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

被引:25
|
作者
Andrisse, Stanley [1 ,2 ]
Feng, Mingxiao [1 ]
Wang, Zhiqiang [1 ]
Awe, Olubusayo [1 ,3 ]
Yu, Lexiang [1 ]
Zhang, Haiying [4 ]
Bi, Sheng [4 ]
Wang, Hongbing [5 ]
Li, Linhao [5 ]
Joseph, Serene [6 ]
Heller, Nicola [7 ]
Mauvais-Jarvis, Franck [8 ,9 ,10 ]
Wong, Guang William [3 ]
Segars, James [11 ]
Wolfe, Andrew [1 ]
Divall, Sara [12 ]
Ahima, Rexford [13 ]
Wu, Sheng [1 ,3 ,6 ,11 ]
机构
[1] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA
[2] Howard Univ, Dept Physiol & Biophys, Washington, DC 20059 USA
[3] Johns Hopkins Univ, Sch Med, Dept Cellular & Mol Physiol, Baltimore, MD USA
[4] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA
[5] Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA
[6] Temple Univ, Dept Cardiovasc Sci, Ctr Metab Dis Res, Sch Med, Philadelphia, PA 19140 USA
[7] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA
[8] Tulane Univ, Dept Med, Hlth Sci Ctr, New Orleans, LA 70118 USA
[9] Tulane Ctr Excellence Sex Based Biol & Med, New Orleans, LA USA
[10] VA Med Ctr, New Orleans, LA USA
[11] Johns Hopkins Univ, Sch Med, Dept Gynecol & Obstet, Baltimore, MD 21205 USA
[12] Univ Washington, Dept Pediat, Seattles Childrens Hosp, Seattle, WA 98195 USA
[13] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA
来源
FASEB JOURNAL | 2021年 / 35卷 / 10期
关键词
androgen; androgen receptor; glucose; insulin signaling; liver; PCOS; POLYCYSTIC-OVARY-SYNDROME; LOW-DOSE DIHYDROTESTOSTERONE; METABOLIC DYSFUNCTION; LIVER; MODEL; MICE; ENDOCRINE; KNOCKOUT; EXCESS; DAMS;
D O I
10.1096/fj.202100961R
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in AR(fl/fl) mice (adLivARKO). We observed normal metabolic function in littermate female Control (AR(fl/fl)) and LivARKO (AR(fl/fl); Cre(+/-)) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.
引用
收藏
页数:16
相关论文
共 50 条
  • [41] Increase of androgen-induced cell death and androgen receptor transactivation by BRCA1 in prostate cancer cells
    Yeh, SY
    Hu, YC
    Rahman, M
    Lin, HK
    Hsu, CL
    Ting, HJ
    Kang, HY
    Chang, CS
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (21) : 11256 - 11261
  • [42] EFFECT OF ADRENALECTOMY ON DEVELOPMENT OF ANDROGEN-INDUCED HYPERTENSION
    MOLTENI, A
    SKELTON, FR
    BROWNIE, AC
    LABORATORY INVESTIGATION, 1970, 23 (04) : 429 - &
  • [43] Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase
    Shen, RQ
    Sumitomo, M
    Dai, J
    Harris, A
    Kaminetzky, D
    Gao, M
    Burnstein, KL
    Nanus, DM
    ENDOCRINOLOGY, 2000, 141 (05) : 1699 - 1704
  • [44] Change of insulin-like growth factor-1 and its receptor in androgen-induced sterile rats
    Li, Gui-ling
    Gui, Sui-qi
    Zhou, Qin-di
    Fudan University Journal of Medical Sciences, 2002, 29 (04): : 306 - 307
  • [45] ANDROGEN-INDUCED GENE ACTIVATION IN RAT PROSTATE
    NYBERG, LM
    HU, AL
    LOOR, RM
    WANG, TY
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1976, 73 (02) : 330 - 335
  • [46] ANESTHETIC PREGNANES COUNTERACT ANDROGEN-INDUCED DEFEMINIZATION
    GONZALEZMARISCAL, G
    FERNANDEZGUASTI, A
    BEYER, C
    NEUROENDOCRINOLOGY, 1982, 34 (05) : 357 - 362
  • [47] INHIBITION OF ANDROGEN-INDUCED PRECOCIOUS PUBERTY BY PROGESTERONE
    NAQVI, RH
    ZARROW, MX
    DENENBERG, VH
    ENDOCRINOLOGY, 1969, 84 (03) : 669 - +
  • [48] ANDROGEN-INDUCED OVARIAN FOLLICULAR ATRESIA IN RAT
    FEBRES, F
    GONDOS, B
    SIITERI, P
    GYNECOLOGIC INVESTIGATION, 1976, 7 (1-2): : 52 - 52
  • [49] ANDROGEN-INDUCED HEPATOCELL CARCINOMA IN A HEMODIALYSIS PATIENT
    ZEVIN, D
    TURANI, H
    LEVI, J
    KIDNEY INTERNATIONAL, 1981, 19 (01) : 105 - 105
  • [50] Ursodeoxycholic acid for the treatment of androgen-induced cholestasis
    Mork, H
    Al-Taie, O
    Klinge, O
    Scheurlen, M
    ZEITSCHRIFT FUR GASTROENTEROLOGIE, 1997, 35 (12): : 1087 - 1091