published_or_final_version / Zoology / Master / Master of Science

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No description available.

PURPOSE: Obese women have increased rates of metabolic diseases compared to those of healthy weight status. Additionally, African-American (AA) women have higher rates of metabolic disease compared to Caucasian (CA) women. Metabolic inflexibility is the inability to adjust substrate oxidation in response to dietary intake; potentially leading to weight gain and the development of metabolic disease. Few studies have investigated the impact of weight status and/or ethnicity on the metabolic response of women to a single high fat meal. An acute unfavorable metabolic response may contribute to the higher incidence of metabolic disease among not only obese, but also AA women. Therefore, the purpose of this study was to determine the impact that weight status (lean vs. overweight/obese) and/or ethnicity (CA vs. AA) has on metabolic health in women in response to a single high fat meal. METHODS: CA (n= 15; age=26.27±5.65 yrs; BMI=30.72±11.92kg/m2) and AA (n= 12; age=26.75±6.65yrs; BMI=28.32±6.91kg/m2) women consumed a high fat shake (1062 calories, 56% fat). Blood was drawn and resting energy expenditure (REE) and substrate oxidation (estimated using indirect calorimetry) were assessed at baseline/fasted (T1), 120 minutes post-shake, (T2) 240 minutes post-shake (T3). RESULTS: Lipid and carbohydrate oxidation significantly increased among all women in response to the high fat meal (p<0.01). Significant increases in fat oxidation were seen from T1-T2 for all women (CA lean: +57.9±24.5%; CA overweight/obese: +30.2±11.8%; AA lean: +10.2±18.1%; AA overweight/obese: +40.6±52.6%; p<0.01). Among the CA women only, CA lean women displayed a significantly higher increase in fat oxidation in response to the meal compared to CA overweight/obese women, but there were no differences among lean and overweight/obese AA women. Similarly, weight status influenced changes in apolipoproteins after consuming the high fat meal among CA women, but not AA women. CONCLUSIONS: CA lean women displayed the most metabolic flexibility in response to the high fat meal. A metabolic system that is less able to respond to metabolic stimuli such as a high fat diet (as noted in all groups compared to lean CA women) may play a role in the increased metabolic disease prevalence among obese and AA women.

Call number: LD2668 .T4 1986 N484 / Master of Science / Animal Sciences and Industry

Cortisol is one of the stress hormones produced as a result of stimulus to the hypothalamus triggering the hypothalamic-pituitary-adrenal axis (HPA).The result of cortisol production after this trigger is to return the body and its relevant systems back to homeostasis. This is a desired state of physiologic equilibrium in the body. A number of physiological and environmental conditions trigger the HPA pathway. This includes hypoglycemia (low blood sugar), dehydration (low blood volume), exercise, which are considered stress triggers, and changes to the circadian cycle. It is no wonder then that extreme diet and exercise can impact the HPA axis due to the stress caused by such activities or lifestyle choices. Fortunately, the production of cortisol in response to exercise has been extensively studied. Generally, studies have shown that the level of plasma cortisol levels increase proportionally during high intensity exercise, while a general decrease has been observed during moderate or low intensity exercise (Davis & Few, 1973). In addition, several scientific texts provide substantial information on the correlation between hypoglycemia and cortisol synthesis. This information in addition to other sources has proven useful for assessing the effect of extreme dieting on cortisol production. The aim of this thesis is to expand on the changes in cortisol caused by extreme exercise and diet as well as elaborate on the physiological effects that these cortisol levels in turn may have.

Diabetes is a complex group of metabolic disorders with genetic, immunological, and environmental etiologies. Decades of diabetes research have elucidated many genetic drivers of normal islet function and dysfunction. Furthermore, genome wide associated studies (GWAS) have discovered that most diabetes susceptibility loci fall outside of coding regions, which suggests a role for noncoding elements in the development of disease. This highlights our incomplete understanding of the islet regulome and suggests the need for detailed functional analyses of noncoding genes to precisely determine their contribution to diabetes susceptibility and disease progression. Transcriptome analyses have revealed that the eukaryotic genome is pervasively transcribed. Strikingly, only a small proportion of the transcriptome is subsequently translated into protein; the majority is made up non-protein coding RNAs (ncRNAs). The most abundant class of these ncRNAs are called long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 nucleotides that lack protein-coding potential. The establishment of lncRNAs, once dismissed as genomic dark matter, as essential gene regulators in many biological processes has redefined the central role for RNA in cells. While evidence suggests a role for lncRNAs in islets and diabetes, in vivo functional characterization of islet lncRNAs is lacking. For my thesis project, I sought to understand the lncRNA regulatory mechanisms that promote pancreas development and function. We conducted comparative transcriptome analyses between embryonic mouse pancreas and adult mouse islets and identified several pancreatic lncRNAs that lie in close proximity to essential pancreatic transcription factors. One of the candidate lncRNAs, Pax6 Upstream Antisense RNA (Paupar), mapped near Pax6, a gene encoding an essential pancreatic regulatory protein. We demonstrate Paupar is enriched in glucagon-producing alpha cells where it promotes the alternative splicing of Pax6 to an isoform required for activation of essential alpha cell genes. Consistently, deletion of Paupar in mice resulted in dysregulation of Pax6 alpha cell target genes and corresponding alpha cell dysfunction. These findings illustrate a distinct mechanism by which lncRNAs can contribute to cell-specific regulation of broadly expressed transcription factors to coordinate critical functions within a cell.

O efeito de refeições ricas em carboidratos e lipídeos sobre a sensibilidade à insulina foi avaliado. Além disso, investigou-se o conteúdo da proteína GLUT4 em músculo esquelético e tecido adiposo branco. Ratos foram realimentados por 1, 2, 4 e 6 horas com: refeição balanceada (B); rica em carboidrato (C) e rica em lipídeo (L). O índice glicose/insulina revelou que C e L apresentavam resistência à insulina 2 horas após o início da ingestão. No teste de tolerância à insulina, uma redução (~47%) na sensibilidade à insulina foi observada em C após 2 e 4 horas de realimentação. O teste de tolerância à glicose confirmou a resistência à insulina em C e L após 2 horas de ingestão. Não houve alteração no conteúdo de GLUT4, nos momentos em que se verificou alteração na sensibilidade à insulina. Tais resultados indicam que, em ratos, refeições não balanceadas (alto teor de carboidrato ou alto teor de lipídeo), induzem menor sensibilidade à insulina 2 horas após o início da ingestão, e este fenômeno não envolve alterações no conteúdo de GLUT4 nos tecidos avaliados. / The effect of high carbohydrate and fat meals on the insulin sensitivity was evaluated. Furthermore, it was investigated the content of GLUT4 protein on the skeletal muscle and white adipose tissue. Rats were refed for 1, 2, 4 and 6 hours with: balanced meal (B); high carbohydrate meal (C) and high fat meal (L). The glucose/insulin index shows that C and L meals exhibited insulin resistance after 2 hours of ingestion. In the insulin tolerance test, a reduction (~47%) in the insulin sensitivity was observed in C group after 2 and 4 hours of refeeding. The glucose tolerance test confirmed the insulin resistance in C and L-groups after 2 hours of ingestion and such phenomena did not involve alterations in the GLUT4 content on both skeletal muscle or white adipose tissue.

Animal models have yet to characterize alterations in body composition, wheel running activity, food intake, and neuroendocrine parameters, in chronic food restriction. This study investigated changes in these measures in food restricted rats, with and without access to running wheels, over four weeks. The data demonstrated that upon initiation of food restriction IGF-1 reductions paralleled loss of lean tissue while leptin levels were rapidly reduced which paralleled losses in body fat. Further, a lower limit threshold of body fat was identified, below which the correlation between leptin and fat mass was disrupted. Lastly, a decrease and plateau in body mass was mirrored by an increase and plateau in voluntary wheel activity in the food restricted population. The data suggest that there is a tight biological link between hyperactivity and body mass and that adequate nutritional support might attenuate the drive for obligate exercise even before weight is fully restored.

In order to elucidate how uncoupling protein 2 (UCP2) influences pancreatic β cells and glucose homeostasis, I have generated and characterized an inducible β cell-specific UCP2 deletion model,MIPCreER×loxUCP2 mice. Male littermates were injected with tamoxifen to induce UCP2 deletion(UCP2 iBKO) or with corn oil (CO). The phenotypes of both short-term (3-4 weeks after the last injection) and long-term (8-9 weeks after the last injection) were determined: Short-term iBKO mice displayed no differences in glucose or insulin tolerance, but enhanced in vivo and in vitro insulin secretion and suppressed islet reactive oxygen species (ROS) levels; while long-term iBKO mice displayed no difference in glucose tolerance, but impaired in vivo and in vitro insulin secretion and enhanced islet ROS levels. In conclusion, short-term UCP2 deletion in β cells promotes insulin secretion, while long-term UCP2 deletion impairs insulin secretion, possibly due to the opposite background of islet ROS.