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Effects of SIRT1 mutation or over-expression in astrocytes on metabolism and reproduction /


Sirtuin 1 (SIRT1) is an NAD+-dependent histone deacetylase, activating and inhibiting gene-expression in several organs, such as the liver, pancreas, adipose tissue, intestine, and brain. Whereas the impact of SIRT1 in these tissues has been extensively studied, its role in astrocytes and effect on reproduction is still elusive. SIRT1 over-expressing mice show phenotypes resembling mice in caloric restriction - inhibited adipogenesis, lowered levels of blood cholesterol, improved glucose tolerance, and increased metabolic activity. Furthermore, during times of caloric restriction, SIRT1 levels increase and reproductive events such as gonadotropin-releasing hormone (GnRH) pulses, luteinizing hormone (LH) pulses, and ovulation cease. I hypothesize that SIRT1 in astrocytes may contribute to this altered reproductive function and also play a role in metabolism and inflammation. To evaluate this, our laboratory has developed conditional over-expressing (OX) and mutant (MUT) SIRT1 using a tamoxifen-inducible cre-recombinase under the control of the glial fibrillary acidic protein (GFAP) promoter, which expresses in astrocytes. The two transgenic lines include either a floxed stop over-expression of SIRT1 or a floxed exon 4 of SIRT1, mimicking a SIRT1 knockout. To prevent any affects on mouse reproductive development, the normal chow (NC) infused tamoxifen diet was not started until 10 weeks of age, maintained for 2 weeks, and a recovery period for 2 weeks before the start of all studies. Differences were seen in weights, food intakes, glucose and insulin tolerance, hormone levels and reproductive cyclicity. High-fat diet (HFD) and 24hr fast were performed to evaluate the effect of stress-induced diets. Reproductive changes were evaluated by monitoring estrous cyclicity, endocrine and steroid hormone levels, as well as gonadal histology

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