, Volume 61, Issue 5, pp 1180–1192 | Cite as

Follicle-stimulating hormone enhances hepatic gluconeogenesis by GRK2-mediated AMPK hyperphosphorylation at Ser485 in mice

  • Xiaoyi Qi
  • Yanjing Guo
  • Yongfeng Song
  • Chunxiao Yu
  • Lifang Zhao
  • Li Fang
  • Dehuan Kong
  • Jiajun Zhao
  • Ling Gao



Increased serum follicle-stimulating hormone (FSH) is correlated with fasting hyperglycaemia. However, the underlying mechanism remains unclear. Because excessive hepatic gluconeogenesis is a major cause of fasting hyperglycaemia the present study investigated whether FSH increases hepatic gluconeogenesis in mice.


Ovariectomised mice supplemented with oestradiol (E2) to maintain normal levels of serum E2 (OVX+E2 mice) were injected with low or high doses of FSH. We knocked out Crtc2, a crucial factor in gluconeogenesis, and Fshr to discern their involvement in FSH signalling. To evaluate the role of the G-protein-coupled receptor (GPCR) kinase 2 (GRK2), which could affect glucose metabolism and interact directly with non-GPCR components, a specific GRK2 inhibitor was used. The pyruvate tolerance test (PTT), quantification of PEPCK and glucose-6-phosphatase (G6Pase), key enzymes of gluconeogenesis, GRK2 and phosphorylation of AMP-activated protein kinase (AMPK) were examined to evaluate the level of gluconeogenesis in the liver. A nonphosphorylatable mutant of AMPK Ser485 (AMPK S485A) was transfected into HepG2 cells to evaluate the role of AMPK Ser485 phosphorylation.


FSH increased fasting glucose (OVX+E2+high-dose FSH 8.18 ± 0.60 mmol/l vs OVX+E2 6.23 ± 1.33 mmol/l), the PTT results, and the transcription of Pepck (also known as Pck1; 2.0-fold increase) and G6pase (also known as G6pc; 2.5-fold increase) in OVX+E2 mice. FSH also enhanced the promoter luciferase activities of the two enzymes in HepG2 cells. FSH promoted the membrane translocation of GRK2, which is associated with increased AMPK Ser485 and decreased AMPK Thr172 phosphorylation, and enhanced the nuclear translocation of cyclic AMP-regulated transcriptional coactivator 2 (CRTC2). GRK2 could bind with AMPK and induce Ser485 hyperphosphorylation. Furthermore, either the GRK2 inhibitor or AMPK S485A blocked FSH-regulated AMPK Thr172 dephosphorylation and gluconeogenesis. Additionally, the deletion of Crtc2 or Fshr abolished the function of FSH in OVX+E2 mice.


The results indicate that FSH enhances CRTC2-mediated gluconeogenesis dependent on AMPK Ser485 phosphorylation via GRK2 in the liver, suggesting an essential role of FSH in the pathogenesis of fasting hyperglycaemia.


AMPK CRTC2 FSH Gluconeogenesis GRK2 Liver 





Alanine aminotransferase


AMP-activated protein kinase


Aspartate aminotransferase


Calcium/calmodulin-dependent protein kinase


Cyclic AMP response element


Cyclic AMP response element-binding protein


Cyclic AMP-regulated transcriptional coactivator 2




Follicle-stimulating hormone


Follicle-stimulating hormone receptor




G-protein-coupled receptor


GPCR kinase 2


Glycogen synthase kinase 3β


Haematoxylin and eosin


High-dose FSH


Insulin tolerance test


Insulin sensitivity index


Low-dose FSH


Liver kinase B1


Mitogen-activated protein kinase




Periodic acid–Schiff


Protein kinase A


Pyruvate tolerance test



We thank Y. Wang (School of Life Sciences, Tsinghua University, China) for providing mice; H. Choi (School of Biological Sciences and Technology, Chonnam National University, Republic of Korea), J. Staňková (Department of Paediatrics, University of Sherbrooke, Canada), F. Mayor (Department of Molecular Biology, Universidad Autónoma de Madrid, Spain) and J. L. Benovic (Department of Biochemistry and Molecular Biology, Thomas Jefferson University, USA) for providing plasmids.

Contribution statement

JZ and LG designed and supervised the project. JZ, LG, CY, YS, YG and XQ designed the experiments. XQ, YG and DK performed the experiments. XQ analysed the data and wrote the manuscript. CY, DK, LF and LZ participated in analysis and interpretation of data. All authors revised the manuscript critically and approved the final version for publication. LG is the guarantor of this work.


This work was supported by the National Natural Science Foundation (81670796) and the National Key R&D Programme of China (2017YFC1309800 and 0909600).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

125_2018_4562_MOESM1_ESM.pdf (626 kb)
ESM (PDF 626 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiaoyi Qi
    • 1
    • 2
    • 3
  • Yanjing Guo
    • 1
    • 2
    • 3
  • Yongfeng Song
    • 1
    • 2
    • 3
  • Chunxiao Yu
    • 1
    • 2
    • 3
  • Lifang Zhao
    • 1
    • 2
    • 3
  • Li Fang
    • 1
    • 2
    • 3
  • Dehuan Kong
    • 4
  • Jiajun Zhao
    • 1
    • 2
    • 3
  • Ling Gao
    • 5
  1. 1.Department of EndocrinologyShandong Provincial Hospital affiliated to Shandong UniversityJinanPeople’s Republic of China
  2. 2.Shandong Provincial Key Laboratory of Endocrinology and Lipid MetabolismJinanPeople’s Republic of China
  3. 3.Institute of Endocrinology and MetabolismShandong Academy of Clinical MedicineJinanPeople’s Republic of China
  4. 4.Department of GeriatricsTai’an City Central HospitalTai’anPeople’s Republic of China
  5. 5.Scientific Centre, Shandong Provincial Hospital affiliated to Shandong UniversityJinanPeople’s Republic of China

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