The role of estrogens in metabolic syndrome in aging rats

Emese Renczés 1 Veronika Borbélyová 1 Katarína Šebeková 1 Peter Celec 1

1Ústav molekulárnej biomedicíny, Lekárska fakulta Univerzity Komenského v Bratislave, Bratislava, Slovenská republika

It is widely presumed that metabolic syndrome (MetS) and obesity are caused by sedentary lifestyle and unhealthy diet. However, none of the therapies focused on physical activity and nutrition is efficient, at least not in long-term. On the other hand, post-menopause in women is associated with higher incidence of metabolic syndrome, which may be attributable to the decline in estrogen production. However, the causal effect of sex hormones on MetS has not been elucidated yet. In this experiment, we aimed to examine whether sex-hormone deficiency in aging female rats may increase the risk of MetS.

For inhibition of estrogen production, twelve-month old female rats were either ovariectomized (OVX) or treated with an aromatase inhibitor, letrozole (1mg/kg). To investigate the effect of exogenous estrogen, OVX females received 17β-estradiol (10µg/kg). Intact male rats were used to examine sex differences. To assess the risk of MetS, Z-scores for waist circumference, plasma triglycerides, mean arterial blood pressure, and glucose response curve were added up, while Z-scores for high-density lipoprotein cholesterol were subtracted. In addition, weight gain, food intake and locomotor activity were measured.

Approximately 1.5-2-fold higher scores for MetS were found in OVX females (p˂0.05) and in letrozole-treated females (p=0.08) in comparison to control females, but no sex differences and no effect of exogenous estradiol were shown on MetS-scores. Females had by 38% lower food intake than males (p˂0.001), and estradiol-supplemented OVX rats ate by 23% less than vehicle-treated OVX rats. On the contrary, females displayed by 74% higher locomotor activity than males (p˂0.001). OVX (p˂0.05), but not letrozole-treated females, moved less (by 27%) when compared to control females, and estradiol treatment restored locomotor activity in OVX rats (p˂0.05). Before the additional hormonal treatment, OVX females gained 7-fold more on weight than control females (p˂0.001). During the treatment period, the weight gain in letrozole-treated females was 2-fold higher than in control group (p˂0.05), while a significant loss (~10%) of body weight was found in estradiol-treated OVX group in comparison to vehicle-treated OVX group (p˂0.001). A slight correlation was found between MetS-scores and locomotor activity (R2=0.07, p=0.06). However, no significant interaction was found either between MetS-scores and weight gain (R2=0.04, p=0.16), or between MetS-scores and food intake (R2=0.007, p=0.58).

Our results indicate that deficient production of ovarian hormones may contribute to MetS. Further studies are needed to elucidate the role of endogenous estrogens, androgens and progestagens - either produced by ovaries, adrenal glands or other tissues - in prevention of metabolic disorders. In addition, decreased activity should be considered as a consequence of MetS. Thus, targeted endocrine-based therapy should be more efficient than recommendations regarding movement.

Funding for this study was provided by the Ministry of Education of Slovak Republic (VEGA 1/0307/19 and VEGA 1/0635/20).