Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

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.

Keywords: PCOS; adiponectin; ameliorates; brown adipose tissue; transplantation.

Fig. 1.

BAT transplantation reverses PCOS BAT activity. BAT activity was assessed at the end of the experiment (3 wk after tissue transplantation) by using PET-CT. BAT transplantation could significantly increase endogenous BAT activity in the DHEA+BAT group compared with the DHEA+sham or DHEA+Mus groups (A). Yellow triangle indicates the anatomical site of the interscapular BAT. The activity of brown adipose tissue, expressed as the standard uptake values (SUVs), dramatically decreased in the DHEA+sham and DHEA+Mus groups compared with the control and BAT transplantation groups (B). Furthermore, BAT transplantation could significantly increase BAT-specific marker gene expression (C) and OXPHOS protein expression (D), as well as UCP1 expression (E), compared with the DHEA+sham or DHEA+Mus groups. Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 8–10 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).

Fig. 2.

BAT transplantation reverses PCOS metabolic abnormality. An infrared thermal image demonstrates that cold exposure significantly reduced body temperature of the DHEA+sham and DHEA+Mus groups whereas BAT transplantation significantly reversed DHEA-induced body temperature reduction (A and B). In addition, BAT transplantation significantly increased whole-body energy expenditure compared with the DHEA+sham or DHEA+Mus groups (C and D). Moreover, results from a glucose tolerance test (E) and insulin tolerance test (F) showed that BAT transplantation significantly reversed DHEA-induced glucose intolerance. Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 8–10 per group. (A and B) P < 0.05. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).

Fig. S1.

Effect of BAT transplantation on body weight and food intake. (A) Food intake and (B) body weight were not changed among groups. n = 8–10 per group. Error bars represent means ± SEM.

Fig. S2.

BAT transplantation reverses PCOS metabolic abnormality. BAT transplantation could significantly reverse DHEA-induced glucose intolerance as evidenced by (A) glucose tolerance test (GTT) and (B) insulin tolerance test (ITT), as well as insulin levels during GTT (C). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 8–10 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).

Fig. 3.

BAT transplantation reverses PCOS acyclicity, ovarian phenotypes, and infertility. BAT transplantation could reverse abnormal estrous cycles in the PCOS rodent compared with abnormal estrous cycles in the DHEA+sham and/or DHEA+Mus groups (A). BAT transplantation further significantly reversed the concentrations of luteinizing hormone (LH) levels, as well as the LH/FSH ratio, to normal control levels compared with the DHEA+sham and DHEA+Mus groups (B and C). (D) Ovarian histology revealed that cystic follicles (arrow) appeared in the DHEA+sham and DHEA+Mus groups but not in the DHEA+BAT group. In addition, few corpora lutea (CL, asterisk) and low levels of TH expression were observed in the BAT transplantation group but not in the muscle transplantation group (D). Consistent with histology results, the expression of ovarian steroidogenic enzymes was dramatically reversed after BAT transplantation (E), and the DHEA+BAT group rats, but not the DHEA+sham and DHEA+Mus group rats, were also able to mate with proven stud males and produce a little (F). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 8–10 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05). D, diestrus; E, estrus; M, metestrus; P, proestrus.

Fig. 4.

Adiponectin recapitulates the beneficial effects of BAT transplantation. Adiponectin treatment could significantly increase endogenous BAT activity compared with DHEA groups as evidenced by PET-CT (A and B). Moreover, Infrared thermal images demonstrated that adiponectin treatment significantly reversed DHEA-mediated body temperature reduction (C and D). A glucose tolerance test (E) and insulin tolerance test (F) showed that adiponectin treatment significantly improved DHEA -induced insulin resistance (inner graph indicating area under the curve of GTT and ITT, respectively). Data were analyzed by one-way ANOVA with Tukey’s post hoc test; n = 6 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).

Fig. 5.

Adiponectin reverses PCOS acyclicity, ovarian phenotypes, and infertility. The concentrations of luteinizing hormone (LH) and the LH/FSH ratio were significantly increased in the DHEA group compared with the control group, and it was reversed to a normal level after adiponectin treatment (A and B). In addition, adiponectin treatment could significantly reverse DHEA-induced acyclicity (C) and pregnant capacity in the PCOS rodent (D). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 6 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).

Fig. S3.

Adiponectin treatment increases energy expenditure. Circulating adiponectin levels were significantly decreased in both the PCOS patient and rat model compared with their respective controls (A and B). Data were analyzed by unpaired t test in A. n = 40 per group. **P < 0.01 versus control or analyzed by one-way ANOVA with Tukey’s post hoc test in B. n = 8–10 per group. Different characters indicate P < 0.05. Adiponectin treatment increases oxygen consumption (C and D). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. n = 6 per group. Different lowercase letters indicate significant differences among groups (One-way ANOVA, with Tukey’s post hoc test, P < 0.05).