Astrocyte-specific deletion of peroxisome-proliferator activated receptor-gamma impairs glucose metabolism and estrous cycling in female mice

Abstract

We previously reported that neuronal PPARis required for obesity-induced leptin-resistance and female fertility. PPARγ is highly expressed in astrocytes, so we created an inducible, conditional knockout of PPARγ (AKO) by crossing male Ppargflox/flox mice with GFAP-Cre-ERT (GCTF-CRE) females to generate Ppargflox/+:GCTF-Cre females, which were bred with flox/flox males to obtain cre+ Ppargflox/flox:GCTF-Cre mice (AKO) and littermate controls (WT). To induce the CRE allele, AKO and WT females were fed Tamoxifen for 2 weeks after 11 weeks of age. Fifteen-week old mice were fed 60 % high-fat (HFD) or 10% low-fat (LFD) diets. Estrous cycles, body weight, glucose tolerance and insulin sensitivity were analyzed before and after diets. Leptin sensitivity, serum gonadotropins, ovarian histology and ovarian, hepatic and hypothalamic gene expression were analyzed after 18 weeks on diets. AKO showed impaired glucose tolerance and hepatic steatosis that did not worsen with HFD, but maintained leptin-sensitivity. Expression of gluconeogenic genes and also genes involved in lipogenesis, lipid transport and storage were elevated in the liver, what could explain the altered glucose tolerance and liver steatosis (p<0.05). Lean AKO had altered estrous cycles and expression of hypothalamic Npvf and Hcrt, and HFD reversed these effects (p<0.05). In AKO, HFD inhibited the increase in LH after Kisspeptin stimulation; however, Gpr54 hypothalamic expression was increased in AKO regardless of diet. AKO showed altered ovarian histology and Cyp19a1 Fshr and Star gene expression, lower serum LH and higher testosterone compared to WT (p<0.05). Our data show that astrocytic PPARγ maintains normal hepatic insulin sensitivity and prevents steatosis, and that is important for the correct regulation of the hypothalamic-pituitary axis and estrous cycles.