Effect of GLP-1 Receptor Agonists in the Cardiometabolic Complications in a Rat Model of Postmenopausal PCOS

Abstract

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and ovulatory dysfunction. Women with PCOS have an elevated prevalence of cardiometabolic risk factors that worsen after menopause. Liraglutide (Lira), a glucagon-like peptide-1 receptor agonist, has shown beneficial metabolic effects in small clinic trials in reproductive-age women with PCOS. We have shown that chronic hyperandrogenemia in an experimental model of postmenopausal PCOS is associated with an adverse cardiometabolic profile and upregulation of the intrarenal renin-angiotensin system (RAS). We analyzed the effect of Lira in the cardiometabolic profile, intrarenal RAS, and blood pressure (BP) in postmenopausal PCOS. Four-week-old female Sprague Dawley rats were treated with DHT or placebo for 17 months. Lira administration during the last 3 weeks caused a bigger reduction in food intake, body weight, fat mass, and homeostasis model assessment of insulin resistance index in PCOS than in control rats. Moreover, Lira improved dyslipidemia and elevated leptin levels in PCOS. In contrast, Lira decreased intrarenal expression of RAS components only in the control group. Lira transiently increased heart rate and decreased BP in control rats. However, Lira did not modify BP but increased heart rate in PCOS. The angiotensin-converting-enzyme inhibitor enalapril abolished the BP differences between PCOS and control rats. However, Lira coadministration with enalapril further reduced BP only in control rats. In summary, Lira has beneficial effects for several cardiometabolic risk factors in postmenopausal PCOS. However, hyperandrogenemia blunted the BP-lowering effect of Lira in postmenopausal PCOS. Androgen-induced activation of intrarenal RAS may play a major role mediating increases in BP in postmenopausal PCOS.

Copyright © 2019 Endocrine Society.

Figures

Figure 1.

Food intake and body weight in postmenopausal PCOS rats. (A) At 17 months of age and before treatment with Lira, food intake was higher in PCOS rats compared with controls. (B, C) Daily and cumulative food intake were higher in vehicle-treated PCOS rats compared with vehicle-treated controls. Lira treatment caused a significant reduction in daily and cumulative food intake in both PCOS and controls. (D) At 17 months of age and before treatment with Lira, body weight was higher in PCOS rats compared with controls. (E, F) Lira treatment decreased body weight in PCOS and controls, expressed as change in (E) grams and (F) percentage before and after Lira treatment; the absolute amount of body weight lost with Lira was higher in PCOS compared with control rats. Data are expressed as mean ± SEM. Data were analyzed by (A, D) t test, (B, C) two-way ANOVA with repeated measures followed by Tukey post hoc tests, or (E, F) two-way ANOVA followed by Tukey post hoc tests. No significant interactions were observed by two-way ANOVA. *P < 0.05; #P < 0.05 vs vehicle-treated controls; &P < 0.05 vs Lira-treated controls. n = 5 to 7 per group.

Figure 2.

Anthropometric measurements and body composition in postmenopausal PCOS rats. (A) At 17 months of age and before treatment with Lira, PCOS rats had higher BMI compared with controls. (B) Lira decreased BMI, expressed as change before and after Lira treatment, in both PCOS and control rats. (C) Abdominal circumference was greater in PCOS; after Lira treatment, a decrease in abdominal circumference was observed only in PCOS rats. (D, F) At 17 months of age and before treatment with Lira, PCOS rats had greater (D) fat and (F) lean mass compared with controls. (E) Lira treatment caused a bigger decrease in fat mass, expressed as change before and after Lira treatment, in PCOS compared with controls. (G) Lira treatment did not modify lean mass, expressed as change before and after Lira treatment, in any group. Data are expressed as mean ± SEM. Data were analyzed by (A, D, F) t test or (B, C, E, G) two-way ANOVA followed by Tukey post hoc tests. No significant interactions were observed by two-way ANOVA. *P < 0.05. n = 5 to 7 per group.

Figure 3.

Metabolic parameters, lipid panel, and DHT levels in postmenopausal PCOS rats. (A, B) At 17 months of age and before treatment with Lira, (A) fasting insulin levels and (B) HOMA-IR were higher in PCOS rats compared with controls. (C) Lira treatment decreased HOMA-IR, expressed as change before and after Lira treatment, in PCOS; however, no significant changes were observed in control rats. (D–H) Lira treatment decreased (D) leptin, (E) total cholesterol, (F) LDL cholesterol, (G) HDL cholesterol, and (H) triglycerides in PCOS; however, no significant changes were observed in control rats. (I) PCOS rats had higher DHT levels that were unaffected by Lira treatment. Data are expressed as mean ± SEM. Data were analyzed by (A, B) t test or (C–H) two-way ANOVA followed by Tukey post hoc tests. No significant interactions were observed by two-way ANOVA. *P < 0.05. n = 5 to 7 per group.

Figure 4.

Expression of intrarenal RAS components in postmenopausal PCOS rats. (A) Renal cortical and medullar mRNA expression of angiotensinogen were four and six times higher, respectively, in PCOS compared with control rats. Lira did not affect renal angiotensinogen mRNA expression. (B) Renal expression of renin was higher in the cortex compared with medulla in both groups. Renal cortical expression of renin was significantly higher in controls than in PCOS rats. Lira lowered renal cortical mRNA expression of renin in control rats but not in PCOS rats. (C) Renal cortical ACE mRNA expression was significantly decreased in PCOS rats; in contrast, no differences were observed in the renal medulla. Lira lowered renal ACE mRNA expression in the cortex and medulla of control rats and had no effect in PCOS. (D) Renal cortical expression of AT1R was significantly higher in controls than in PCOS rats. Lira lowered renal cortical mRNA expression of renin in control rats but not in PCOS rats. (E) Renal cortical and medullar mRNA expressions of mineralocorticoid receptor were higher in control rats. Lira did not affect renal mineralocorticoid mRNA expression. *P < 0.05. Data are expressed as mean ± SEM. Data were analyzed by three-way ANOVA followed by Tukey post hoc tests. Significant interaction was observed by three-way ANOVA only for renin, whereas it was not significant for all other analyzed genes. *P < 0.05. n = 5 to 7 per group.

Figure 5.

Measurements of BP and HR in postmenopausal PCOS rats. (A, B, C) Female Sprague Dawley rats were treated with DHT or placebo pellets for 16.5 months, implanted with telemetry probes, and allowed to recover for 2 weeks. Animals were injected daily with saline (Veh), and BP was recorded for 3 days. Then, animals were treated daily with Lira and BP recorded for 21 days (phase 1). Animals were subjected to a 10-day washout period and then treated with enalapril, and BP was recorded for 7 days (phase 2). Then, animals were cotreated with enalapril and Lira, and BP was recorded for 7 days (phase 3). DHT treatment was maintained throughout the experimental period. (A) Mean, (B) systolic, and (C) diastolic arterial BP were higher in PCOS rats than in controls at baseline. Lira treatment decreased BP in control rats; however, it did not lower BP in PCOS rats (phase 1). Enalapril treatment abolished the BP differences between PCOS rats and controls (phase 2). The combination of enalapril and Lira further decreased BP in controls but not in PCOS rats (phase 3). (D) HR was significantly lower in PCOS rats at baseline. Lira caused a significant increase in HR in controls over 8 days. From day 9 until the end of the treatment, HR returned to the baseline level (phase 1). In contrast, Lira caused a significant increase in HR in PCOS rats compared with baseline; this increase in HR remained throughout the treatment period (phase 1). Enalapril treatment increased HR in both groups and abolished the differences between them (phase 2). Although Lira and enalapril coadministration further increased HR in PCOS and control groups, the increase in HR was greater in controls than in PCOS rats (phase 3). Data are expressed as mean ± SEM. Data were analyzed by two-way ANOVA followed by multiple-comparison tests corrected by Benjamini and Hochberg false discovery rate method. Significant interactions (treatment and time) were observed in all cases by two-way ANOVA. *P < 0.05 vs controls; #P < 0.05 vs baseline, same treatment; &P < 0.05 vs enalapril, same treatment. n = 6 per group.

Figure 6.

Light/dark cycle variations of BP and HR in postmenopausal PCOS rats. (A) MAP was higher in PCOS during light and dark cycles compared with control. Lira lowered MAP in controls during light and dark cycles; however, no changes were observed in PCOS. (B) HR was higher in control rats during light and dark cycles. Lira increased HR during both light and dark cycles only in PCOS. Data are expressed as mean ± SEM. Data were analyzed by three-way ANOVA followed by Tukey post hoc tests. No significant interactions were observed by three-way ANOVA. *P < 0.05. n = 6 per group.