UC San Diego

Thiazolidinediones are PPAR-g agonist drugs used to treat type 2 diabetes and improve symptoms of infertility in polycystic ovarian syndrome (PCOS) patients. Because both disorders correlate with obesity, which increases inflammation in the central nervous system, we hypothesized PPAR-g in astrocytes may be involved in regulating metabolic and reproductive functions centrally. We therefore generated astrocyte-specific PPAR-g knockout (AKO) mice using Cre-loxP technology to study these effects. On normal chow, AKO mice had reduced numbers of estrous cycles but normal pituitary response to GnRH suggesting a central defect. Loss of PPAR-g did not cause astrocyte activation, as Gfap expression in the brain was unchanged. When maintained on low-fat diet (LFD), they showed decreased food intake which was not further suppressed by leptin. Body weights were normal, but they displayed slight glucose intolerance, faster recovery from insulin-induced hypoglycemia, and increased liver expression of G6pase, Cidec, and Gfap. At the reproductive level, AKO mice had decreased estrous cycles, lower diestrus LH levels, abolished FSH response to kisspeptin, and increased hypothalamic expression of Gnrh1, Kiss1, Npvf, and Hcrt. AKO mice challenged with a high-fat diet (HFD) showed significantly increased glucose tolerance which was associated with their decreased G6pase expression but increased Cidec and Gfap expression in the liver. Food intake and leptin response were normal. They also had significantly more estrous cycles than AKO mice on LFD, but still had suppressed diestrus LH levels and impaired gonadotropin response to kisspeptin. Gfap expression in the brain was also significantly increased suggesting astrocyte activation by HFD