adipose tissue expansion and activation and may reveal novel therapeutic targets for the activation of brown fat in humans.

This research evaluated photonic imaging devices for assessment of body size and shape. In aim one, laser imaging measurements of circumference, volume, and % fat were examined in 70 women. Bland-Altman analysis indicated minimal error in girth of the waist and hip by laser imaging as compared to tape measure (95% limits of agreement for waist, -2.02-2.29 cm; hip, -3.39-2.90 cm). Volume by laser imaging was related to hydrodensitometry (r = 0.99, p < 0.01), and % fat estimates were not significantly different from hydrodensitometry or dual energy X-ray absorptiometry (DXA) (3.95 ± 1.74, 32.54 ± 1.28, and 35.86 ± 1.06, respectively, p > 0.05). In aim two, 120 adults were evaluated via stereovision imaging. Stereovision was significantly related to volume by air displacement plethysmography (ADP) and hydrodensitometry (R² > 0.99, p < 0.01). However, Bland-Altman analysis indicated variations in body fat between stereovision and ADP (95% limits of agreement, -16.77-16.05 kg). Therefore, aim three was development of a prediction equation to estimate fat from 13 stereovision measurements of body size and shape. These parameters combined to form upper and lower body factor scores, which, with gender, predicted 88.6% of variation in fat mass by ADP (p < 0.01). The equation improved 95% limits of agreement from -16.77-16.05 kg via direct volume measurement to -11.47-8.45 kg compared to ADP. Finally, in aim four, a subset of 56 women from aim two was evaluated for visceral fat by magnetic resonance imaging (MRI). Visceral fat was compared to a new indicator of abdominal adiposity via stereovision imaging: central obesity depth. Central obesity depth was correlated with visceral fat, following adjustment for age and ethnicity (r = 0.75, p < 0.01). Additionally, each 1 cm rise in central obesity depth raised the odds of being in the high versus low visceral fat tertile (Odds Ratio 8.59, 95% Confidence Interval 1.33-55.63, p < 0.05). Thus, both laser and stereovision body imaging appear to be valid techniques for evaluation of body size and shape. Furthermore, central obesity depth is a promising new measurement for assessment of visceral adiposity. / text

published_or_final_version / abstract / Medicine / Master / Master of Philosophy