Insulin Signaling Displayed a Differential Tissue-specific Response to Low-dose Dihydrotestosterone in Female Mice

Overview

Journal Am J Physiol Endocrinol Metab

Publisher American Physiological Society

Specialties Endocrinology
Physiology

Date 2018 Jan 20

PMID 29351485

Citations 11

Authors

Stanley Andrisse

Katelyn Billings

Ping Xue

Sheng Wu

Affiliations

Soon will be listed here.

Abstract

Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

Citing Articles

Reappraising the relationship between hyperinsulinemia and insulin resistance in PCOS.

Houston E, Templeman N, Templeman N J Endocrinol. 2025; .

PMID: 40013621 PMC: 11906131. DOI: 10.1530/JOE-24-0269.

Comparison of Reproductive Function Between Normal and Hyperandrogenemia Conditions in Female Mice With Deletion of Hepatic Androgen Receptor.

Feng M, Divall S, Jones D, Ubba V, Fu X, Yang L Front Endocrinol (Lausanne). 2022; 13:868572.

PMID: 35757434 PMC: 9218244. DOI: 10.3389/fendo.2022.868572.

Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females.

Andrisse S, Feng M, Wang Z, Awe O, Yu L, Zhang H FASEB J. 2021; 35(10):e21921.

PMID: 34547140 PMC: 9097557. DOI: 10.1096/fj.202100961R.

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue.

Wawrzkiewicz-Jalowiecka A, Lalik A, Soveral G Int J Mol Sci. 2021; 22(10).

PMID: 34069293 PMC: 8157194. DOI: 10.3390/ijms22105226.

DHT causes liver steatosis via transcriptional regulation of SCAP in normal weight female mice.

Seidu T, McWhorter P, Myer J, Alamgir R, Eregha N, Bogle D J Endocrinol. 2021; 250(2):49-65.

PMID: 34060475 PMC: 8240729. DOI: 10.1530/JOE-21-0040.

References

Wu S, Divall S, Wondisford F, Wolfe A . Reproductive tissues maintain insulin sensitivity in diet-induced obesity. Diabetes. 2011; 61(1):114-23. PMC: 3237653. DOI: 10.2337/db11-0956. View

Kurlawalla-Martinez C, Stiles B, Wang Y, Devaskar S, Kahn B, Wu H . Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Mol Cell Biol. 2005; 25(6):2498-510. PMC: 1061603. DOI: 10.1128/MCB.25.6.2498-2510.2005. View

Azziz R, Carmina E, Chen Z, Dunaif A, Laven J, Legro R . Polycystic ovary syndrome. Nat Rev Dis Primers. 2016; 2:16057. DOI: 10.1038/nrdp.2016.57. View

Book C, Dunaif A . Selective insulin resistance in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1999; 84(9):3110-6. DOI: 10.1210/jcem.84.9.6010. View

Olefsky J . Insulin-stimulated glucose transport minireview series. J Biol Chem. 1999; 274(4):1863. DOI: 10.1074/jbc.274.4.1863. View

Greenbaum D, Colangelo C, Williams K, Gerstein M . Comparing protein abundance and mRNA expression levels on a genomic scale. Genome Biol. 2003; 4(9):117. PMC: 193646. DOI: 10.1186/gb-2003-4-9-117. View

Purcell S, Chi M, Lanzendorf S, Moley K . Insulin-stimulated glucose uptake occurs in specialized cells within the cumulus oocyte complex. Endocrinology. 2012; 153(5):2444-54. PMC: 3339650. DOI: 10.1210/en.2011-1974. View

Ma Y, Andrisse S, Chen Y, Childress S, Xue P, Wang Z . Androgen Receptor in the Ovary Theca Cells Plays a Critical Role in Androgen-Induced Reproductive Dysfunction. Endocrinology. 2016; 158(1):98-108. PMC: 5412974. DOI: 10.1210/en.2016-1608. View

Corbould A, Dunaif A . The adipose cell lineage is not intrinsically insulin resistant in polycystic ovary syndrome. Metabolism. 2007; 56(5):716-22. PMC: 2427369. DOI: 10.1016/j.metabol.2006.12.021. View

10.

Eriksen M, Porneki A, Skov V, Burns J, Beck-Nielsen H, Glintborg D . Insulin resistance is not conserved in myotubes established from women with PCOS. PLoS One. 2011; 5(12):e14469. PMC: 3012693. DOI: 10.1371/journal.pone.0014469. View

11.

Lystedt E, Westergren H, Brynhildsen J, Lindh-Astrand L, Gustavsson J, Nystrom F . Subcutaneous adipocytes from obese hyperinsulinemic women with polycystic ovary syndrome exhibit normal insulin sensitivity but reduced maximal insulin responsiveness. Eur J Endocrinol. 2005; 153(6):831-5. DOI: 10.1530/eje.1.02027. View

12.

Jenssen T, Hartmann A . Emerging treatments for post-transplantation diabetes mellitus. Nat Rev Nephrol. 2015; 11(8):465-77. DOI: 10.1038/nrneph.2015.59. View

13.

Andrisse S, Koehler R, Chen J, Patel G, Vallurupalli V, Ratliff B . Role of GLUT1 in regulation of reactive oxygen species. Redox Biol. 2014; 2:764-71. PMC: 4116627. DOI: 10.1016/j.redox.2014.03.004. View

14.

Lizneva D, Gavrilova-Jordan L, Walker W, Azziz R . Androgen excess: Investigations and management. Best Pract Res Clin Obstet Gynaecol. 2016; 37:98-118. DOI: 10.1016/j.bpobgyn.2016.05.003. View

15.

Legro R, Kunselman A, Dodson W, Dunaif A . Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999; 84(1):165-9. DOI: 10.1210/jcem.84.1.5393. View

16.

Munir I, Yen H, Geller D, Torbati D, Bierden R, Weitsman S . Insulin augmentation of 17alpha-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells. Endocrinology. 2003; 145(1):175-83. DOI: 10.1210/en.2003-0329. View

17.

Landay M, Huang A, Azziz R . Degree of hyperinsulinemia, independent of androgen levels, is an important determinant of the severity of hirsutism in PCOS. Fertil Steril. 2008; 92(2):643-7. PMC: 3714600. DOI: 10.1016/j.fertnstert.2008.06.021. View

18.

Zhou Q, Chen X, Leng L, Zhang J, Tang N . [Effects of dibutyl phthalate and monobutyl phthalate on testosterone secretion and insulin-like factor 3 expression of Leydig tumor cells in mice]. Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2013; 31(2):83-7. View

19.

Andrisse S, Childress S, Ma Y, Billings K, Chen Y, Xue P . Low-Dose Dihydrotestosterone Drives Metabolic Dysfunction via Cytosolic and Nuclear Hepatic Androgen Receptor Mechanisms. Endocrinology. 2016; 158(3):531-544. PMC: 5460775. DOI: 10.1210/en.2016-1553. View

20.

Suski J, Lebiedzinska M, Wojtala A, Duszynski J, Giorgi C, Pinton P . Isolation of plasma membrane-associated membranes from rat liver. Nat Protoc. 2014; 9(2):312-22. DOI: 10.1038/nprot.2014.016. View