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Background - Healthy perivascular adipose tissue (PVAT) exerts an anticontractile effect in response to various vasoconstrictor agonists and this is lost in obesity. A recent study reported that bariatric surgery reverses the damaging effects of obesity on PVAT function. However, PVAT function has not been previously characterised following weight loss induced by caloric restriction, which is often the first line treatment for obesity. This study investigated the mechanisms by which PVAT modulates vascular tone in health and how these are altered in animal models of obesity and diet-induced weight loss. Methods - Male Sprague Dawley rats were fed a 45% fat diet ad libitum for 16 weeks to induce obesity, they were then randomly allocated into two groups; obese rats maintained on the 45% fat diet and weight loss rats that were subjected to 50% caloric restriction for a further four weeks. A weight maintenance group was also established where a cohort of weight loss rats were provided with 70 kcal/day for a further four weeks at the end of the caloric restriction period. A control group was also provided with a 10% fat diet during the 20 week period. The effect of PVAT on the contractility of isolated mesenteric arteries in response to norepinephrine in the presence of pharmacological tools was investigated by wire myography Changes in the PVAT environment were assessed also using western blotting, immunohistochemistry and assays of secretion. Results - PVAT from healthy control rats elicited an anticontractile effect in response to norepinephrine through release of relaxing factors, one of which was nitric oxide. The anticontractile effect was abolished in diet-induced obesity through a mechanism involving local inflammation and reduced nitric oxide bioavailability within PVAT. In addition, reduced KCNQ expression and enhanced COX activation contributed to the loss of anticontractility. Four-week caloric restriction did not restore PVAT anticontractile capacity. However, sustained weight loss led to restoration of PVAT anticontractile function associated with restoration of adipocyte size, reduced inflammation and increased nitric oxide synthase expression. Sustained weight loss and the restoration of PVAT function was associated with reversal of obesity-induced hypertension and normalisation of adipokine levels, including leptin and insulin. Conclusions - Sustained weight loss reverses obesity-induced PVAT damage through a mechanism involving reduced inflammation and reduced nitric oxide bioavailability. Reduced KCNQ activity and enhanced COX activation also contribute to the obesity-associated loss of PVAT anticontractile effect. These data reveal the beneficial effects of weight loss induced by dietary restriction on PVAT function and identify several potential targets for the treatment of PVAT dysfunction associated with obesity.

Pasture feeding depresses adipose tissue development in beef cattle whereas grain feeding, enhances adipogenesis. Therefore, we hypothesized that specific fatty acids would differentially affect lipogenesis in explants of bovine subcutaneous (SC) and intramuscular (IM) adipose tissues. Angus steers were harvested at 12, 14, and 16 mo of age, and IM and SC adipose tissue explants from the 8-11th thoracic rib region were dissected and cultured in media. Media contained no supplemental fatty acids or 40 microM of five fatty acids, stearic acid (18:0), oleic acid (18:1 n-9), trans-11 vaccenic acid (18:1 trans-11), conjugated linoleic acid (CLA, 18:2 trans-10, cis-12), or alpha-linolenic acid (18:3 n-3). After 48 h of culture, lipogenesis using [U-14C]glucose and [1-14C]acetate was measured. Lipogenesis from glucose decreased between 12 and 16 mo of age in SC adipose tissue (from 8.9 to 4.0 nmol per 2 h per 100 mg; P = 0.001) and IM adipose tissue (from 4.4 to 2.7 nmol per 2 h 100 mg ; P = 0.08). Lipogenesis from acetate did not change over time in SC adipose (approximately 56 nmol per 2 h per 100 mg; P = 0.23), but increased over time in IM adipose tissue (from from 11.3 to 17.1 nmol per 2 h 100 mg; P = 0.02). Oleic acid increased lipid synthesis from glucose 125 percent (P = 0.04) in IM adipose tissue, whereas stearic acid and trans-vaccenic acid increased lipogenesis from glucose in SC adipose tissue by approximately 50 percent (P = 0.04). In SC adipose tissue only, trans-vaccenic and increased, lipogenesis from glucose (P < 0.02). Lipogenesis from acetate was depressed by CLA nearly 50 percent in SC adipose tissue. PPARγ gene expression increased between 14 and 16 mo of age in control IM and SC adipocytes. The increase in activity was also observed in AMPK gene expression. C/EBPβ and SCD gene expression did not increase in control samples until 16 mo of age. SC adipose tissue responded to stearic acid by increased GPR43 and AMPK gene expression at 12 mo of age. We conclude that fatty acids differentially affect lipid synthesis in IM and SC adipose tissues, which may account for the effects of pasture and grain feeding on adiposity.

We hypothesized that subcutaneous (s.c.) adipose tissue would differ in monounsaturated (MUFA) and saturated fatty acid (SFA) composition among different depots throughout a beef carcass. To test this, 50 carcasses from a variety of breed types and backgrounds were sampled. External fat samples were collected from eight different carcass locations: round, sirloin, loin, rib, chuck, brisket, plate and flank. Samples were used to provide information on slip points, fatty acid composition and MUFA:SFA ratios. Lipids were extracted from s.c. adipose tissue by a modified chloroform:methanol procedure, and fatty acid composition and slip points were measured. The brisket was significantly lower in palmitic (16:0) and stearic (18:0) acid than the other seven sampling sites (P = 0.001). The brisket demonstrated the highest values of MUFA (P = 0.001) with the exception of possessing the lowest value of transvaccenic (18:1t11) acid (P = 0.002). There were also significant differences in the amounts of PUFA among the eight sampling sites. The lowest values were from the brisket with a mean of 25.1. The flank had the highest slip point with a mean of 39.0 (P < or = 0.001). There was a high negative correlation shown between palmitoleic and stearic acid (R2 = 0.827). The brisket displayed the highest values for MUFA:SFA ratios (P = 0.001), whereas the flank was the lowest. Due to the significant differences amongst fat depots within bovine carcasses in their fatty acid composition we conclude that substantial differences exist across fat depots.

Brown adipose tissue (BAT) is a unique organ in existence in mammals. It can induce non-shivering thermogenesis to control body temperature and energy balance through the expression of uncoupling protein 1 (UCP1). In our study, we aimed to evaluate the prevalence of BAT, as detected by fluorine 18-fluorodeoxyglucose (18F-FDG) positron emission tomography combined computer tomography (PET/CT), in a Hong Kong Chinese population. We also assessed the influence of age and sex to BAT in Hong Kong Chinese population. We also determined the factors associated with it, in particular, its relationship with overweight and other metabolic disorders such as diabetes mellitus. We analyzed 1765 consecutive 18F-FDG PET-CT scans of 1442 Chinese for the presence of BAT. Comparison of the variables between positive and negative BAT scans was performed using Student’s t-test. The association between maximum value of standardized uptake value (SUVmax) and variables were explored by Spearman correlation. The predictors of observed BAT were analyzed by multiple logistic regression to determine the significant predictors of positive BAT. The relationship between the monthly numbers of subjects with BAT and the respective mean monthly outdoor temperature was evaluated by Pearson’s correlation co-efficient. P < 0.05 was considered to be statistically significant. Brown adipose tissue was detected in 66 out of 1442 subjects (4.6%). BAT was significantly more commonly found in younger (43.7±13.5 years old vs. 61.4±14.2 years old, P<0.001) and female (59% vs. 46%, P<0.05) subjects. BAT also existed more frequently in subjects with lower body mass index (BMI) (21.2±3.1 kg/m2 vs. 22.4±3.7 kg/m2, P<0.01) and lower blood glucose level (5.9±0.9 mmol/L vs. 6.4±1.6 mmol/L, P<0.01). Also, BAT was detected only in subjects with no history of diabetes meallitus (DM) (0 vs. 10%, P<0.01). Moreover, lower outdoor temperature (21.6±4.6。C vs. 23.4±4.7。C, P<0.005) resulted in higher prevalence of detected BAT. In the multiple logistic regression test, age and mean monthly temperatures were the significant independent predictors of the presence of BAT (P< 0.001 and P=0.001). Age was also significantly correlated to SUVmax (P< 0.001). The monthly prevalence of positive BAT correlated negatively with mean monthly temperature by Pearson’s correlation (r = -0.79; P<0.01). To summarize, BAT was more commonly found in young, female subjects with lower BMI and blood glucose levels, and non-diabetes subjects. Age was the most important factor associated with the prevalence of BAT in humans. Lower outdoor temperature in winter can increase the prevalence of BAT even in Hong Kong’s sub-tropical climates. Also, there was an association of BAT with normal BMI (<=23) and lower blood sugar levels supporting the notion that BAT may potentially be a therapeutic target for obesity and diabetes. / published_or_final_version / Diagnostic Radiology / Master / Master of Philosophy

Thesis (M.S.)--Florida State University, 2003. / Advisor: Dr. J. Michael Overton, Florida State University, College of Human Sciences, Dept. of Nutrition, Food and Exercise Sciences. Title and description from dissertation home page (viewed Aug. 27, 2004). Includes bibliographical references.

Thesis (Ph. D.)--University of Chicago, Committee on Human Nutrition and Nutritional Biology, August 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Impact of the chromatin remodeller SMARCAD1 on murine intestinal intraepithelial lymphocyte and white adipose tissue biology. Chromatin remodelling factors use the energy of ATP hydrolysis to drive the movement of and/or affect molecular changes to the nucleosome. One such factor, SMARCAD1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A containing DEAD/H box 1), has been previously shown to restore heterochromatin at the replication fork in vitro. This project aimed to assess the impact of SMARCAD1 on mammalian biology, utilising an animal model in which the catalytic ATPase domain of murine SMARCAD1 had been deleted using Cre/lox technology. Preliminary results had implicated SMARCAD1 in adaptive-immunity and white adipose tissue biology, and SMARCAD1 expression in these tissues/cells was confirmed by tissue-panel western blot. This project therefore aimed to build on these results to understand better the impact of SMARCAD1 on adaptive immune development and white adipose tissue biology. In addition, fewer than expected viable Smarcad1-/- homozygous offspring were produced during Smarcad1+/- x +/- matings, which both confirmed the observation from a previous knockout model of Smarcad1, and limited the number of knockout animals available for this study. Investigation of systemic B- and T-cells in the bone marrow, thymus and spleen had previously suggested there was no significant defect in adaptive immune development in Smarcad1-/- mice, however a tissue-specific and age-related loss of intra-epithelial (IEL) T-lymphocytes was found in the small intestine by flow cytometry. Analysis by qPCR of duodenal RNA suggested that differentiation rather than inflammation may underpin any loss-of-IEL phenotype, although further examination of cell-proliferation and crypt/villus anatomy by EdU incorporation and immunofluorescence revealed no overt cell-anatomical or proliferative difference in the knockout mice. The requirement for large numbers of aged mice made further investigation of the intestinal IEL phenotype logistically prohibitive. The reduction of epididymal white adipose tissue (eWAT) size had also been observed in male Smarcad1-/- mice, and serum from these mice showed elevated triglyceride (TG) and free fatty acids (FFA) levels. Transcriptomic analysis by RNA-seq of whole-WAT revealed an elevation in macrophage-related markers in knockout mice, which was confirmed by flow cytometry. As a number of reports have implicated SMARCAD1 in stem cell biology, putative adipose stem cells were isolated from +/+ and -/- mice by FACS and used for adipogenic differentiation assays ex-vivo In parallel, mouse embryonic fibroblasts from +/- and -/- mice were also assayed for adipogenic differentiation. While no significant differences in adipogenesis were observed, Smarcad1-/- mice challenged with a (60%) high fat diet did show increased weight gain over +/+ mice, and measurements of adipocyte size and cell cycle/cell proliferation analysis suggested hyperplasia rather than defects in adipogenesis may drive any WAT-related pathology in these mice.

Leptin, a 16kDa protein, is secreted primarily by adipose tissue. Its effects are pleiotropic, with known roles in body mass regulation, haematopoiesis, immune function and reproduction. Studies of the leptin system in females were undertaken to complement existing animal and human studies. Serum leptin levels were found to increase in the luteal phase of the menstrual cycle raising the possibility of a role for leptin at the time of implantation. RT-PCR studies showed that leptin receptors were expressed in the human endometrium throughout the menstrual cycle. In these preliminary studies, these receptors appeared to be functional in response to leptin; increasing proliferation and decreasing TNF-a production in cultured endometrial cells. This implies that leptin has a local effect at the level of the endometrium. Many cytokines are bound to proteins in serum; a proportion of this binding can be attributed to a soluble cytokine receptor. Soluble receptors and binding proteins have a variety of roles, acting as scavengers, carriers, agonists and antagonists. In order to investigate this phenomenon in the leptin system, a radio-receptor assay was developed to measure leptin-binding activity (LBA). The leptin receptor has an extracellular domain that is common to all isoforms and therefore, LBA may also reflect the binding parameters of cell surface receptors. Serum leptin levels of LBA were found to be low at birth, high in early childhood, to fall steadily through puberty and remain at the post-pubertal levels throughout adult life. This suggests that leptin and LBA has an important role in the initiation of puberty. There was no significant variation in LBA during the menstrual cycle. Several single nucleotide polymorphisms (SNP) exist in the leptin receptor gene. Studies of two of these SNPs, GLN223ARG and LYS656ASN, present in the extracellular domain of the receptor were undertaken to assess if genetic changes are associated with differences in phenotype or effect ligand binding. Homozygosity of the G allele of GLN223ARG is associated with lower fat mass, BMI and leptin levels in postmenopausal Caucasian females. This polymorphism changes the binding characteristics of the receptor, with a higher LBA being associated with homozygosity of the G allele. This suggests that the actual binding of leptin to its receptor may be an important factor in the regulation of body weight and adiposity.