HONG KONG — Researchers in China have demonstrated that endogenous brown adipose tissue (BAT) is closely related to the development of a polycystic ovarian syndrome (PCOS) phenotype in rats, suggesting that BAT activation might represent a promising therapeutic option for management of PCOS in humans.

One of the most common endocrine problems, affecting 5 to 10 percent of all women of reproductive age, PCOS is a common cause of infertility. It is characterized by anovulation and hyperandrogenism, as well as by polycystic ovaries.

Consequently, women with the syndrome may suffer from "irregular, long, or no periods, polycystic ovaries seen on pelvic ultrasound scanning, and effects due to high androgen levels, such as having excessive hair and a high serum testosterone level," said Ernest Hung Yu Ng, a clinical professor in the Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong.

PCOS is also associated with a significant burden of disease. "It can lead to infertility, metabolic syndrome, diabetes mellitus, depression, a lower quality of life and an increased incidence of endometrial cancer," he said.

Nevertheless, the treatments available for PCOS are mainly symptomatic, including "weight reduction for those patients who are obese, drugs for inducing periods..., and treatment to induce ovulation in women attempting to get pregnant," said Ng.

However, apart from generally being considered to be due to a combination of environmental and genetic factors, the cause of PCOS at the molecular level remains largely unknown, hence there is currently no cure or specific treatment available for the condition.

"PCOS is not curable, but the symptoms may resolve when the patients get older," advised Ng – somewhat cold comfort to those patients who are struggling with infertility.

Now, research by Zi-Jiang Chen, a professor in obstetrics and gynecology and director of the Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, and colleagues has shown that BAT transplantation reversed the characteristics of PCOS in rats in which PCOS had been induced by injection of the endogenous human steroid dehydroepiandrosterone (DHEA).

"The transplantation of exogenous BAT into the rat models of PCOS was shown to activate endogenous BAT and then reverse hyperandrogenism, anovulation and polycystic ovaries," said Chen, who led the research team together with Wan-Zhu Jin, a professor in the Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing.

BAT transplantation into PCOS rats was also shown to significantly stabilize menstrual irregularity and improve systemic insulin sensitivity up to a normal level – the key features of PCOS – with that effect not being shown in the sham-operated or muscle-transplanted PCOS rats that were used as controls.

"The sham-operated group acted as normal controls, which eliminated the influence of the operation [on the results], while the same amount of muscle being transplanted served as the negative controls," explained Chen, noting that each group contained eight to 10 rats and that each experiment was repeated separately three times.

The finding that BAT transplantation stabilized menstrual irregularity and improved systemic insulin sensitivity was of particular significance. "PCOS is a complex and heterogeneous syndrome that is associated with a high risk for the development of insulin resistance, type 2 diabetes, obesity, dyslipidemia and cardiovascular disease," Chen told BioWorld Today.

"Because the clinical features are complex and vary among PCOS patients, it is hard to provide first-line treatment for PCOS," she noted. "We showed that BAT transplantation can improve the insulin sensitivity of PCOS rats and ultimately alleviate the symptoms of PCOS, such as menstrual irregularity, a finding which provides a clue to the clinical treatment of PCOS patients."

Moreover, BAT transplantation, but not the sham operation or the transplantation of muscular tissue, surprisingly improved fertility in the PCOS rats, the Shandong University researchers reported in the Feb. 23, 2016, early online edition of Proceedings of the National Academy of Sciences.

"BAT transplantation increased the activity of endogenous BAT, which was shown to secrete a series of cytokines, including fibroblast growth factor 21, interleukin-6 and adiponectin, et cetera," said Chen. "Our results prove that adiponectin plays an important role in improving insulin resistance of PCOS rats and ultimately partly ameliorates the symptoms of PCOS, including infertility."

BAT transplantation was shown to activate endogenous BAT, thereby increasing the circulating level of adiponectin, the protein hormone secreted by adipose tissue that plays a prominent role in whole-body energy metabolism via glucose regulation and fatty acid oxidation, and in ovarian physiology.

Mechanistically, transplanted BAT enhanced endogenous BAT activity and thereby increased the circulating adiponectin level, which was found to be lower in both PCOS patients and in the PCOS rat models. That is an important finding, as it confirms that BAT is the endocrine organ that secretes the cytokines involved in the pathophysiology of the PCOS, said Chen. "When compared to the normal control individuals, the adiponectin level were significantly lower in the PCOS patients," she told BioWorld Today.

Furthermore, as with BAT transplantation, the administration of exogenous adiponectin protein dramatically rescued DHEA-induced PCOS phenotypes in the rat models.

"In a publication last year in the journal Endocrinology, we showed that after BAT transplantation, the level of adiponectin was significantly elevated compared with sham-operated animals. Therefore, we speculate that adiponectin is the BAT-secreted adipokine that is involved in the pathophysiology of the PCOS," said Chen.

"Taken together, these data highlight the important role of BAT in the development of PCOS and that BAT-induced adiponectin might open up a new way in the treatment of PCOS," she said.

"In our next step, we will focus on how to activate and/or recruit endogenous BAT through a safer, simpler and more effective method, such as by screening out some natural molecules besides cold stimulation, which accumulating evidence indicates is the safest way to activate BAT. Our ultimate goal is the treatment of PCOS patients with a safe and effective BAT activator agent."