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Interactions among Peroxisome Proliferator Activated Receptor-, Insulin Signaling Pathways, and Steroidogenic Acute Regulatory Protein in Human Ovarian Cells

G. J. Friedman Diabetes Institute and the Division of Endocrinology, Department of Medicine (D.S.-Y., D.A., M.S., G.P., P.P., J.K., L.P.), Department of Obstetrics and Gynecology (K.H.), Beth Israel Medical Center and Albert Einstein College of Medicine, New York, New York 10003; Institute of Biology and Immunology of Reproduction (D.A.), Bulgarian Academy of Sciences, Sofia 1113, Bulgaria; and Center for Reproductive Medicine and Infertility (Z.R.), Weill Medical College of Cornell University, New York, New York 10021

Address all correspondence and requests for reprints to: Leonid Poretsky, M.D., or Donna Seto-Young, Ph.D., Division of Endocrinology, Beth Israel Medical Center, Seventh Floor, Fierman Hall, 317 East 17th Street, New York, New York 10003. E-mail: lporetsk{at}bethisraelny.org and dyoung{at}chpnet.org, respectively.

Context and Objective: Peroxisome proliferator activated receptor- (PPAR-) agonists thiazolidinediones (TZDs) are thought to ameliorate hyperandrogenism in polycystic ovary syndrome by reducing hyperinsulinemia. However, TZDs also exhibit direct effects in the human ovary. We examined interactions among PPAR-, insulin signaling pathways, and steroidogenic acute regulatory (StAR) protein in human ovarian cells.

Materials and Methods: Mixed human ovarian tissue culture that contained granulosa, theca, and stromal cells, and a culture of purified granulosa cells obtained during in vitro fertilization, were established as previously described. Cells were cultured in the presence or absence of insulin, with or without 25 or 50 µM rosiglitazone or pioglitazone. Expression of PPAR-, insulin receptor, or insulin receptor substrate (IRS)-1 in both cell systems and of the StAR protein in granulosa cells was measured using immunoprecipitation and immunoblotting.

Results: Rosiglitazone stimulated expression of PPAR-, insulin receptor - and ß-subunits, and IRS-1 up to 168% (P < 0.05), 679% (P < 0.006), 290% (P < 0.037), and 323% (P < 0.01) of baseline, respectively. Pioglitazone stimulated expression of PPAR-, insulin receptor - and ß-subunits, and IRS-1 up to 222% (P < 0.01), 362% (P < 0.001), 402% (P < 0.029), and 492% (P < 0.03), respectively. Insulin alone stimulated expression of PPAR-, -subunit and ß-subunit of insulin receptor, and IRS-1 up to 174% (P < 0.001), 692% (P < 0.014), 275% (P < 0.024), and 431% (P < 0.01), respectively. In purified granulosa cell culture, rosiglitazone stimulated expression of StAR protein up to 540% (P < 0.007), and pioglitazone stimulated expression of StAR protein up to 670% (P < 0.007). Insulin alone stimulated expression of StAR protein up to 600% (P < 0.012).

Conclusions: Insulin and TZDs independently stimulate expression of PPAR-, insulin receptor, IRS-1, and StAR protein in human ovarian cells. Thus, PPAR-, insulin receptor with its signaling pathways, and StAR protein constitute a novel human ovarian regulatory system with complex interactions among its components.

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