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

KATHERINE HSUEH; SUN KIM; CONSUELO SAUCEDA; SUMANA MAHATA; MARINA FERNANDEZ; VICKY HWANG; NICHOLAS J.G. WEBSTER

CABA

Congreso; REUNIÓN CONJUNTA DE SOCIEDADES DE BIOCIENCIAS; 2017

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