Obesity is a complex disorder which has become a growing health concern. Twin studies have demonstrated a strong genetic component to the development of obesity and genome wide association studies have identified several genetic loci associated with it. However, most of these loci are still poorly understood in a functional context. Interestingly, many of the hormones and neurobiological messengers responsible for regulating feeding behaviour and metabolism are also linked to controlling aggression, but it is still not understood how they interact to maintain metabolic homeostasis. In this thesis, the model organism Drosophila melanogaster was employed to dissect the molecular mechanisms of the genetic cascades regulating aggressive behaviour and metabolic homeostasis. In paper I and II, the role of transcription factor AP-2 (TfAP-2) and Tiwaz Twz, Drosophila homologues of two human obesity-linked genes were investigated in aggression and feeding behaviour. Paper I demonstrated that TfAP-2 and Twz genetically interact in octopaminergic neurons to modulate male aggression by controlling the expression of genes necessary for octopamine (fly analogue of noradrenaline) production and secretion. Moreover, it was revealed that octopamine in turn regulates aggression through the Drosophila cholecystokinin (CCK) satiation hormone homologue Drosulfakinin (Dsk). Paper II revealed that TfAP-2 and Twz also initiate feeding through regulation of octopamine poduction and secretion. Octopamine then induces Dsk expression leading to inhibition of feeding. Paper III established that the activity of the small GTPase Ras-related C3 botulinum toxin substrate 2 (Rac2) is required in Drosophila for the proper regulation of metabolic homeostasis, as well as overt behaviours. Rac2 mutants were starvation susceptible, had less lipids and exhibited disrupted feeding behaviour. Moreover, they displayed aberrant aggression and courtship behaviour towards conspecifics. Paper IV studied Protein kinase D (PKD), the homologue of a third obesity-linked gene PRKD1, and another kinase Stretchin-Mlck (Strn-Mlck). Reducing PKD transcript levels in the insulin producing cells led to flies with increased starvation susceptibility, decreased levels of lipids and diminished insulin signalling compared to controls. Reduced Strn-Mlck expression resulted in a starvation phenotype and slight reduction in insulin signalling and lipid content. These findings imply a function for PKD and Strn-Mlck in insulin release.

No description available.

Bicaudal-C, a Drosophila gene, is required for centripetal follicle cell migration in the egg chamber and anterior patterning of the embryo; its exact functions are unknown. BICAUDAL-C carries five KH domains required for in vitroRNA-binding and for in vivo activity. Here, I show that Bicaudal-C functions, through RNA-binding, to regulate oskar expression during mid-oogenesis. Females carrying mutations in Bicaudal-C in the regions encoding its KH domains display premature, ectopic translation of OSKAR at the anterior of their stages 8--10 oocytes; this likely accounts for the disruption of anterior patterning in embryos of Bicaudal-C/+ females. Also here, I propose that oskar and gurken share common regulators, including Bicaudal-C. This is based on the discovery of dorsalized progeny of Bicaudal-C/+ females, and on the dominant enhancement of the Bicaudal-C/+ phenotype by specific gurken and cornichon alleles. Finally, I describe a yeast two-hybrid screen used to investigate BICAUDAL-C-protein interaction.

Bicaudal-D (Bic-D) is essential in Drosophila for the establishment of oocyte fate and polarity within the developing oocyte. To study these processes we have engineered a chimeric Bic-D::GFP fusion protein which behaves like the endogenous Bic-D polypeptide. We have identified three genes which are required for the normal subcellular distribution of Bic-D::GFP two genes predicted to encode RNA binding proteins (egalitarian and orb) and Dynein heavy chain. In particular, they affect Bic-D::GFP localization during the early germarial stages of oogenesis during which oocyte fate is established, or later when anterior-posterior polarity is initiated. Our results support the model that Bic-D acts in conjunction with mRNA binding proteins and a negative-end directed microtubule motor in localizing mRNAs. Throughout stages 1--6 of oocyte development, Bic-D::GFP accumulates in the oocyte in a strong posterior cortical focus, resembling a spool, that is aligned with a crater-like indentation in the oocyte nucleus. The aligned focus and crater reveal an early oocyte polarity and a previously undescribed asymmetric subcellular structure that may be involved in tethering the oocyte nucleus. Shape, positioning and orientation of the oocyte nucleus change around stage 6--7, concomitantly with a change in position of the Bic-D::GFP focus to the presumptive dorsoanterior corner. This re-orientation appears to anticipate the establishment of a new dorsoventral polarity in the oocyte and egg chamber. Dhc and Bic-D are both involved in the process of re-orientation of the oocyte nucleus and in polarity formation.

No description available.

Typescript. / Thesis (Ph. D.)--University of Hawaii at Manoa, 1983. / Bibliography: leaves 283-290. / Microfiche. / xix, 290 leaves, bound ill. 29 cm

Thesis (Ph. D.)--University of Hawaii at Manoa, 1996. / Includes bibliographical references (leaves 159-175). / Microfiche. / xv, 175 leaves, bound ill. 29 cm

Typescript. / Thesis (Ph. D.)--University of Hawaii, 1968. / Bibliography: leaf 82. / ix, 82 l tables

Typescript. / Thesis (Ph. D.)--University of Hawaii, 1969. / Bibliography: leaves 92-96. / viii, 96 l illus

Thesis (M.S.)--University of Hawaii at Manoa, 2007. / Includes bibliographical references (leaves 63-69). / 69 leaves, bound ill. (some col.) 29 cm