Thesis--University of Oklahoma. / Bibliography: leaves 125-129.

Thesis (M. Nurs.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 95-103).

Thesis (Ph. D.)--Marshall University, 2003. / Title from document title page. Document formatted into pages; contains p. ix, 130 p. and illustrations. Includes abstract. Includes bibliographical references (p. 93-128).

Obesity is associated with numerous co-morbidities, such as chronic low-grade inflammation, oxidative stress, insulin resistance, cardiovascular disease, and some cancers. However, the role of estrogen in the susceptibility to obesity and its co-morbidities is not clear. To determine the role of estrogen in the above morbidities, we used C57BL/6J mice (15/group): 1)males 2)nonovariectomized females (novx) 3)ovariectomized females (ovx) and 4) ovariectomized females supplemented with estrogen (ovx-E), which were randomized to receive a 30% calorie-restricted, low-fat or high-fat diet. Our results showed that male and ovx-female mice were more susceptible to obesity compared to novx-female and ovx-female+E mice. Specifically, we observed that estrogen protected novx-female and ovx-female+E mice from adiposity and glucose intolerance by decreasing adipocyte size and key adipogenic and lipogenic mRNA expression levels. Further experimentation established that estrogen decreased abdominal adiposity by decreasing the number of large adipocytes. Our findings implied that estrogen stimulated lipolysis in novx-female and ovx-female+E mice. Additionally, the enlarged adipocytes observed in the male and ovx-female mice were accompanied with crown-like structures surrounding necrotic adipocytes and F480+ macrophages and elevated mRNA expression levels of CD68, IL6, and TNF[alpha]. Lastly, male and ovx-female mice exhibited liver steatosis, elevated serum ALT levels, and increased insulin resistance. To determine if there were sex differences in oxidative stress, we showed that estrogen protected the novx-female and ovx-female+E mice from adipose tissue oxidative stress as evidenced by fewer γH2AX stained nuclei and lower iNOS, P47x, GP90x, but higher catalase mRNA levels. In order to further understand the role of estrogen in adipocyte inflammation, we differentiated 3t3L1 pre-adipocytes in charcoal-stripped FBS +/- 1nM estrogen. Our findings mimicked our in vivo results; the presence of estrogen significantly decreased adipogenesis and down regulated IL6, TNF[alpha], and GP90x in 3t3L1 adipocytes. Additionally, using 4-hydroxytamoxifen, we demonstrated that the protective effects of estrogen on IL6 and TNF[alpha] mRNA expression were blocked; suggesting that estrogen could mediate its anti-inflammatory effects through ERα. In conclusion, this dissertation demonstrates that estrogen protects female mice from obesity-associated inflammation, oxidative stress, and insulin resistance by altering adipocyte morphology possibly through ER[alpha]. / text

Malignant melanoma is cancer arising from melanocytes that have acquired the ability to metastasize and colonize secondary organs such as the lungs, liver, and brain. According to the Melanoma Research Foundation, malignant melanoma is the most rapidly increasing type of cancer with an annual incidence increase of ~ 4% despite the therapeutic and medical breakthroughs in cancer treatment. Melanoma is the most common cancer in young adults ages 20-30, and it is the leading cause of cancer death in females ages 25-30. Non-modifiable risk factors include age, gender, and inherited predisposition to moles. As for modifiable risk factors, exposure to UV rays from the sun is well-established, but obesity has recently emerged as a factor through recent epidemiological and animal studies. Our results showed that obesity modulates the expression of the transcription factor Snai1, which has been shown to be a key gene in the regulation of the Epithelial-to-Mesenchymal Transition (EMT). Serum from obese ob/ob mice, as well as conditioned media from 3T3L1 adipocytes, increased the invasive ability of melanoma cells and the expression of the transcription factor Snai1. Yet, the cytokine IL-6 may not be a critical component of obesity-mediated B16BL6 melanoma cell invasiveness. / text

The purpose of the present study is to examine group differences between Hispanic adolescent females participating in a mental health focused obesity intervention and those in a treatment-as-usual (control) condition on Body Mass Index (BMI), self-esteem, coping strategies, and binge eating symptoms. The intervention teaches skills useful in managing emotions and situations impacting weight. Treatment-as-usual entails attending weight management clinic appointments. Participants will be obese Hispanic adolescent females attending a weight management clinic at a children's hospital in Texas. BMI will be taken and self-report questionnaires addressing self-esteem, coping strategies, and binge eating symptoms will be completed by participants pre- and post-intervention. Analysis of covariance, controlling for scores pre-intervention, will be utilized to examine group differences. It is hypothesized that participants in the ACES PLUS condition will demonstrate greater gains in self-esteem, coping strategies, and decreased binge eating symptoms and BMI relative to their treatment as usual counterparts. Implications for future research include additional focus on skills-building addressing psychosocial challenges faced by obese adolescent females in the treatment of pediatric obesity within this population. / text

Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ER alpha) positive, postmenopausal patients. It has also been correlated with elevated levels of inflammation, which can stimulate adipose tissue aromatase expression and subsequent estrogen production. Given that obese patients have a lower response rate to aromatase inhibitor treatment and greater mammary tissue aromatase levels, it was hypothesized that obesity promotes ER alpha positive postmenopausal breast cancer progression in part via an inflammation-induced increase in mammary tissue aromatase expression and ER alpha activity. These studies utilized an in vitro model of obesity in which cultured cells were exposed to postmenopausal breast cancer patients’ serum samples, pooled by body mass index category (Obese (OB): ≥30.0 kg/m2; Normal weight (N): 18.5-24.9 kg/m2). OB versus N patient sera induced greater breast cancer cell (BCC) aromatase expression, as well as higher ER alpha activity and cell viability in the presence of testosterone, the substrate for aromatase. Pre-adipocytes exposed to OB versus N patient sera also indirectly stimulated greater BCC aromatase expression, ER alpha activity, and viability. A retrospective review of breast cancer patient data demonstrated that daily use of non-steroidal anti-inflammatory drugs, which inhibit cyclooxygenase-2 (COX-2) activity, is associated with reduced ER alpha positive breast cancer recurrence in obese and overweight women. The mechanisms mediating this effect were examined using the same in vitro model. Exposure to OB versus N patient sera stimulated greater macrophage and BCC COX-2 expression and prostaglandin E2 production, leading to enhanced pre-adipocyte aromatase expression. These OB patient sera-induced effects were further linked with greater BCC ER alpha activity, proliferation, and migration in the presence of testosterone, and these differences were eliminated or reduced with aromatase inhibition. Based on these findings, prospective studies designed to examine the clinical benefit of NSAID use in obese ER alpha positive postmenopausal breast cancer patients are warranted. Additional obesity-associated mechanisms that may also promote breast cancer progression were also explored, including enhanced cross-talk between non-genomic ER alpha and growth factor signaling pathways, reduced estrogen receptor beta expression, and resistance to chemotherapy. Finally, the impact of obesity on tumor incidence and characteristics in the MMTV-Wnt1 mouse model of mammary carcinogenesis was explored. / text

published_or_final_version / Pharmacology and Pharmacy / Master / Master of Philosophy

Obesity features increased accumulation of fat in the body and results in adverse health consequences, including type II diabetes mellitus and cardiovascular diseases. The global epidemic of obesity and lack of effective treatments call for the search of new anti-obesity medication. Activation of prostaglandin receptor subtype 4 (EP4) had been shown to produce potent anti-inflammatory effect and possibly induce brite adipocytes to increase energy expenditure, both of which can potentially ameliorate obesity. The purpose of this dissertation is to characterize the metabolic phenotypes of EP4 receptor in mice and to elucidate whether administration of CAY10580, a selective EP4 agonist, could protect against obesity and its related complications. The experiments were carried out on diet-induced obese mice and EP4 knockout mice. Anthropometric measurement, glucose and insulin tolerance test, indirect calorimetry, quantitative real-time PCR, plasma analytes measurement and histological studies were performed. The findings revealed that EP4 activation by CAY10580 prevented high-fat diet fed mice from becoming obese, but it did not exhibit a curative effect in reversing obesity in mice. Activation of EP4 by CAY10580 suppressed body weight gain and adiposity in high-fat diet fed mice by reducing the weight of epididymal, subcutaneous and peri-renal white adipose tissues, inter-scapular brown adipose tissue and liver. The lower adiposity resulted in improved glucose and insulin sensitivity and lower plasma leptin level. The cause of reduced adiposity by EP4 activation is not due to changes in energy intake, obligatory energy expenditure, locomotor activities, adaptive thermogenesis and lipolysis. EP4- mediated reduction in adiposity was characterized by smaller adipocyte size and greater proportion of small adipocytes in subcutaneous white adipose tissue. Furthermore, mice deficient in EP4 also showed reduced adiposity at epididymal, subcutaneous and peri-renal white adipose tissues, and inter-scapular brown adipose tissue. The reduced adiposity in EP4 deficient mice was associated with impaired cold intolerance. Taken together, EP4 activation is effective in preventing obesity and relieving obesity-associated glucose and insulin tolerance, and EP4 might play an essential role in adiposity maintenance through the modulation on adipocyte development. / published_or_final_version / Pharmacology and Pharmacy / Master / Master of Medical Sciences

Background: The epidemic of childhood obesity is of increasing public health concern, with major implications for long-term health. Prevention strategies are urgently needed. Most of the evidence concerning risk factors for childhood obesity comes from observational studies, mainly from Western populations. In the West, socio-economic position (SEP) is often associated with potential risk factors and with childhood obesity, making these observational studies open to residual confounding. Evidence from a setting with a different confounding structure can be valuable in disentangling whether associations observed in Western settings reflect potentially reversible causal effects of risk factor or are confounded by SEP. Objectives: This thesis took advantage of a large (n=8327), population-representative Chinese birth cohort from a developed non-Western setting, Hong Kong, where the confounding structure between potential risk factors and childhood obesity is different, to examine the association of four modifiable risk factors (mode of delivery, the timing of solid food introduction, type of child care and dairy product consumption) with adiposity from infancy to early puberty. Methods: Adiposity from infancy to early puberty was proxied by age- and sex-specific body mass index (BMI) standardized scores (z-scores) from 3 months to 13 years, relative to the 2006 World Health Organization (WHO) child growth standards for 0-5 years and the 2007 WHO growth reference for 5-19 years. Overweight (including obesity) was defined according to International Obesity Task Force cut-off. I compared three marginal models (maximum likelihood estimation, generalized estimating equations and quantile regression) to ascertain the optimal way of modeling the population-averaged association of early life risk factors with BMI z-score because of the complex data structure with inevitably some missing data. All three methods were used to examine the adjusted associations of mode of delivery and the timing of solid food introduction with BMI z-score from infancy to early puberty and with overweight (including obesity) from early childhood to early puberty. Multivariable linear and logistic regression were used to examine the adjusted associations of the type of child care at 6 months, 3 years, 5 years and 11 years with BMI z-score and overweight (including obesity) at 13 years, and the association of dairy product consumption at 11 years with BMI z-score at 13 years. Results: My analyses were robust to the choice of marginal model. Mode of delivery, the timing of solid food introduction and dairy product consumption were not associated BMI z-score or overweight (including obesity), but informal child care was associated with higher BMI z-score and overweight at early puberty. Conclusions: In this population-representative birth cohort from an understudied non- Western developed setting with little patterning of childhood adiposity by SEP, informal child care (by family members and/or in-home employed help) may be a target for intervention. Conversely, cesarean section, early introduction of solid food and lack of dairy product consumption do not appear to be contributing to the current obesity epidemic. Non-replication in a different context suggests some observed associations in the West may be indicators of residual confounding rather than of causality. / published_or_final_version / Public Health / Doctoral / Doctor of Philosophy