Growth Hormone as a Model for Reversible Activation of Adipose Tissue Fibrosis

Summary

Background: Adipose tissue fibrosis denotes excessive pathological accumulation of extracellular matrix (ECM) in adipose tissue and is a marker of dysfunction. Growth hormone (GH) activates adipose tissue lipolysis and stimulates collagen synthesis in lean tissues. Intriguingly, we have novel pilot data to suggest that GH excess (acromegaly) also induces reversible fibrosis in vivo and potently activates the expression of fibroblast activation protein alpha (FAPα). Hypothesis: GH induces adipose tissue fibrosis by increased FAPα expression together with proliferation and fibrogenic differentiation of fibro-adipogenic progenitor (FAP) cells. Aim: To unravel the mechanisms underlying GH-induced adipose tissue fibrosis with emphasis on FAPα expression and proliferation of FAP cells. Subjects and methods: In a single blinded, randomized, double-dummy crossover design, 10 adult, moderately overweight individuals will be subjected to one week of GH and GH receptor blockade (Pegvisomant). We will use single-cell technologies, fluorescence-activated cell sorting (FACS), RNA sequencing, and cell culture studies on adipose tissue samples, combined with in vivo assessment of adipose tissue turnover and metabolism. Perspectives: Understanding fibrosis formation in human models may identify new targets for treatment of obesity-associated disorders.

Timeline

Start

2021-08-01

Primary completion

2023-12-31

Completion

2023-12-31

Publications

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• Background Hamson EJ, Keane FM, Tholen S, Schilling O, Gorrell MD. Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. Proteomics Clin Appl. 2014 Jun;8(5-6):454-63. doi: 10.1002/prca.201300095. Epub 2014 Mar 24.
• Background Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. J Biol Chem. 1999 Dec 17;274(51):36505-12. doi: 10.1074/jbc.274.51.36505.
• Background Christiansen VJ, Jackson KW, Lee KN, McKee PA. Effect of fibroblast activation protein and alpha2-antiplasmin cleaving enzyme on collagen types I, III, and IV. Arch Biochem Biophys. 2007 Jan 15;457(2):177-86. doi: 10.1016/j.abb.2006.11.006. Epub 2006 Nov 17.
• Background Levy MT, McCaughan GW, Marinos G, Gorrell MD. Intrahepatic expression of the hepatic stellate cell marker fibroblast activation protein correlates with the degree of fibrosis in hepatitis C virus infection. Liver. 2002 Apr;22(2):93-101. doi: 10.1034/j.1600-0676.2002.01503.x.
• Background Fan MH, Zhu Q, Li HH, Ra HJ, Majumdar S, Gulick DL, Jerome JA, Madsen DH, Christofidou-Solomidou M, Speicher DW, Bachovchin WW, Feghali-Bostwick C, Pure E. Fibroblast Activation Protein (FAP) Accelerates Collagen Degradation and Clearance from Lungs in Mice. J Biol Chem. 2016 Apr 8;291(15):8070-89. doi: 10.1074/jbc.M115.701433. Epub 2015 Dec 9.
• Background Arlien-Soborg MC, Grondahl C, Baek A, Dal J, Madsen M, Hogild ML, Pedersen SB, Bjerre M, Jorgensen JOL. Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment. J Clin Endocrinol Metab. 2020 Jan 1;105(1):dgz033. doi: 10.1210/clinem/dgz033.
• Background Farup J, Madaro L, Puri PL, Mikkelsen UR. Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis. 2015 Jul 23;6(7):e1830. doi: 10.1038/cddis.2015.198.
• Background Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang J, Rudnicki MA, Rossi FM. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat Cell Biol. 2010 Feb;12(2):153-63. doi: 10.1038/ncb2015. Epub 2010 Jan 17.
• Background Uezumi A, Fukada S, Yamamoto N, Takeda S, Tsuchida K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat Cell Biol. 2010 Feb;12(2):143-52. doi: 10.1038/ncb2014. Epub 2010 Jan 17.

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Indications

No indication recorded.