Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance

Abstract

Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females.

Exposure to a Healthy Gut Microbiome Protects Against Reproductive and Metabolic Dysregulation in a PCOS Mouse Model

“…As reported in previous studies (27, 29, 30), five weeks of letrozole treatment resulted in increased FBG and insulin levels and insulin resistance (Fig. 1D-F).…”

“…1B, weight was measured each week during the 5 weeks of treatment. Similarly to previously published studies (27, 30), 2 weeks of letrozole treatment resulted in increased weight compared to placebo treatment that was maintained for the rest of the study (Fig. 1B).…”

“…1B-C). It is noteworthy that our previous study showed that letrozole treatment induced weight gain and abdominal adiposity in female mice without a change in food intake or total energy expenditure (30). Since studies have indicated that obesity may be influenced by an increased capacity of the gut microbiome to harvest energy from dietary fiber (21), it would be informative to test whether this occurs in the letrozole-treated gut microbiome and whether exposure to a healthy gut microbiome ameliorated this effect.…”

“…Letrozole treatment of pubertal female mice results in the recapitulation of many reproductive hallmarks of PCOS including hyperandrogenism, acyclicity, polycystic ovaries, and elevated luteinizing hormone (LH) levels. This model also exhibits metabolic dysregulation similar to the phenotype in women with PCOS including weight gain, abdominal adiposity, increased fasting blood glucose (FBG) and insulin levels, impaired glucose stimulated-insulin secretion, insulin resistance, and dyslipidemia (30). A caveat is that low estrogen levels in this model do not reflect estrogen levels in women with PCOS.…”

Letrozole treatment of pubertal female mice results in activational effects on reproduction, metabolism and the gut microbiome

“…Letrozole treatment resulted in many reproductive hallmarks of PCOS including hyperandrogenism, acyclicity, polycystic ovaries, and elevated luteinizing hormone (LH) levels [26]. This model also exhibited metabolic dysregulation including weight gain, abdominal adiposity, increased fasting blood glucose (FBG) and insulin levels, and insulin resistance [27]. In addition, we demonstrated that changes in the gut microbiome were associated with letrozole treatment [28].…”