| dc.contributor.author | Lagace, Diane Carol. | en_US |
| dc.date.accessioned | 2014-10-21T12:37:59Z | |
| dc.date.available | 2004 | |
| dc.date.issued | 2004 | en_US |
| dc.identifier.other | AAINQ94044 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54658 | |
| dc.description | Objective. Valproic acid (VPA) is a medication for the treatment of bipolar disorder, epilepsy, or migraine headache. VPA treatment is associated with weight gain and in women can induce symptoms of polycystic ovary syndrome (PCOS). This thesis attempted to develop an animal model for VPA induced side effects in vivo and determined in vitro the effect of VPA on the development of adipocytes (adipogenesis) and secretion of the hormone leptin. | en_US |
| dc.description | Results. In rats, VPA treatment was not associated with alterations in estrous cycling, weight gain, aromatase activity, or serum levels for estradiol, testosterone, or leptin. However, cystic follicles were present in 50% of the drug treatment animals compared to 25% of saline treated animals. In mouse and human preadipocytes, VPA inhibited adipogenesis and reduced the growth rate of mouse preadipocytes. VPA treatment during adipogenesis reduced mRNA levels for the transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma) and steroid regulatory binding protein (SREBP)1a, as well as the protein levels for PPARgamma, SREBP1a, and CCAAT/enhancer binding protein alpha (C/EBPalpha). VPA and other histone deacetylase (HDAC) inhibitors blocked adipogenesis, whereas valpromide, which does not inhibit HDACs, did not prevent adipogenesis. In mature adipocytes, acute VPA treatment reduced leptin mRNA levels and protein secretion, and VPA catabolites were incorporated into lipids. The reduction of leptin occurred independent of changes in glucose uptake, PPARgamma, SREBP1a, or C/EBPalpha protein levels, degradation of leptin mRNA, or alterations in the rate of lipogenesis or amount of intracellular free fatty acids. | en_US |
| dc.description | Conclusions. In vivo, VPA treatment in female rats had limited usefulness for modeling VPA-induced PCOS symptoms, with the exception of the development of cystic follicles. In vitro VPA inhibited adipogenesis highlighting a requirement for HDAC activity in adipogenesis. VPA also reduced preadipocyte growth, decreased leptin production and secretion, and did not alter lipid metabolism in mature adipocytes. Paradoxically, in humans VPA treatment induces weight gain and increases serum leptin levels, suggesting that VPA may be affecting multiple systems that regulate energy balance. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2004. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.subject | Health Sciences, Pathology. | en_US |
| dc.title | Analysis of valproic acid induced side effects: Polycystic ovary syndrome and weight gain. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
