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.

Impact of SGLT-2 Inhibition on Cardiometabolic Abnormalities in a Rat Model of Polycystic Ovary Syndrome

“…Our PCOS model mimics several of the cardiometabolic features observed in women with PCOS, such as increases in BP and BMI, and decreases in insulin sensitivity. BP in this PCOS model is elevated by ~10 mmHg [ 25 , 29 , 30 ]. We also previously reported that blocking the RAS with an ACE inhibitor eliminated BP differences between treated PCOS and control rats [ 30 ], implicating activation of the RAS in the elevation of BP in our model.…”

“…BP in this PCOS model is elevated by ~10 mmHg [ 25 , 29 , 30 ]. We also previously reported that blocking the RAS with an ACE inhibitor eliminated BP differences between treated PCOS and control rats [ 30 ], implicating activation of the RAS in the elevation of BP in our model. Indeed, women with PCOS have hyperreninemia [ 23 ] and blockade of the AT1R was effective in decreasing the BP of women with PCOS [ 24 ].…”

“…During EMPA treatment, food intake and fluid intake were recorded daily and body weight was recorded weekly. Body composition (fat and lean mass) was measured before and after EMPA treatment by EchoMRI (4in1-900 model Body Composition Analyzer, EchoMRI, Houston, TX, USA), as we previously reported [ 30 ]. At the end of the experimental period, body length (nose–anus length) was measured to calculate BMI.…”

“…Then, rats were euthanized, and blood was collected for DHT, leptin, and HbA1c levels. Plasma leptin was measured by ELISA (R & D Systems, Inc., Minneapolis, MN, USA) as we previously reported [ 30 ]. Leptin was reported as ng/mL.…”

“…We showed that the hyperandrogenemic rat model of PCOS recapitulates several cardiometabolic features observed in women with PCOS, including increased body mass index (BMI), IR, BP, hyperleptinemia, albuminuria, and activation of the intrarenal RAS [ 25 , 29 , 30 ]. In this study, we hypothesized that androgens upregulate the expression of renal SGLT2 and that SGLT2 inhibition ameliorates the cardiometabolic complications in an experimental model of PCOS.…”