Bains, Randip Kaur; (2001) Neuroendocrine physiology in the transgenic SLOB rat: A new obesity model. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Previously two lines of transgenic rats with a cosmid containing both vasopressin (VP) and oxytocin (OT) genes, engineered to express human growth hormone (hGH) and bovine neurophysin (bNP) as reporter genes respectively were generated. Unexpectedly, males of one line, bearing multiple copies of the transgene, exhibited an autosomal dominant phenotype of Severe Late-onset OBesity (SLOB) with selective accretion of visceral fat despite normal intake of a low fat diet. Presented in this thesis are the physiological and some genetic studies carried out to characterise the SLOB phenotype. Studies include analysis of the sex-specific phenotype such as ovariectomy and high fat feeding, both of which result in a rapid development of visceral obesity in young SLOB rats. Lipid analyses revealed reduced lipolytic activity and increased hepatic very low-density lipoprotein (VLDL) production. Despite severe obesity, these animals were not diabetic or insulin resistant. Investigation of hypothalamic feeding neuropeptides showed some changes, including a reduced arcuate neuropeptide Y (NPY) mRNA expression and an increased supraoptic tub mRNA expression. The SLOB phenotype could not easily be explained by the known transgene products. Further analysis of the transgene construct revealed a novel gene, which was termed 5'OT-EST. Studies assessing the possible role of this gene in SLOB obesity indicated it being a good candidate for contributing to the SLOB phenotype. Whatever the underlying genetic mechanism of the SLOB phenotype, this rat is a unique model for late-onset male specific visceral obesity.

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