Effect of the Lack of Post-Pubertal, Ovary-Dependent Programming on Metabolic-Endocrine and Liver Functions

VILLAGARCÍA H; CASTRO MC; MASSA ML; SPINEDI E; FRANCINI F

Congreso; ENDO2017 The Endocrine Society´s 99th annual meeting; 2017

Background & Aim: Post-pubertal bilateral ovariectomy (OVX)-induced Metabolic Syndrome (MS) phenotype in rats is characterized by increased body weight (BW)/fat and endocrine-metabolic dysfunctions. Our aim was to evaluate the effect of the lack of pubertal programming, by the endogenous peak of ovary-derived estradiol (E2), on endocrine-metabolic and liver functions when adulthood (90 days old) was reached. Materials and Methods: Sprague-Dawley rats were either OVX on day 23/25 of life (pre-pubertal OVX; ppOVX) or sham (ppSHX) operated (dorsal approach) under mild anesthesia. Recovered rats were allocated 3 per cage, with free access to rat chow and water up to 69 days of age; then divided in groups either receiving drinking water (C) or fructose rich diet (FRD; 10% F in drinking water and rat chow provided ad libitum during 3 weeks). Built groups were: ppSHX-C, ppOVX-C, ppSHX-F and ppOVX-F. Subsets of these groups were sacrificed in non-fasting (basal) condition or, after overnight fasting, submitted to an ip glucose tolerance test (GTT; 2 g/kg BW). BWs, food-intake and drank solution were recorded day after day. Circulating levels of glucose (GLU), triglyceride (TG) and estradiol (E2) were quantified. Glycemias were monitored throughout (0-120 min) the GTT, and individual area under the curve (AUC) of circulating GLU levels was calculated. Finally, liver gene expression levels of lipogenesis-related proteins (SREBP-1c, FAS and GPAT) and estrogen receptor-A (ER-A) were quantified. Results: Non-fasting ppOVX rats showed (p<0.05 vs ppSHX) increased food intake and BW gain, decreased triglyceridemia, and blunted circulating E2 levels, although similar glycemias. Regarding animals submitted to FRD-intake, ppOVX-F developed increased BW gain (p<0.05 vs ppOVX-C), however glycemia increased only in SHX-F rats (p<0.05 vs ppSHX-C), being values even greater than in ppOVX-F rats. Fasting-induced BW loss indicated that ppOVX were more resistant than ppSHX ones. FRD intake significantly increased TG in both groups, regardless of surgery, although FRD-induced hyperlipidemia was attenuated in ppOVX rats. While FRD intake elicited glucose intolerance to glucose overload in ppSHX-F rats, this effect was overridden by ppOVX. Finally, liver ER-A mRNA levels did not differ among groups and, a clear tendency to a diminished gene expression levels of proteins involved in the lipogenic process was noticed in ppOVX rats, regardless of the diet. Conclusions: Increased ppOVX-dependent BW gain seems to be related to the lack of E2 anorectic activity. Moreover, the lack of ovarian hormones/factors could avoid tissues related to TG synthesis, liver among others, from the pubertal E2 peak-induced overall metabolic programming in the female rat that, in turn, could render in an undesirable high risk for developing dyslipidemia and pre-diabetes and, as a consequence cardiovascular disease.