| Abstract: | Polycystic ovary syndrome (PCOS), which is characterized by anovulation, hyperandrogenism, and polycystic ovaries, is a complex endocrinopathy. Because the cause of PCOS at the molecular level is largely unknown, there is no cure or specific treatment for PCOS. Here, we show that transplantation of brown adipose tissue (BAT) reversed anovulation, hyperandrogenism, and polycystic ovaries in a dehydroepiandrosterone (DHEA)-induced PCOS rat. BAT transplantation into a PCOS rat significantly stabilized menstrual irregularity and improved systemic insulin sensitivity up to a normal level, which was not shown in a sham-operated or muscle-transplanted PCOS rat. Moreover, BAT transplantation, not sham operation or muscle transplantation, surprisingly improved fertility in PCOS rats. Interestingly, BAT transplantation activated endogenous BAT and thereby increased the circulating level of adiponectin, which plays a prominent role in whole-body energy metabolism and ovarian physiology. Consistent with BAT transplantation, administration of adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes. These results highlight that endogenous BAT activity is closely related to the development of PCOS phenotypes and that BAT activation might be a promising therapeutic option for the treatment of PCOS.Polycystic ovary syndrome (PCOS) is now recognized as one of the most common endocrine diseases in women of reproductive age. The prevalence of PCOS ranges from 9% to 18%, depending on the criteria used for its definition and ethnicity (1, 2). The core feature of PCOS includes polycystic ovaries, hyperandrogenism, and chronic anovulation. Furthermore, PCOS is a complex and heterogeneous syndrome because it is associated with a high risk for the development of insulin resistance, type 2 diabetes (T2D), obesity, dyslipidemia, and cardiovascular disease (3–5). There are three different criteria used for the diagnosis of PCOS: androgen excess, irregular menstruation, and polycystic ovary appearance on ultrasound after excluding other causes of hyperandrogenism and anovulation (6). Because a single etiologic factor is not able to fully account for all of the clinical features in PCOS, the pathogenesis of PCOS is largely unknown. Several genetic and environmental factors may contribute to the development of PCOS; however, the underlying cellular mechanism of the induction and progression of PCOS remains to be elucidated.Insulin resistance, which is common among PCOS patients, seems to be a key etiological characteristic, and about 85% of women with PCOS suffer from insulin resistance (7). Compensatory hyperinsulinemia can directly stimulate ovarian and adrenal secretion of androgen and decrease hepatic sex hormone binding globulin (SHBG) synthesis, resulting in an increased bioavailability of free testosterone levels (8, 9). Thus, insulin resistance and hyperandrogenism contribute to the key clinical presentation of PCOS. Because the clinical features are complex and vary among PCOS patients, it is hard to provide the first-line treatment of PCOS. Most treatment guidelines recommend that patients change lifestyles, including exercise and dietary modification. Patients can take oral contraceptive pills (OCPs) to control symptoms of hyperandrogenism or take insulin-sensitizing medicines such as metformin or pioglitazone when they have impaired glucose tolerance or features of a metabolic syndrome (10). However, there is a lack of effective treatment for PCOS at present.It has been reported that the functional abnormality of adipose tissue in PCOS patients is primarily linked to insulin resistance, even in the absence of obesity (11, 12). In humans and other mammals, there are mainly two types of adipose tissue with opposing functions: white adipose tissue (WAT) and brown adipose tissue (BAT). The main function of WAT is to store excess energy in WAT as a form of triglycerides whereas BAT contains large numbers of mitochondria that uncouple large amounts of fuel for heat generation and the maintenance of body temperature (13). Recent studies using positron emission tomography (PET) have demonstrated that human adults also possess metabolically active BAT (14, 15) and that BAT activation inversely correlates with age and body mass index (BMI) (16). Therefore, increasing BAT mass and/or function is a promising strategy to treat obesity and metabolic diseases. Indeed, studies by our group and others have shown that BAT transplantation reverses metabolic disorders in various obese mouse models (17–19).Given the several common features between PCOS and a metabolic syndrome, we aimed to investigate whether BAT possibly plays an important role in the development of PCOS phenotypes and the treatment of PCOS. In the current study, we show that BAT activity was dramatically reduced in a dehydroepiandrosterone (DHEA) (a precursor of androgen)-induced PCOS rat compared with a normal control rat. Notably, the key features of PCOS, such as insulin resistance, irregular estrous cycle, and low birth rate, were significantly improved after BAT transplantation in PCOS rats. Interestingly, transplanted BAT in PCOS rats enhanced endogenous BAT activity and thereby increased the circulating adiponectin level, which was lower in both PCOS patients and PCOS rats. In parallel, exogenous adiponectin protein administration in a PCOS rat recapitulated the effects that were seen in a BAT-transplanted PCOS rat. Taken together, these data suggest that BAT is one of the important organs regulating the features of PCOS and that the increase of BAT mass or its activity might provide a new therapeutic strategy for the treatment of PCOS. |
