Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of type 2 diabetes (T2D) compared with age-matched men, but this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating 17β-estradiol (E₂). Fasting hyperglycemia is a hallmark of T2D derived largely from dysregulation of hepatic glucose production (HGP), in which Foxo1 plays a central role in the regulation of gluconeogenesis. Here, we investigated the action of E₂ on glucose homeostasis in male and ovariectomized (OVX) female control and liver-specific Foxo1 knockout (L-F1KO) mice and sought to understand the mechanism by which E₂ regulates gluconeogenesis via an interaction with hepatic Foxo1. In both male and OVX female control mice, subcutaneous E₂ implant improved insulin sensitivity and suppressed gluconeogenesis; however, these effects of E₂ were abolished in L-F1KO mice of both sexes. In our use of mouse primary hepatocytes, E₂ suppressed HGP and gluconeogenesis in hepatocytes from control mice but failed in hepatocytes from L-F1KO mice, suggesting that Foxo1 is required for E₂ action on the suppression of gluconeogenesis. We further demonstrated that E₂ suppresses hepatic gluconeogenesis through activation of estrogen receptor (ER)α–phosphoinositide 3-kinase–Akt–Foxo1 signaling, which can be independent of insulin receptor substrates 1 and 2 (Irs1 and Irs2), revealing an important mechanism for E₂ in the regulation of glucose homeostasis. These results may help explain why premenopausal women have lower incidence of T2D than age-matched men and suggest that targeting ERα can be a potential approach to modulate glucose metabolism and prevent diabetes.

With the increasing knowledge that gender influences normal physiology, much biomedical research has begun to focus on the differential effects of sex on tissue function. Sexual dimorphism in mammals is due to the combined effects of both genetic and hormonal factors. Hormonal factors are mutable particularly in females in whom the estrous cycle dominates the hormonal milieu. Given the severity of the obesity epidemic and the fact that there are differences in the obesity rates in men and women, the role of sex in white adipose tissue function is being recognized as increasingly important. Although sex differences in white adipose tissue distribution are well established, the mechanisms affecting differential function of adipocytes within white adipose tissue in males and females remain largely understudied and poorly understood. One of the largest differences in the endocrine environment in males and females is the concentration of circulating androgens and estrogens. This review examines the effects of androgens and estrogens on lipolysis/lipogenesis, adipocyte differentiation, insulin sensitivity and adipokine production in adipocytes from white adipose tissue with a specific emphasis on the sexual dimorphism of adipocyte function in white adipose tissue during both health and disease.

The effects of androgens have been extensively studied in a variety of organs and cell types with an increasing focus on the sexually dimorphic role androgens play not only with respect to cellular functions but also in metabolism. Although the classical mechanism of androgen action is via ligand-dependent binding with the nuclear transcription factor, androgen receptor (AR), cytosolic AR can also activate second messenger signaling pathways. Given that cytosolic AR can signal in this manner, there has been increased interest in the mechanisms by which androgens may control cellular organelle function. This review highlights the effects that androgens have on mitochondrial structure and function with emphasis on biogenesis, fusion/fission, mitophagy, bioenergetics (oxidative phosphorylation), and reactive oxygen species production. There are a number of publications on the effects of androgens in these general areas of mitochondrial function. However, the precise mechanisms by which androgens cause these effects are not known. In addition, given that the nucleus and mitochondria work in tandem to control mitochondrial function and the mitochondria have their own DNA, future research efforts should focus on the direct, mechanistic effects of androgens on mitochondrial function.

The discrete effects of obesity on infertility in females remain undefined to date. To investigate obesity-induced ovarian dysfunction, we characterized metabolic parameters, steroidogenesis, and folliculogenesis in obese and lean female Ossabaw mini-pigs. Nineteen nulliparous, sexually mature female Ossabaw pigs were fed a high fat/cholesterol/fructose diet (n=10) or a control diet (n=9) for eight months. After a three-month diet-induction period, pigs remained on their respective diets and had ovarian ultrasound and blood collection conducted during a five-month study period after which ovaries were collected for histology, cell culture, and gene transcript level analysis. Blood was assayed for steroid and protein hormones. Obese pigs developed abdominal obesity and metabolic syndrome, including hyperglycemia, hypertension, insulin resistance and dyslipidemia. Obese pigs had elongated estrous cycles and hyperandrogenemia with decreased LH, increased FSH and luteal phase progesterone, and increased numbers of medium, ovulatory, and cystic follicles. Theca cells of obese, compared to control, pigs displayed androstenedione hypersecretion in response to in vitro treatment with LH, and up-regulated 3-beta-hydroxysteroid dehydrogenase 1 and 17-beta-hydroxysteroid dehydrogenase 4 transcript levels in response to in vitro treatment with LH or LH + insulin. Granulosa cells of obese pigs had increased 3-beta-hydroxysteroid dehydrogenase 1 transcript levels. In summary, obese Ossabaw pigs have increased transcript levels and function of ovarian enzymes in the delta 4 steroidogenic pathway. Alterations in LH, FSH, and progesterone, coupled with theca cell dysfunction, contribute to the hyperandrogenemia and disrupted folliculogenesis patterns observed in obese pigs. The obese Ossabaw mini-pig is a useful animal model in which to study the effects of obesity and metabolic syndrome on ovarian function and steroidogenesis. Ultimately, this animal model may be useful toward the development of therapies to improve fertility in obese and/or hyperandrogenemic females or in which to examine the effects of obesity on the maternal-fetal environment and offspring health.