Follicle Stimulating Hormone; Luteinizing Hormone; Mice; Female; Animals; Follicle Stimulating Hormone/genetics; Follicle Stimulating Hormone/metabolism; Pituitary Gland/metabolism; Luteinizing Hormone/metabolism; Lipid Metabolism; Fatty Liver/metabolism; Fatty Liver; Pituitary Gland; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Multidisciplinary; Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
Abstract :
[en] Inter-organ communication is a major hallmark of health and is often orchestrated by hormones released by the anterior pituitary gland. Pituitary gonadotropes secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to regulate gonadal function and control fertility. Whether FSH and LH also act on organs other than the gonads is debated. Here, we find that gonadotrope depletion in adult female mice triggers profound hypogonadism, obesity, glucose intolerance, fatty liver, and bone loss. The absence of sex steroids precipitates these phenotypes, with the notable exception of fatty liver, which results from ovary-independent actions of FSH. We uncover paracrine FSH action on pituitary corticotropes as a mechanism to restrain the production of corticosterone and prevent hepatic steatosis. Our data demonstrate that functional communication of two distinct hormone-secreting cell populations in the pituitary regulates hepatic lipid metabolism.
Disciplines :
Biotechnology
Author, co-author :
Qiao, Sen ; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany ; Assisted Reproduction Center, Northwest Women's and Children's Hospital, Xi'an, China
Alasmi, Samer; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Wyatt, Amanda ; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Wartenberg, Philipp; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Wang, Hongmei; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Candlish, Michael; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany ; Institute of Cell Biology and Neuroscience, Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Frankfurt am Main, Germany
Das, Debajyoti; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Aoki, Mari; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Grünewald, Ramona; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Zhou, Ziyue; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Tian, Qinghai; Molecular Cell Biology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Yu, Qiang; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Götz, Viktoria; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Belkacemi, Anouar; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Raza, Ahsan; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Ectors, Fabien ; Université de Liège - ULiège > Fundamental and Applied Research for Animals and Health (FARAH) > FARAH: Santé publique vétérinaire
Kattler, Kathrin ; Department of Genetics and Epigenetics, Saarland University, Saarbrücken, Germany
Gasparoni, Gilles ; Department of Genetics and Epigenetics, Saarland University, Saarbrücken, Germany
Walter, Jörn ; Department of Genetics and Epigenetics, Saarland University, Saarbrücken, Germany
Lipp, Peter ; Molecular Cell Biology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
Mollard, Patrice ; IGF, University of Montpellier, CNRS, INSERM, Montpellier, France
Bernard, Daniel J ; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
Karatayli, Ersin; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
Karatayli, Senem Ceren; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
Lammert, Frank; Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
Boehm, Ulrich ; Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany. ulrich.boehm@uks.eu
This project was supported by the Deutsche Forschungsgemeinschaft (DFG) through grants SFB 894 and SFB/TR 152 to U.B. and Canadian Institutes of Health Research Project Grant PJT-156249 to D.J.B.
Friesen, H. & Astwood, E. B. Hormones of the anterior pituitary body. N. Engl. J. Med. 272, 1328–1335 (1965). CONCL.
Dingman, J. F. Pituitary function. N. Engl. J. Med. 285, 617–619 (1971).
Hodson, D. J., Molino, F., Fontanaud, P., Bonnefont, X. & Mollard, P. Investigating and modelling pituitary endocrine network function. J. Neuroendocrinol. 22, 1217–1225 (2010).
Le Tissier, P. et al. An updated view of hypothalamic-vascular-pituitary unit function and plasticity. Nat. Rev. Endocrinol. 13, 257–267 (2017).
Gromada, J., Chabosseau, P. & Rutter, G. A. The alpha-cell in diabetes mellitus. Nat. Rev. Endocrinol. 14, 694–704 (2018).
Bonnefont, X. et al. Revealing the large-scale network organization of growth hormone-secreting cells. Proc. Natl Acad. Sci. USA 102, 16880–16885 (2005).
Budry, L. et al. Related pituitary cell lineages develop into interdigitated 3D cell networks. Proc. Natl Acad. Sci. USA 108, 12515–12520 (2011).
Featherstone, K. et al. Pulsatile patterns of pituitary hormone gene expression change during development. J. Cell Sci. 124, 3484–3491 (2011).
Childs G. V. Gonadotropes and Lactotropes. in Knobil and Neill’s Physiology of Reproduction (ed Neill J. D.). 3rd edn. (Academic Press, Elsevier, 2006).
Herbison, A. E. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat. Rev. Endocrinol. 12, 452–466 (2016).
Sun, L. et al. FSH directly regulates bone mass. Cell 125, 247–260 (2006).
Liu, P. et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature 546, 107–112 (2017).
Guo, Y. et al. Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol. Cell Res. 29, 151–166 (2019).
Wang, N. et al. Follicle-stimulating hormone associates with prediabetes and diabetes in postmenopausal women. Acta Diabetol. 53, 227–236 (2016).
Wang, N. et al. Follicle-stimulating hormone is associated with non-alcoholic fatty liver disease in Chinese women over 55 years old. J. Gastroenterol. Hepatol. 31, 1196–1202 (2016).
Shieh, A. et al. Estradiol and follicle-stimulating hormone as predictors of onset of menopause transition-related bone loss in pre- and perimenopausal women. J. Bone Min. Res. 34, 2246–2253 (2019).
Allan, C. M. et al. Follicle-stimulating hormone increases bone mass in female mice. Proc. Natl Acad. Sci. USA 107, 22629–22634 (2010).
Wen, S. et al. Functional characterization of genetically labeled gonadotropes. Endocrinology 149, 2701–2711 (2008).
Buch, T. et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2, 419–426 (2005).
Wen, S. et al. Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology 152, 1515–1526 (2011).
Kumar, T. R., Wang, Y., Lu, N. & Matzuk, M. M. Follicle stimulating hormone is required for ovarian follicle maturation but not male fertility. Nat. Genet 15, 201–204 (1997).
Zhang, F. P., Poutanen, M., Wilbertz, J. & Huhtaniemi, I. Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol. Endocrinol. 15, 172–183 (2001).
Wong, S. K., Chin, K. Y., Suhaimi, F. H., Fairus, A. & Ima-Nirwana, S. Animal models of metabolic syndrome: a review. Nutr. Metab. (Lond.) 13, 65 (2016).
Zadravec, D. et al. Ablation of the very-long-chain fatty acid elongase ELOVL3 in mice leads to constrained lipid storage and resistance to diet-induced obesity. FASEB J. 24, 4366–4377 (2010).
Gokey, N. G., Lopez-Anido, C., Gillian-Daniel, A. L. & Svaren, J. Early growth response 1 (Egr1) regulates cholesterol biosynthetic gene expression. J. Biol. Chem. 286, 29501–29510 (2011).
Shin, D., Howng, S. Y., Ptacek, L. J. & Fu, Y. H. miR-32 and its target SLC45A3 regulate the lipid metabolism of oligodendrocytes and myelin. Neuroscience 213, 29–37 (2012).
Li, T. et al. Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice. Hepatology 52, 678–690 (2010).
Quinn, M. A., Xu, X., Ronfani, M. & Cidlowski, J. A. Estrogen deficiency promotes hepatic steatosis via a glucocorticoid receptor-dependent mechanism in mice. Cell Rep. 22, 2690–2701 (2018).
Brosch, M. et al. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat. Commun. 9, 4150 (2018).
Zhang, S. et al. Single-cell transcriptomics identifies divergent developmental lineage trajectories during human pituitary development. Nat. Commun. 11, 5275 (2020).
Candlish, M., De Angelis, R., Gotz, V. & Boehm, U. Gene targeting in neuroendocrinology. Compr. Physiol. 5, 1645–1676 (2015).
Seibel, M. J., Dunstan, C. R., Zhou, H., Allan, C. M. & Handelsman, D. J. Sex steroids, not FSH, influence bone mass. Cell 127, 1079 (2006). author reply 1080-1071.
Baron, R. FSH versus estrogen: who’s guilty of breaking bones? Cell Metab. 3, 302–305 (2006).
Riggs, B. L., Khosla, S. & Melton, L. J. III. Sex steroids and the construction and conservation of the adult skeleton. Endocr. Rev. 23, 279–302 (2002).
Danilovich, N. et al. Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice. Endocrinology 141, 4295–4308 (2000).
Abel, M. H., Huhtaniemi, I., Pakarinen, P., Kumar, T. R. & Charlton, H. M. Age-related uterine and ovarian hypertrophy in FSH receptor knockout and FSHbeta subunit knockout mice. Reproduction 125, 165–173 (2003).
Azziz, R. et al. Polycystic ovary syndrome. Nat. Rev. Dis. Prim. 2, 16057 (2016).
Essah, P. A., Wickham, E. P. III, Nunley, J. R. & Nestler, J. E. Dermatology of androgen-related disorders. Clin. Dermatol 24, 289–298 (2006).
Ishikawa, T., Yamaguchi, K., Kondo, Y., Takenaka, A. & Fujisawa, M. Metabolic syndrome in men with Klinefelter’s syndrome. Urology 71, 1109–1113 (2008).
Smith, M. R. et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N. Engl. J. Med. 345, 948–955 (2001).
Smith, M. R. Treatment-related osteoporosis in men with prostate cancer. Clin. Cancer Res. 12, 6315s–6319s (2006).
Strom, J. O., Theodorsson, A., Ingberg, E., Isaksson, I. M. & Theodorsson, E. Ovariectomy and 17beta-estradiol replacement in rats and mice: a visual demonstration. J. Vis. Exp. 64, e4013 (2012).
Tong, W. H., Abdulai-Saiku, S. & Vyas, A. Testosterone reduces fear and causes drastic hypomethylation of arginine vasopressin promoter in medial extended amygdala of male mice. Front. Behav. Neurosci. 13, 33 (2019).
Hellier, V. et al. Female sexual behavior in mice is controlled by kisspeptin neurons. Nat. Commun. 9, 400 (2018).
Qiao, S. et al. Molecular plasticity of male and female murine gonadotropes revealed by mRNA sequencing. Endocrinology 157, 1082–1093 (2016).
Aoki, M. et al. Widespread cell-specific prolactin receptor expression in multiple murine organs. Endocrinology 160, 2587–2599 (2019).
Labun, K. et al. CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing. Nucleic Acids Res. 47, W171–W174 (2019).
Bae, S., Park, J. & Kim, J. S. Cas-OFFinder: a fast and versatile algorithm that searches for potential off-target sites of Cas9 RNA-guided endonucleases. Bioinformatics 30, 1473–1475 (2014).
Concordet, J. P. & Haeussler, M. CRISPOR: intuitive guide selection for CRISPR/Cas9 genome editing experiments and screens. Nucleic Acids Res. 46, W242–W245 (2018).
Makarova, K. S. et al. An updated evolutionary classification of CRISPR-Cas systems. Nat. Rev. Microbiol. 13, 722–736 (2015).
Mehlem, A., Hagberg, C. E., Muhl, L., Eriksson, U. & Falkevall, A. Imaging of neutral lipids by oil red O for analyzing the metabolic status in health and disease. Nat. Protoc. 8, 1149–1154 (2013).
Clement, K. et al. CRISPResso2 provides accurate and rapid genome editing sequence analysis. Nat. Biotechnol. 37, 224–226 (2019).
Stilley, J. A. W. & Segaloff, D. L. FSH actions and pregnancy: looking beyond ovarian FSH receptors. Endocrinology 159, 4033–4042 (2018).
Weivoda, M. M. et al. Osteoclast TGF-beta receptor signaling induces Wnt1 secretion and couples bone resorption to bone formation. J. Bone Min. Res. 31, 76–85 (2016).
