Obesity in adults and children is associated with increased cardiovascular mortality and morbidity. This is forecast to increase markedly in the next decade as childhood obesity is a burgeoning epidemic. Excess weight is clearly associated with insulin resistance, increased circulating triglycerides, and hypertension, all of these are related to progressive heart and liver disease. Ectopic fat deposition within organs is reported to cause lipotoxicity, which may lead to dysfunction and disease, but there have been few human studies to confirm this. This doctoral thesis set out to study the early pathophysiology of obesity in adults and children using in vivo magnetic resonance (MR) imaging and spectroscopy to assess the composition and function of the heart and liver in lean and obese individuals. The central tenet of this project was to establish and validate a clinically viable method for measuring the fat content of viscera safely and accurately, and to determine a normal range for the triglyceride content of the heart and liver. The initial study demonstrated that the heart remodels in response to weight loss, with over 20% reduction in LV mass, confirming that excess weight is genuinely a modifiable risk factor. Then, using spectroscopy, it was established that the healthy myocardium has a median triglyceride content of 0.37% (IQR 0.24% - 0.47%), which increases linearly in overweight and obese adults. Obesity, in the absence of any confounders, was also associated with a 10% reduction in cardiac contractile function. In comparison, healthy liver median lipid content was 0.67% (IQR 0.44% – 0.88%), which increased in obese adults to 2.9% (IQR 1.6% - 7.6%). There was a graded association between ectopic fat deposition in the liver and dyslipidaemia in adults, characterised by increased circulating triglycerides and reduced high-density lipoprotein. This dyslipidaemia may impair reverse cholesterol transport, and thus could be expected to exacerbate weight gain. Among obese and overweight subjects, there were some with severe steatosis and evidence of coexistent hepatic inflammation and fibrosis. To verify the accuracy of these spectroscopic measures for ectopic fat, a blinded, prospective comparison of non-invasive assessment of unselected liver disease in liver biopsy patients was completed. Liver disease presents with one or more of steatosis, fibrosis and haemosiderosis, all of which are associated with adverse cardiovascular outcomes. Fifty patients were recruited, and interobserver variability among pathologists was measured for histological reference standards for fat, fibrosis and iron deposition. MR measures of each of these metrics predicted the fibrosis, steatosis and haemosiderosis scores accurately. This enabled precise tissue characterisation of all forms of liver disease, including steatohepatitis, with one non-invasive test, to allow the diagnosis and monitoring of hepatic conditions. Lastly, all these new biomarkers of early cardiac and liver disease associated with excess weight were applied to obese and lean children, to understand whether ectopic fat played a substantial role in early life. Obese children had increased ectopic fat in their hearts and livers, as well as impaired strain, evidence of dyslipidaemia, and in some cases evidence of active steatohepatitis, comparable to adults with severe disease. The thesis therefore demonstrates that in vivo magnetic resonance techniques can be used for accurate measurement of visceral lipid content. Furthermore, there is evidence of significant ectopic fat deposition in both adults and children, with evidence of organ dysfunction, which raises the possibility that cardiovascular magnetic resonance may be of value to risk stratify obese individuals based on organ involvement. Finally, the developed methods may have broader applicability and offer a promising new method for the non-invasive diagnosis of chronic liver disease in other clinical settings.

>Magister Scientiae - MSc / The incidence of type 2 diabetes (T2D) is persistently increasing globally. T2D is associated with pancreatic β cell dysfunction and insulin resistance in peripheral tissues such as the liver and skeletal muscle. Skeletal muscle is the major site for insulin stimulated glucose uptake. Maintenance on a gestational high fat diet may programme insulin resistance. Programming is induced by the exposure of organisms to either a stimulus or insult during foetal and/or early neonatal life and alters offspring physiology and metabolism. The aim of the present study was therefore to investigate the effects of maternal diets, varying in fat content, on neonatal hepatic and skeletal muscle gene (mRNA) and protein (immunoreactivity) expression of proximal insulin signalling factors: insulin receptor alpha (IRα), insulin receptor substrate 2 (IRS2) and phosphoinositide 3-kinase-p110 alpha (PI3K-p110α), and to assess the therapeutic potential of Aspalathus linearis extract after high fat programming. Pregnant rats were randomised into groups maintained on diets with varying fat proportions: 10% (control), 20% (20F), 30% (30F) and 40% (40F) fat as energy throughout gestation. Neonatal liver and skeletal muscle were collected to determine the proximal insulin signalling expression profiles of the target factors: IRα, IRS2 and PI3K-p110α. Quantitative polymerase chain reaction (qPCR) was applied to determine mRNA expression of these target insulin signalling factors. Immunostaining of the target proteins in the liver and skeletal muscle was performed followed by relative quantification with image analysis software. Further, Aspalathus linearis (Al) extract was orally administered to mothers during gestation in the 10% (Control-Al) and 40% (HFD-Al) diets at a dose of 150 mg/kg. Body weight, food intake and blood glucose concentrations were monitored throughout gestation in mothers. Maternal diets, varying in the percentage of fat content, showed no significant effect on neonatal hepatic IR and IRS2 mRNA expression. However, hepatic PI3K mRNA expression was elevated in 30F neonates compared to 20F neonates. Skeletal muscle IR and PI3K mRNA expression were reduced in the 30F and 40F neonates compared to 20F neonates. There was reduced hepatic IRα immunoreactivity in 40F neonates compared to control and 20F neonates. Further, skeletal muscle IRα immunoreactivity was significantly reduced in 30F and 40F neonates compared to control neonates. Therefore foetal high fat programming reduced IRα in both the liver and skeletal muscle which may impair proximal insulin signalling in these glucose recipient organs. Aspalathus linearis had no effect on maternal serum insulin and glucagon concentrations. In addition, maternal caloric intake, body weight and organ weights (liver, brain and pancreas) were not altered amongst the groups. Further, HFD-Al neonates were heavier than control neonates. In conclusion, Aspalathus linearis, at a dose of 150 mg/kg, had neither harmful nor ameliorative effects in pregnant mothers fed high fat diet during gestation. In addition, Aspalathus linearis treatment had no ameliorative effects on neonates from mothers fed high fat diet throughout gestation.

No description available.

To examine the effect of diet fat type on rates of cholesterol synthesis and esterification during feeding and fasting, nine healthy male subjects were fed solid-food diets of 40% fat as predominantly either olive oil (MONO), safflower-oil margarine (POLY), or butter (SAT). At the end of each two-week diet trial, subjects were given deuterium (D) oxide orally and de novo synthesis was measured from D incorporation into cholesterol and interpreted as rates of fractional synthesis (FSR) (pools/day) into the rapidly exchangeable free cholesterol (FC) pool. Absolute synthesis rates (ASR) were calculated as the product of FSR and the FC pool. Pool size for each subject was obtained from analysis of the specific activity decay curve of an intravenous injection of 4-14C-cholesterol over nine months. Synthesis was measured over two consecutive 12-h fed periods followed by two consecutive 12-h fasted periods. Serum samples were also assayed for lathosterol concentration, an index of cholesterol synthesis. Serum cholesterol and non-HDL cholesterol concentrations were highest on the SAT diet, lowest (P<0.001) on the POLY diet and intermediate on the MONO diet, triglyceride levels were greater (P<0.03) on the SAT diet than on the POLY diet, and HDL levels were lowest (P<0.05) on the SAT diet and highest on the MONO diet. Cholesterol D enrichment and FSR during each 12-h period were greater (P<0.014) on the POLY diet than on the SAT diet; MONO enrichment and FSR were not significantly different from those on the other two diets. Similar results were obtained for rates of cholesterol esterification (P<0.001). Deuterium enrichment data suggested, and lathosterol data confirmed, that free cholesterol synthesis was greater during the fed period than during the fasted period (P<0.01); however, this could not be confirmed for rates of cholesterol esterification. Results suggest that POLY fat feeding augments de novo cholesterol synthesis without adverse effects on total serum cholesterol concentrations, and that the deleterious effects of SAT fat on serum cholesterol are not brought about by augmented de novo synthesis. Finally, the combination of deuterium incorporation and mathematical modelling produces estimates of daily cholesterol synthesis which are compatible with those invoked by more laborious techniques. / Land and Food Systems, Faculty of / Graduate

Binge Eating Disorder (BED) is a deadly, psychiatric condition which affects about 10 million people in the USA. It is characterized by discrete and recurrent binge eating episodes consisting of rapid consumption of excessive amounts of highly palatable, energy-dense food (e.g. rich in sugars and fats) within discrete periods of time. Our laboratory has been focusing on the understanding of the behavioral, metabolic, and neurobiological factors underlying BED, through the development of an animal model of binge-like eating. This model is based on a limited access schedule in which rats are exposed 1-hour/day to a high-sucrose diet (HSD) in operant conditioning self-administration boxes. However, the consummatory and metabolic outcomes of exposing rats to a high-fat diet (HFD) in the same procedure are unknown. The aim of this thesis was to test the consummatory and metabolic effects of 1-hour limited access to either a HSD or a HFD in an operant rat model of binge-like eating. For this purpose, female rats were subjects of the binge-like eating procedure by limiting access to a HSD, a HFD, or a standard Chow diet. Our results show that limiting access to either a HSD or a HFD promoted binge-like eating as compared to control Chow diet. HSD binge-like eating was based on a true increase in the amount of food consumed, that is, an increased eating rate. Such suggests increase in palatability and a decrease in the home-cage standard chow intake, likely due to a negative contrast effect. Conversely, binge-like eating of the high-fat diet resulted from passive energy consumption due to the high energy-density of the food. Also, HFD binge-like eating was accompanied by neither increased eating rate nor rejection of the home-cage chow. Moreover, while HSD rats consumed less energy than HFD rats, the former were more energy efficient and gained more body weight than the latter. These results provide information on how the quality of food can deeply influence the behavioral and metabolic outcomes of binge-like eating. / 2022-06-07T00:00:00Z

As obesity and obesity-associated diseases become more prevalent in western societies, new methods to promote weight-loss and protect patients from the dangerous consequences of excess adipose tissue are needed. While both researchers and clinicians previously turned to chemical uncouplers for many decades to create a negative energy balance and thus promote weight-loss, these compounds proved to be extremely dangerous treatment options, even when taken in mild dosages. Substances like 2-4 dinitrophenol (DNP), were able to significantly induce weight loss, however many life-threatening conditions such as fatal hyperthermia are commonly attributed to these uncoupling agents. Recently, with the discovery of natural brown/beige fat reservoirs in humans, many members of the medical community have become heavily invested in the targeting of more localized, less systemic uncoupling tissues. The action of UCP-1 in human thermogenic adipose introduces an opportunity to harness a natural, yet futile cycle, and hence boost a patient’s basal metabolism without ultimately compromising their long-term health. Many challenges remain before such a treatment is viable, including deciphering the biochemical pathways that induce brown fat thermogenesis. It appears that several uncoupling signals may govern the genetic programs that lead to this thermogenic activity, and the "browning" of white adipose stores in humans. Particularly in the last ten years, many studies have uncovered new components of the thermogenic program by ablating target genes in mice. While a direct pathway of thermogenic activation does exist when subjects are placed in a cold environment, a successful, high-adoption, anti-obesity treatment through a thermogenic regimen will likely involve a gene-therapy or protein-based biopharmaceutical intervention. It is conceivable that thermogenic manipulation could play a significant role in the battle against obesity and obesity-associated diseases, however a significant intellectual breakthrough in appetite suppression and/or appetite management (i.e. a successful intervention of the orexigenic and anorexigenic physiological pathways) could in theory supplant this approach.

This thesis explores the Hicoria genus and focuses on the Stuart variety of pecan tree. Experimentation yielded the ash constituents, fats, fat constants, crude fiber, protein, and sugar in shelled pecan samples.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Remarkably, animals can develop a strong preference for sugar even if they lack a functional sweet taste receptor, pointing to a detection mechanism independent of the sense of taste. Here, I demonstrate that a specific population of neurons in the brainstem is activated via the vagus nerve to create preference for sugar. These neurons are stimulated in response to sugar but not to artificial sweeteners, and are activated by direct delivery of sugar to the gut. By functional imaging of vagal neurons activated by intestinal delivery of glucose, we molecularly identified the glucose-specific transducer, SGLT1, in the gut. Next, I engineered animals where synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioral preference for sugar. Moreover, I demonstrated that these sugar preference neurons are genetically marked by enriched expression of the gene Penk, and that hijacking this circuit with a designer drug can condition preferences to initially non-preferred stimuli. These findings uncover a gut-brain circuit mediating sugar’s highly appetitive effects. Intriguingly, I discovered that dietary fat is also sensed via a post-ingestive gut-to-brain pathway, and engages the same preference-creating brainstem circuit as sugar. My results unveil an elegant convergent system where sugar and fat, which are likely sensed separately by specific gut transducers, share a unified gut-brain preference circuit for reinforcing their consumption. In the bigger picture, my findings suggest that it may be possible to develop a new class of chemicals that target the gut-brain preference axis to moderate the cravings for sugar and fat.

Dercum's disease, also known as adiposis dolorosa, is a rare disease characterized by the accumulation of painful subcutaneous deposits of mature adult fatty tissue around the thighs, trunk, and upper arms and usually in a multifocal distribution. We are reporting an unusual presentation of Dercum's disease, presenting as a single painful, erythematous lesion around the left hip in a 71-year old postmenopausal woman. This report emphasizes the unusual presentation of adiposa dolorosa with a new modality for therapy. A summary of the major clinical associations, diagnostic challenges, and treatment modalities are also included in this manuscript. Wiley Periodicals, Inc.

No description available.