published_or_final_version / Medicine / Master / Master of Philosophy

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Thesis (M. Phil.)--University of Hong Kong, 1996. / Includes bibliographical references (leaf 92-112).

In 1971 Schally and co-workers (Schally et al., 1971) isolated gonadotropin-releasing hormone (now called luteinizing hormone-releasing hormone (LH-RH)) from sheep hypothalami and established that the hormone was a decapeptide with the amino acid sequence: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH₂. The peptide was subsequently synthesised (Matsuo et al., 1971b) and shown to stimulate the release of gonadotropins (luteinizing hormone and follicle-stimulating hormone) in a wide range of mammalian species (Schally et al., 1973, 1976). With the exception of amphibians, nonmammalian vertebrates have a poor gonadotropin response to synthetic mammalian LH-RH (for reviews, see Ball, 1981; Jackson, 1981; King and Millar, 1981a). Since there is considerable molecular heterogeneity in the related neurohypophysial nonapeptide hormones (oxytocin-vasopressin) amongst vertebrates (Acher et al., 1972), we postulated that differences might exist in the structure of hypothalamic LH-RH in different vertebrate classes, Utilising a combination of regionspecific antisera and chromatographic techniques, we established that amphibian hypothalamic LH-RH is identical to the mammalian peptide while avian, reptilian, and piscine hypothalamic LH-RHs differ structurally in the region Gly⁶-Leu⁷-Arg⁸ (King and Millar, 1979a, 1980), We have now conducted further studies on avian hypothalamic LH-RH, which indicate that the arginine residue in position eight of mammalian LH-RH is substituted by glutamine in this vertebrate class. Purification of LH-RH from chicken hypothalami and determination of the amino acid composition have confirmed that the structure of avian LH-RH is: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Gln-Pro-Gly-NH₂.

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Electrolytic lesions of the ventromedial hypothalamus produce an obesity syndrome in experimental animals characterized by behavioural and metabolic disturbances. Historically, theories of VMH obesity have considered a single disturbance, either behavioural or metabolic, to be the primary effect of the lesion, which in turn causes other components of the syndrome. An alternative view suggests that VMH lesions simultaneously disturb both behavioural and metabolic mechanisms due to the anatomical proximity of these mechanisms in the hypothalamus. Therefore, more discrete lesions in the VMH may produce some syndrome components but not others. This thesis presents a series of experiments that test this "dissociative" perspective of the VMH obesity syndrome. First, rats having different hypothalamic ablations were compared on: caloric intakes on a series of test diets, body weight changes, and body fat. Bilateral parafornical hypothalamic knife cuts (PFKC) that spared the ventromedial hypothalamic nucleus (VMN), produced overeating and weight gain characteristic of VMH lesions. However, measurement of percentage body fat (i.e. level of obesity) indicated that PFKC rats were less obese than VMH rats, even though PFKC lesions produced a greater hyperphagia and weight gain than VMH lesions. In contrast, lesions restricted to VMN produced obesity, but did not produce hyperphagia or weight gain. Since parafornical knife cuts produced a greater hyperphagia than VMH lesions, it is possible that VMN damage actually reduces caloric intake in VMH rats. To test this hypothesis, the effects of VMH, PFKC, and combined PFKC/VMN lesions on caloric intake and body weight were compared. PFKC and VMH lesions produced hyperphagia and weight gain. However, knife cuts were not significantly more effective than VMH lesions for producing these disturbances in this experiment. Therefore, PFKC lesions do not invariably produce a greater hyperphagia than VMH lesions. Furthermore, VMN lesions had no effect on the level of overeating or weight gain in rats bearing PFKC lesions. Therefore, damage to VMN does not reduce the hyperphagia produced by PFKC lesions. Finally, the effects of these different hypothalamic manipulations on metabolic measures were determined. To eliminate the confound of hyperphagia on metabolic variables, all lesion rats were fed a daily food ration sufficient to maintain their body weight at the level of controls. VMH and PFKC lesions resulted in elevated parasympathetic tone, indicated by elevated basal gastric acid secretion. VMN lesions did not affect gastric acid secretion. In contrast, only VMH and VMN lesions produced obesity when overeating was prevented. PFKC rats did not become obese. These experiments demonstrate that separate hypothalamic mechanisms underly the hyperphagia and obesity characteristic of VMH lesions. Furthermore, different mechanisms underly obesity and elevated parasympathetic tone following VMH lesions. Therefore, these observations support a dissociative model of the VMH obesity syndrome. / Thesis / Doctor of Philosophy (PhD)

Although research has linked central nervous system activity with changes in immunoresponsivity, research on the possible role of the central nervous system in altering a specific class of antibody is lacking. This study was an investigation of the possible relationship between anterior or medial hypothalamic functions on Immunoglobulin G. concentrations in rat serum. Thirty-six male albino rats were randomly assigned to three groups of equal size. Animals within the anterior hypothalamic group received bilateral electrode implants in the anterior hypothalamus while animals in the medial hypothalamic group received electrode implants within the ventromedial area of the hypothalamus. A control group received bilateral electrode implants within the lateral hypothalamus. Electrical brain stimulation was administered to animals in both experimental groups. Control animals spent a comparable time in an operant chamber but did not receive electrical brain stimulation. Following brain stimulation of animals within the experimental groups, Immunoglobulin G. concentrations were determined for all groups 3, 6, 12, and 24 hours post-stimulation sessions.

The Siberian hamster (Phodopus sungorus) undergoes a suite of physiological changes in response to short day (SD) photoperiod which includes a marked reduction in body mass (up to 40%). This altered physiology can be reversed by a return to long day (LD) photoperiod and is driven by changes hypothalamic gene expression. Additionally, stimulation of weight regain occurs through spontaneous exercise when hamsters are provided with a running wheel (RW), despite intact photoperiod appropriate hypothalamic gene expression. The foundation hypothesis for this investigation was that the change in body weight in both paradigms is underpinned by an alteration of the growth hormone (GH) axis. Pasireotide, a somatostatin agonist, was utilised to inhibit GH secretion from the pituitary in both paradigms. Measurement of body mass, mass of internal organs, body composition by magnetic resonance imaging, hormonal analysis and in situ hybridization were used to determine the effect of a blockade of GH secretion by pasireotide. Pasireotide suppressed the GH axis in Siberian hamsters; with reduced circulating insulin-like growth factor-1 and altered hypothalamic gene expression of somatostatin (srif) and growth hormone – releasing hormone (ghrh) consistent with an inhibition of pituitary GH secretion. Pasireotide treatment inhibited RW and LD stimulated growth, and when administered to LD hamsters caused weight loss in a similar manner to that which occurs in SD and accompanied by testicular atrophy. In addition, pasireotide increased the incidence of torpor and increased bout length of this hypometabolic state in sedentary SD hamsters. In conclusion, evidence is provided for the hypothalamic – pituitary – growth hormone axis in the determination of photoperiod and RW induced body weight changes. Furthermore, the data show evidence for a novel muscle – brain pathway and evidence for a neuroendocrine pathway involved in torpor induction.