Rat BAT xenotransplantation recovers the fertility and metabolic health of PCOS mice

Du, Lei; Wang, Yang; Li, Congrong; Chen, Liang-Jian; Cai, Jinyang; Xia, Zhengrong; Zeng, Wentao; Wang, Zibin; Chen, Xichen; Hu, Fan; Zhang, Dong; Xing, Xiaowei; Yang, Zhiyun

doi:10.1530/joe-20-0068

Cited by 25 publications

(24 citation statements)

References 37 publications

(63 reference statements)

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“…Emerging evidence indicates that brown adipose tissue (BAT) transplantation plays a role in improving both the reproductive and metabolic phenotypes in PCOS animal models ( 8 , 9 ). Interestingly, several studies suggest that BAT plays an endocrine role by secreting brown adipokines, such as growth and differentiation factor 15 and fibroblast growth factor 21 ( 9 , 10 ). These brown adipokines could protect beta cell function, improve insulin sensitivity, and mediate the metabolic effects in obese mice ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

et al. 2021

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Polycystic ovary syndrome (PCOS) is a complex reproductive, endocrine, and metabolic disorder in reproductive-age women. In order to explore the active metabolites of brown adipose tissue (BAT) transplantation in improving the reproductive and metabolic phenotypes in a PCOS rat model, the metabolites in the recipient’s BAT were explored using the liquid chromatography–mass spectrometry technique. In total, 9 upregulated and 13 downregulated metabolites were identified. They were roughly categorized into 12 distinct classes, mainly including glycerophosphoinositols, glycerophosphocholines, and sphingolipids. Ingenuity pathway analysis predicted that these differentially metabolites mainly target the PI3K/AKT, MAPK, and Wnt signaling pathways, which are closely associated with PCOS. Furthermore, one of these differential metabolites, sphingosine belonging to sphingolipids, was randomly selected for further experiments on a human granulosa-like tumor cell line (KGN). It significantly accelerated the apoptosis of KGN cells induced by dihydrotestosterone. Based on these findings, we speculated that metabolome changes are an important process for BAT transplantation in improving PCOS. It might be a novel therapeutic target for PCOS treatment.

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Section: Introductionmentioning

confidence: 99%

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

et al. 2021

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“…In multiple studies, improvement of PCOS was accompanied by recovery of BAT activity ( 30 , 35 ). Research also indicates that BAT transplantation can reverse polycystic ovaries, insulin resistance, and infertility in PCOS rats and mice ( 27 , 29 ). Notably, BAT transplantation is a technique that requires a high level of clinical complexity, which increases the challenges of its clinical application.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that human PCOS patients had lower BAT activity (28). BAT transplantation significantly increased insulin sensitivity, and ameliorated hyperandrogenism, acyclicity, and infertility in rat and mouse models of PCOS (27,29). Treatment with rutin, a novel compound that activates BAT, dramatically increased BAT activity, improved systemic insulin resistance, and restored ovarian function (30).…”

Section: Introductionmentioning

confidence: 98%

Brown Adipose Tissue Activation by Cold Treatment Ameliorates Polycystic Ovary Syndrome in Rat

Yan

Zhou

et al. 2021

Front. Endocrinol.

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Polycystic ovary syndrome (PCOS) is a common endocrine disease accompanied by energetic metabolic imbalance. Because the etiology of PCOS is complex and remains unclear, there is no effective and specific treatment for PCOS. It is often accompanied by various metabolic disorders such as obesity, insulin resistances, and others. Activated brown adipose tissue (BAT) consumes excess energy via thermogenesis, which has positive effects on energy metabolism. Our previous research and that of others indicates that BAT activity is decreased in PCOS patients, and exogenous BAT transplantation can improve PCOS rodents. Notably however, it is difficult to apply this therapeutic strategy in clinical practice. Therapeutic strategies of enhancing endogenous BAT activity and restoring whole-body endocrine homeostasis may be more meaningful for PCOS treatment. In the current study, the dehydroepiandrosterone-induced PCOS rat was exposed to low temperature for 20 days. The results show that cold treatment could reverse acyclicity of the estrous cycle and reduce circulating testosterone and luteinizing hormone in PCOS rats by activating endogenous BAT. It also significantly reduced the expression of steroidogenic enzymes as well as inflammatory factors in the ovaries of PCOS rats. Histological investigations revealed that cold treatment could significantly reduce ovary cystic follicles and increase corpus luteum, indicating that ovulation was recovered to a normal level. Concordant with these results, cold treatment also improved fertility in PCOS rats. Collectively, these findings suggest that cold treatment could be a novel therapeutic strategy for PCOS.

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“…Polycystic ovary syndrome (PCOS) is a complicated and heterogeneous reproductive-endocrine-metabolic disorder in women and is closely associated with obesity, insulin resistance, type 2 diabetes, liver damage, etc. Recent studies suggest that adipose tissues, including white adipose tissue (WAT) and brown adipose tissue (BAT), play important roles in the occurrence, development, and prognosis of PCOS [ 1 , 2 ]. About half of all women with PCOS suffer from central obesity and overweight [ 3 ], and the incidence rates of infertility, cardiovascular disease, diabetes, and non-alcohol fatty liver in PCOS patients with obesity are significantly higher than in lean PCOS patients.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional visualization of electroacupuncture-induced activation of brown adipose tissue via sympathetic innervation in PCOS rats

Gao

Tong

et al. 2022

Chin Med

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Background Low-frequency electroacupuncture (EA) has been shown to ameliorate obesity and reproductive dysfunctions in patients with polycystic ovary syndrome (PCOS), and further explorations in PCOS-like rats showed that EA could affect white adipose tissue. However, the function and neuromodulation of brown adipose tissue (BAT) in PCOS and after EA treatment have remained unknown. The present study focused on the role of BAT in PCOS-like rats and its relationship with EA and characterized the three-dimensional (3D) innervation of BAT associated with activation molecules. Methods Female rats (21 days old) were implanted with dihydrotestosterone or fed with a high fat diet to establish PCOS-like and obesity models, respectively, and then EA treatment at “Guilai” (ST 29) and “Sanyinjiao” (SP 6) was carried out for 4 weeks. In the present study, morphological analysis, 3D imaging, molecular biology, and other experimental techniques were used to study the sympathetic nerves and activity of BAT. Results PCOS-like rats showed both obvious weight gain and reproductive dysfunction, similar to what was seen in obese rats except for the absence of reproductive dysfunction. The body weight gain was mainly caused by an increase in white adipose tissue, and there was an abnormal decrease in BAT. Because both the lipid metabolism and reproductive disorders could be improved with bilateral EA at “Guilai” (ST 29) and “Sanyinjiao” (SP 6), especially the restoration of BAT, we further investigated the neuromodulation and inflammation in BAT and identified the sympathetic marker tyrosine hydroxylase as one of the key factors of sympathetic nerves. Modified adipo-clearing technology and 3D high-resolution imaging showed that crooked or dispersed sympathetic nerves, but not the twisted vasculature, were reconstructed and associated with the activation of BAT and are likely to be the functional target for EA treatment. Conclusion Our study highlights the significant role of BAT and its sympathetic innervations in PCOS and in EA therapy.

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Rat BAT xenotransplantation recovers the fertility and metabolic health of PCOS mice

Cited by 25 publications

References 37 publications

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

Brown Adipose Transplantation Improves Polycystic Ovary Syndrome-Involved Metabolome Remodeling

Brown Adipose Tissue Activation by Cold Treatment Ameliorates Polycystic Ovary Syndrome in Rat

Three-dimensional visualization of electroacupuncture-induced activation of brown adipose tissue via sympathetic innervation in PCOS rats

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