Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy affecting women of reproductive age. Although a comorbidity of PCOS is obesity, many are lean. We hypothesized that increased saturated fat consumption and obesity would exacerbate metabolic and stress indices in a rodent model of PCOS. Female rats were implanted with the nonaromatizable androgen dihydrotestosterone (DHT) or placebo pellets prior to puberty. Half of each group was maintained ad libitum on either a high-fat diet (HFD; 40% butter fat calories) or nutrient-matched low-fat diet (LFD). Irrespective of diet, DHT-treated animals gained more body weight, had irregular cycles, and were glucose intolerant compared with controls on both diets. HFD/DHT animals had the highest levels of fat mass and insulin resistance. DHT animals demonstrated increased anxiety-related behavior in the elevated plus maze by decreased distance traveled and time in the open arms. HFD consumption increased immobility during the forced-swim test. DHT treatment suppressed diurnal corticosterone measurements in both diet groups. In parallel, DHT treatment significantly dampened stress responsivity to a mild stressor. Brains of DHT animals showed attenuated c-Fos activation in the ventromedial hypothalamus and arcuate nucleus; irrespective of DHT-treatment, however, all HFD animals had elevated hypothalamic paraventricular nucleus c-Fos activation. Whereas hyperandrogenism drives overall body weight gain, glucose intolerance, anxiety behaviors, and stress responsivity, HFD consumption exacerbates the effect of androgens on adiposity, insulin resistance, and depressive behaviors.

Discovery of novel lipid profiles in PCOS: Do insulin and androgen oppositely regulate bioactive lipid production?

“…The model has a number of clinical and pathological features in common with obese patients with PCOS, such as obesity, hyperinsulinemia, hyperandrogenism, ovarian follicle immaturity, and ovulation disorders (37, 38). Compared with the control group (CON; normal diet), the HF group had significantly higher body mass and prominent hyperinsulinemia.…”

Maternal androgen excess and obesity induce sexually dimorphic anxiety‐like behavior in the offspring

“…However, the specific role of androgens and the mechanisms underlying these complications are largely unknown. Studies in female rodents have demonstrated that continuous exposure to androgens (testosterone or DHT) increases anxiety-like behavior (23,24), but studies of androgens and anxietylike behaviors in males have yielded inconsistent findings (25) and show either anxiolytic (26)(27)(28) or anxiogenic effects (29).…”

Obesity induces ovarian inflammation and reduces oocyte quality

“…Interestingly, the level of cytokines and MDA are also higher in obese PCOS compared to obese non-PCOS women, although both have higher TNFα and MDA levels than lean PCOS and lean controls (Alshammari et al 2017, Artimani et al 2018. These data suggest that PCOS exacerbates obesity-dependent ovarian inflammation and oxidative stress (Ressler et al 2015). Distinct metabolic differences between obesity and PCOS include hyperandrogenemia, that is, obese women without PCOS have circulating total testosterone concentrations similar to lean control women (Keskin Kurt et al 2014, Alshammari et al 2017, Usta et al 2018.…”