Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Adiposity and Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep

Abstract

Prenatally testosterone (T)-treated sheep present metabolic disruptions similar to those seen in women with polycystic ovary syndrome. These females exhibit an increased ratio of small to large adipocytes, which may be the earliest event in the development of adult insulin resistance. Additionally, our longitudinal studies suggest the existence of a period of compensatory adaptation during development. This study tested whether 1) in utero cotreatment of prenatally T-treated sheep with androgen antagonist (flutamide) or insulin sensitizer (rosiglitazone) prevents juvenile insulin resistance and adult changes in adipocyte size; and 2) visceral adiposity and insulin sensitivity are both unaltered during early adulthood, confirming the predicted developmental trajectory in this animal model. Insulin sensitivity was tested during juvenile development and adipose tissue distribution, adipocyte size, and concentrations of adipokines were determined during early adulthood. Prenatal T-treated females manifested juvenile insulin resistance, which was prevented by prenatal rosiglitazone cotreatment. Neither visceral adiposity nor insulin sensitivity differed between groups during early adulthood. Prenatal T-treated sheep presented an increase in the relative proportion of small adipocytes, which was not substantially prevented by either prenatal intervention. A large effect size was observed for increased leptin concentrations in prenatal T-treated sheep compared with controls, which was prevented by prenatal rosiglitazone. In conclusion, gestational alterations in insulin-glucose homeostasis likely play a role in programming insulin resistance, but not adipocyte size distribution, in prenatal T-treated sheep. Furthermore, these results support the notion that a period of compensatory adaptation of the metabolic system to prenatal T exposure occurs between puberty and adulthood.

Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits

“…In addition to gestational T exposure, fetal T-exposed female monkeys experience transient, mid-gestational hyperglycemia from their dams’ diminished ability to regulate glucose [24], a trait emulated by T-treated pregnant ewes that deliver T-exposed female lambs [25]. As might be expected from such gestational hyperglycemia, fetal female size increases, along with a ~5% enlarged ultrasonography-assessed head diameter, elevated late gestation circulating insulin levels (exceeding the control range in 33–55% of cases), and abnormal fetal lipids levels [24].…”

“…In T-exposed female lambs, prenatal anti-androgen normalizes anogenital distance, prevents early onset of puberty, normalizes LH surge responses to estrous synchronization in the first breeding season, but does not ameliorate metabolic abnormalities [15, 25]. In comparison, insulin sensitizer prenatal treatment prevents insulin resistance and normalizes onset of puberty.…”

Androgens in polycystic ovary syndrome

“…Adipose tissue dysfunction is also present in PCOS, with studies reporting enlarged adipocytes and a decrease in adiponectin circulating levels in PCOS patients [40,41]. Neonatal androgenization of mice decreases adiponectin levels [42], whereas prenatally T-treated sheep exhibit elevated leptin concentrations [43]. In the female rhesus monkey PCOS model, prenatal T excess leads to impaired adult preadipocyte differentiation to adipocytes in abdominal adipose, which may constrain the ability of the adipose depot to safely store fat, thus promoting lipotoxicity [44].…”

“…In the female rhesus monkey PCOS model, prenatal T excess leads to impaired adult preadipocyte differentiation to adipocytes in abdominal adipose, which may constrain the ability of the adipose depot to safely store fat, thus promoting lipotoxicity [44]. Prenatal T-treated sheep also exhibit changes in adipocyte morphology, however, these are not prevented by cotreatment with an androgen antagonist, inferring that estrogenic effects via the aromatization of T to estradiol may be predominant in the altered programming [43]. Insulin resistance and glucose intolerance are observed in a rodent, sheep, and primate androgenized PCOS animal model, indicating that androgenic actions play a pivotal role in glucose and insulin homeostasis.…”

“…Insulin resistance and glucose intolerance are observed in a rodent, sheep, and primate androgenized PCOS animal model, indicating that androgenic actions play a pivotal role in glucose and insulin homeostasis. However, interestingly, in the prenatal DHT rodent model, adipocyte hypertrophy is observed without insulin resistance [18], and in the T-treated sheep model changes in adipocyte size are evident before insulin insensitivity and adiposity [43]. These findings suggest that alterations in adipocyte morphology precede the onset of metabolic dysfunctions, and that possibly it is changes in adipocyte function that in turn lead to the dysregulation of glucose-insulin homeostasis and the manifestation of other metabolic disturbances, however, this remains speculative.…”