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.

Thesis (M. Sc.)--University of Hong Kong, 1972. / Typewritten.

In mammals distinct steroid hormones termed mineralocorticoids (MCs) and glucocorticoids (GCs) regulate hydromineral balance and the stress response, respectively. In contrast, it is thought that a single corticosteroid, 1[alpha]-hydroxycorticosterone (1[alpha]-B) serves as both a GC and MC in elasmobranchs. I investigated the putative dual MC and GC roles of 1[alpha]-B by examining ex vivo regulation of interrenal 1[alpha]-B synthesis by osmoregulatory and stress hormones in the euryhaline stingray Dasyatis sabina. A commercial enzyme-linked immunoassay was adapted for the quantification of 1[alpha]-B. I also isolated cDNA sequences encoding two rate-limiting steroidogenic enzymes, the steroidogenic acute regulatory protein (StAR) and P450 cholesterol side-chain cleavage (P450scc), and characterized the steroidogenic activity of the encoded proteins using a heterologous expression system. Both the stress hormone adrenocorticotropic hormone (ACTH) and the antinatriuretic peptide angiotensin II (ANG II) were potently steroidogenic in ex vivo interrenal cultures, whereas C-type natriuretic peptide (CNP) inhibited 1[alpha]-B synthesis. StAR and P450scc mRNA levels were increased by 24 h incubation with ACTH and decreased by both ANG II and CNP. To examine changes in osmoregulatory hormone systems that impinge upon 1[alpha]-B synthesis, I also isolated the cDNA sequences of the ANG II and CNP receptors, AT and NPR-B. Both AT and NPR-B mRNA levels were significantly elevated in osmoregulatory tissues of freshwater (FW; Lake Monroe, FL) versus saltwater (SW; Corpus Christi Bay, TX) populations of D. sabina. Interrenal StAR and NPR-B mRNA levels were also significantly higher in FW individuals. The physiological roles of 1[alpha]-B were further investigated in vivo by examining the effects of stress and FW transfer on interrenal synthesis of 1[alpha]-B. Plasma 1[alpha]-B and glucose were significantly elevated by hook-and-line capture stress, indicating that 1[alpha]-B acts in classical GC fashion to facilitate the stress response. In contrast, 1[alpha]-B was significantly decreased 24 h after SW-FW transfer. In light of the osmotic strategy of euryhaline elasmobranchs, this result is consistent with a MC role for 1[alpha]-B. Taken together, the results of this research strongly support a dual role for 1[alpha]-B in facilitating both hydromineral balance and the stress response in elasmobranchs. / text

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<p> Population based descriptive studies, clinical trials, and evidence analysis of the literature have identified regular breakfast consumption as opposed to breakfast omission, as a habit independently associated with a more healthy weight. Recent studies have identified differences in insulin sensitivity and satiety hormones between breakfast eating and skipping groups, which help to explain the association between breakfast consumption and weight regulation. Evaluation of fasting insulin sensitivity, behavior, and the postprandial satiety response between breakfast groups were used to further elucidate the physiologic response to skipping breakfast. </p><p> First, through a review of the literature the proposed physiologic response to consuming breakfast as well as omitting breakfast is presented. A connection is made between the satiety hormone response and key components of the breakfast meal, which include composition, caloric load, energy density, volume, and time of day. The review findings suggest that breakfast consumption as opposed to breakfast omission stimulates a physiologic response that may help promote a healthy body weight. </p><p> Chapter 2 examines if self reported habitual breakfast skipping was related to fasting insulin resistance in a sample of 321 adults. Participants completed a questionnaire that focused on eating occurrences throughout the day and were then classified by how frequently they ate breakfast. Breakfast eating was related to fasting insulin and HOMA2-IR, both before and after adjusting for age, sex, BMI, and exercise. These data suggest that fasting insulin resistance is affected by breakfast omission, and supports previous intervention studies that report a decline in postprandial insulin action after breakfast omission. </p><p> Chapter 3 evaluates the relationship between cognitive perception and the satiety hormone response. In a crossover intervention, satiety hormones (insulin and GLP-1), the hunger hormone ghrelin, and subjective ratings of meal satisfaction and eating behavior were compared before and after a low or high fiber breakfast meal. We found that reported perceptions of meal satisfaction, the perception of the breakfast meal, and the behavioral description of cognitive restraint can influence the physiologic regulation of satiety hormones measured in response to meal ingestion. Further evaluation of food consumption habits should consider cognitive perception as it may be important for optimal satiety and influence food intake regulation. </p><p> Lastly, chapter 4 was a cross-sectional study to assess the hormones insulin, leptin, GLP-1, and glucagon following a standard lunch meal in 30 women who were habitual breakfast eaters or habitual skippers. We found clear differences in circulating hormones between breakfast eaters and breakfast skippers even though all participants had similar hormone values at the start of the protocol. Our data further support the idea that regularly eating breakfast promotes changes in the postprandial pattern of satiety hormones.</p>

<p> There are two main patterns of development within animals: direct and indirect. Direct developers are animals such as humans, whose offspring are basically smaller versions of the adult. Indirect developers have a larval stage that can be dramatically different than the adult, and consequently go through a transformation known as metamorphosis. Frogs are a well-known example of vertebrate indirect development, developing first into an aquatic, herbivorous tadpole that later transforms into a terrestrial, carnivorous frog. This transformation is largely regulated by a single hormone&mdash;thyroid hormone (TH). Changes in TH play a vital role in tissue transformations such as, differentiation and growth of the limbs, remodeling of the gut tube and liver, as well as resorption of larval features such as the tail. In addition, the timing of metamorphic changes can differ substantially among species. For instance, the average rate of metamorphosis for a majority of frogs/toads (anurans) is between 3-5 weeks, yet there are a multitude of frogs and toads that take several months or even years to go through this process (Duellman and Trueb, 1994; Gilbert, 2010; Petranka, 2007; Provenzano and Boone, 2009). At the other extreme are frogs that have reduced or even eliminated the free-living larval period such as the Eastern Spadefoot toad, <i>Scaphiopus holbrookii, </i> which has one of the shortest larval periods found in metamorphosing frogs or direct developing frogs, like <i>Eleutherodactylus coqui</i> which have no free-living larval stage. This diversity of developmental patterns sparks many questions about the precise molecular and developmental roles TH has on metamorphosis in frogs. How can a single regulator produce such a wide range of responses, not only between species that differ in metamorphic timing, but also among tissues within a single individual? The vast majority of recent studies that examine tissue specific responses to TH have focused on the genes that code for TH binding proteins or for TH receptors (Hollar et al., 2011; Buchholz et al., 2011). However, a very important aspect is being overlooked in these studies, which is the actual level of the TR proteins themselves. </p><p> There are three distinct mechanisms that regulate tissue responses to TH: deiodinase enzymes, cytosolic thyroid hormone binding proteins (CTHBPs), and thyroid hormone receptors (TRs) (Morvan-Dubois <i>et al.,</i> 2008: Buchholz <i>et al.,</i> 2006). The overall objective of the current study is to develop a technique that will allow protein level analysis of two of the three components implicated in the regulation of tissue specific responses to TH during tadpole metamorphosis: CTHBPs and TRs. I hypothesize that changes in the affinity and/or capacity of thyroid hormone receptors and cytosolic thyroid hormone binding proteins to bind TH throughout metamorphosis underlie the timing and extent of tissue remodeling. In fresh tissue, saturation binding assays suggest a difference in binding capacity among tissues.</p>

<p> Aging is broadly defined as the deterioration of bodily tissues over time. Excluding death due to infectious disease or accidents, aging is what ultimately places finite limits on lifespan and healthspan, the time in which in individual remains active and in good health. Although healthspan and lifespan are intimately linked, it is the extension of human healthspan that is a major goal of gerontological research. Such an achievement would have broad social and economic benefits and importantly would mitigate the dire consequences of the predicted future rise in the prevalence of age-related diseases due to the growing proportion of the population that is of advanced age (65yr and over). A broad understanding of the physiological, metabolic, hormonal, cellular and molecular factors that contribute to aging and lifespan determination will allow for the development of strategies to extend healthspan. </p><p> The work presented herein describes the use of three unique mouse models of extended healthspan and maximum lifespan, including calorie restricted (CR), Snell Dwarf and rapamycin-treated mice, to investigate several factors linked to healthspan and lifespan determination in mammals. These factors include reduced insulin-like growth factor-1 (IGF-1) expression, reduced cell proliferation, reduced protein synthesis and enhanced proteome stability. Using these three models the following conclusions have been drawn: 1) Physiological adaptations to CR previously suggested to confer the healthspan and lifespan benefits of CR in rodents cannot account for the global cell proliferation rate-lowering effect of CR; 2) Fibroblast growth factor 21 (FGF21) is not necessary for the reduction in IGF-1 or the reduction in global cell proliferation rates in response to moderate CR in adult mice; 3) A reduction in global cell proliferation rates is not a consistent predictor of maximum lifespan extension in mice; 4) A reduction in hepatic protein replacement rates is a sensitive and early predictor of maximum lifespan extension in mice and likely reflects a more stable and functional proteome.</p>

<p> Ovulation requires neural circuits in the brain to be sequentially exposed to estradiol and progesterone in the female rat. Estradiol-induced neuroprogesterone is essential for the luteinizing hormone (LH) surge and subsequently, ovulation to occur. The LH surge is regulated by gonadotropin-releasing hormone (GnRH) neurons in the diagonal band of Broca (DBB) which do not express progesterone receptors (PR), but are closely associated with anteroventral periventricular nucleus (AVPV) PR-expressing kisspeptin neurons. I tested the hypothesis that estradiol-induced neuroprogesterone activates AVPV kisspeptin neurons to trigger the LH surge. Inhibiting progesterone synthesis blocked estradiol induction of the LH surge that was rescued by subsequent treatment with either progesterone or DBB kisspeptin infusion. Estradiol treatment triggered a robust LH surge that was blocked by AVPV kisspeptin asODN infusion. These results support the hypothesis that neuroprogesterone induces kisspeptin release from AVPV neurons to activate DBB GnRH neurons and trigger the LH surge.</p>

<p> The neural dimorphisms in the zebra finch present one of the most unique examples of sexual differentiation observed in vertebrates. Although knowledge of these differences has been established for over 45 years, the exact mechanism by which they arise is not known. This dissertation provides additional support for estrogens' involvement in brain development. Specifically, blocking of estrogen receptors with ICI 182,780 decreased neuron soma size of song control regions in both sexes during development. These results are distinctive since previous attempts to block estrogen receptors failed to see the large degree of difference my work displayed. I further supported the role of estrogens in neural brain dimorphisms by decreasing the synthesis of aromatase, an enzyme needed for estradiol production, with the administration of Fadrozole. This successfully decreased neuron soma sizes, neuron number, and nuclear volume in song control regions in males and females, which had not been seen in prior attempts from other laboratories. I have concluded that the route of delivery used in these experiments is likely the largest contributing factor to generating these unique results. I also provide evidence of a potential role for ER alpha by displaying its presence at an early post-hatching age in two auditory processing regions. Taken together, my work provides further support for the role of estrogens in the dimorphic development of the brain, and establishes that it is unlikely that ER alpha contributes to neural dimorphisms in the zebra finch.</p>