Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

Yuan, Xiaoxue; Hu, Tao; Zhao, Han; Huang, Yuanyuan; Ye, Rongcai; Lin, Jun; Zhang, Chuanhai; Zhang, Hanlin; Wei, Gang; Zhou, Huiqiao; Dong, Meng; Zhao, Jun; Wang, Haibin; Liu, Qingsong; Lee, Hyuek Jong; Jin, Wanzhu; Chen, Zi‐Jiang

doi:10.1073/pnas.1523236113

Cited by 148 publications

(124 citation statements)

References 41 publications

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“…Adiponectin, postulated to be a beneficial adipokine due to its insulin-sensitizing property and antiatherogenic action (40), is reduced in women with PCOS (41). Treatment with adiponectin in a rat model of PCOS ameliorates the PCOS phenotype by reversing acyclicity and PCOS ovarian features, and also improves glucose homeostasis (42). Serum adiponectin levels were reduced in our PCOS mouse model, and this effect was protected by global loss of AR function but not by neuronor granulosa cell-specific loss of AR actions.…”

Section: Discussionmentioning

confidence: 99%

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Caldwell

Edwards

Desai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

168

185

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Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanismbased treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.PCOS | androgen | animal model | neuroendocrine P olycystic ovary syndrome (PCOS) is the most frequent endocrine disorder of young women, with a prevalence of 6 to 15% (1), and accounts for more than 75% of anovulatory infertility (2). It is characterized by reproductive hormone dysregulation involving luteinizing hormone (LH) hypersecretion and hyperandrogenism (3), the consequences of which can be acne and hirsutism, as well as reduced fertility, due to aberrant follicular maturation, ovulatory disturbance, and miscarriage (3). Associated nonreproductive abnormalities, such as obesity, metabolic syndrome, hyperinsulinemia, insulin resistance, hepatic steatosis, and dyslipidemia predispose affected women to heightened risk of cardiovascular disease and type 2 diabetes (3, 4). However, despite the high prevalence and significant health impact, the pathogenesis of PCOS remains unclear so that mechanism-based treatments remain unattainable.Hyperandrogenism, the most consistent feature of PCOS (5), is implicated as a key mediator in the pathogenesis of PCOS. Supportive evidence includes that androgen excess from endogenous [congenital adrenal hyperplasia (6)] or exogenous [female-to-male transsexuals (7)] sources can produce polycystic ovaries. Furthermore, androgens induce reproductive, metabolic, and endocrine features of PCOS in rodent, sheep, and primate animal models of PCOS (8-10). As all androgen action is mediated via the androgen receptor (AR),...

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Section: Discussionmentioning

confidence: 99%

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Caldwell

Edwards

Desai

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

168

185

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“…Furthermore, the expression pattern of the adiponectin system (adiponectin, AdipoRs and APPL1) has been studied in patients with PCOS, and a reduction of APPL1 and the adiponectin system was observed in human granulosa cells (Dehghan et al 2016). Furthermore, recently Yuan and coworkers showed that brown adipose tissue (BAT) transplantation activated endogenous BAT and increased the circulating level of adiponectin in a dehydroepiandrosterone (DHEA)-induced PCOS rat (Yuan et al 2016). Comim and coworkers also showed that a lower proportion of theca cells expressed AdipoRs in polycystic ovaries than that in normal ovaries (Comim et al 2013).…”

Section: Potential Involvement Of Adiponectin and Resistin In Some Pamentioning

confidence: 99%

Adiponectin and resistin: potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species

Rak¹,

Mellouk²,

Froment³

et al. 2017

Reproduction

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Adipokines, including adiponectin and resistin, are cytokines produced mainly by the adipose tissue. They play a significant role in metabolic functions that regulate the insulin sensitivity and inflammation. Alterations in adiponectin and resistin plasma levels, or their expression in metabolic and gonadal tissues, are observed in some metabolic pathologies, such as obesity. Several studies have shown that these two hormones and the receptors for adiponectin, AdipoR1 and AdipoR2 are present in various reproductive tissues in both sexes of different species. Thus, these adipokines could be metabolic signals that partially explain infertility related to obesity, such as polycystic ovary syndrome (PCOS). Species and gender differences in plasma levels, tissue or cell distribution and hormonal regulation have been reported for resistin and adiponectin. Furthermore, until now, it has been unclear whether adiponectin and resistin act directly or indirectly on the hypothalamo-pituitary-gonadal axis. The objective of this review was to summarise the latest findings and particularly the species and gender differences of adiponectin and resistin on female and male reproduction known to date, based on the hypothalamo-pituitary-gonadal axis.Reproduction (2017) 153 R215-R226

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“…Postprandial thermogenesis increases by 0.5-1 degree thanks to this BAT-mediated process, keeping the energy balance stable despite the caloric surplus. Many improvements such as increased body temperature, increased oxygen use and diminished insulin counter regulation have been proved after transplants of BAT in PCOS-suffering experimental models [9].…”

Section: Brown Adipose Tissue and Pcosmentioning

confidence: 99%

PCOS and diabetes mellitus: from insulin resistance to altered beta pancreatic function, a link in evolution

Condorelli

Calogero

Mauro

et al. 2017

Gynecological Endocrinology

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Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

Cited by 148 publications

References 41 publications

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Adiponectin and resistin: potential metabolic signals affecting hypothalamo-pituitary gonadal axis in females and males of different species

PCOS and diabetes mellitus: from insulin resistance to altered beta pancreatic function, a link in evolution

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