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

NCT04998500 | Unknown

• 1 other identifier: 1-10-72-283-20
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Fibrosis

Keywords

Adipose tissue; Fibrosis; Growth hormone; Fibro-adipogenic progenitors

Outcome Measures

Primary Outcomes (3)

• Fibro-adipogenic progenitor (FAP) cells

  Quantification of FAP cells in adipose tissue, and in vitro determination of proliferation and fibro-/adipogenic differentiation potential

  Anticipated approximately 1-5 months

• Fibroblast activation protein (FAPα)

  FAPα concentration and activity in blood, and expression in adipose tissue

  Anticipated approximately 1-5 months

• Adipose tissue fibrosis

  Markers of fibrosis in adipose tissue assessed by light microscopy and immunohistochemically, RNA sequencing and heavy water labeled connective tissue turnover

  Anticipated approximately 1-5 months

Secondary Outcomes (4)

• Circulating biomarkers of collagen turnover

  Anticipated approximately 1-5 months

• Protein turnover in muscle tissue

  Anticipated approximately 1-5 months

• Metabolism and fatty acid turnover

  Anticipated approximately 1-5 months

• Temperature

  Anticipated approximately 1-5 months

Study Arms (2)

GH intervention - control intervention

EXPERIMENTAL

Participants will receive daily subcutaneous injections of growth hormone for 7 days. Approximately 1-4 months later, the participants will receive daily subcutaneous injections of control intervention for 7 days consisting of saline and GH receptor blockade (Pegvisomant).

Biological: Growth hormone, saline and GH receptor blockade (Pegvisomant)

Control intervention - GH intervention

EXPERIMENTAL

Participants will receive daily subcutaneous injections of control intervention for 7 days consisting of saline and GH receptor blockade (Pegvisomant). Approximately 1-4 months later, the participants will receive daily subcutaneous injections of growth hormone for 7 days.

Biological: Growth hormone, saline and GH receptor blockade (Pegvisomant)

Interventions

Growth hormone, saline and GH receptor blockade (Pegvisomant) BIOLOGICAL

This study aims to uncover physiological effects of growth hormone (GH). The intervention with GH and GH receptor blockade (Pegvisomant) will therefore be used as tools to activate a well-known physiological response. Thus, this study is not a drug trial.

Control intervention - GH intervention; GH intervention - control intervention

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Written and oral consent before enrollment
• Legally competent subjects
• Healthy (except uncomplicated hypertension and hypercholesterolemia)
• Male sex
• Age ≥ 18 years and ≤ 50 years
• BMI 25-35

You may not qualify if:

• Any condition which the investigator considers might affect the participant's ability to complete the study
• Known of presumed acute of chronic illness

Sponsors & Collaborators

• University of Aarhus: lead
• University of Copenhagen: collaborator

Study Sites (1)

Aarhus University

Aarhus, DK-8200, Denmark

Location

Related Publications (18)

• Munoz A, Abate N, Chandalia M. Adipose tissue collagen and inflammation in nonobese Asian Indian men. J Clin Endocrinol Metab. 2013 Aug;98(8):E1360-3. doi: 10.1210/jc.2012-3841. Epub 2013 Jun 18.

  PMID: 23780376 BACKGROUND

• Lawler HM, Underkofler CM, Kern PA, Erickson C, Bredbeck B, Rasouli N. Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects. J Clin Endocrinol Metab. 2016 Apr;101(4):1422-8. doi: 10.1210/jc.2015-4125. Epub 2016 Feb 12.

  PMID: 26871994 BACKGROUND

• Moller N, Jorgensen JO. Effects of growth hormone on glucose, lipid, and protein metabolism in human subjects. Endocr Rev. 2009 Apr;30(2):152-77. doi: 10.1210/er.2008-0027. Epub 2009 Feb 24.

  PMID: 19240267 BACKGROUND

• Melmed S. Acromegaly pathogenesis and treatment. J Clin Invest. 2009 Nov;119(11):3189-202. doi: 10.1172/JCI39375. Epub 2009 Nov 2.

  PMID: 19884662 BACKGROUND

• Longobardi S, Keay N, Ehrnborg C, Cittadini A, Rosen T, Dall R, Boroujerdi MA, Bassett EE, Healy ML, Pentecost C, Wallace JD, Powrie J, Jorgensen JO, Sacca L. Growth hormone (GH) effects on bone and collagen turnover in healthy adults and its potential as a marker of GH abuse in sports: a double blind, placebo-controlled study. The GH-2000 Study Group. J Clin Endocrinol Metab. 2000 Apr;85(4):1505-12. doi: 10.1210/jcem.85.4.6551.

  PMID: 10770189 BACKGROUND

• Doessing S, Heinemeier KM, Holm L, Mackey AL, Schjerling P, Rennie M, Smith K, Reitelseder S, Kappelgaard AM, Rasmussen MH, Flyvbjerg A, Kjaer M. Growth hormone stimulates the collagen synthesis in human tendon and skeletal muscle without affecting myofibrillar protein synthesis. J Physiol. 2010 Jan 15;588(Pt 2):341-51. doi: 10.1113/jphysiol.2009.179325. Epub 2009 Nov 23.

  PMID: 19933753 BACKGROUND

• Doessing S, Holm L, Heinemeier KM, Feldt-Rasmussen U, Schjerling P, Qvortrup K, Larsen JO, Nielsen RH, Flyvbjerg A, Kjaer M. GH and IGF1 levels are positively associated with musculotendinous collagen expression: experiments in acromegalic and GH deficiency patients. Eur J Endocrinol. 2010 Dec;163(6):853-62. doi: 10.1530/EJE-10-0818. Epub 2010 Sep 21.

  PMID: 20858702 BACKGROUND

• Householder LA, Comisford R, Duran-Ortiz S, Lee K, Troike K, Wilson C, Jara A, Harberson M, List EO, Kopchick JJ, Berryman DE. Increased fibrosis: A novel means by which GH influences white adipose tissue function. Growth Horm IGF Res. 2018 Apr;39:45-53. doi: 10.1016/j.ghir.2017.12.010. Epub 2017 Dec 20.

  PMID: 29279183 BACKGROUND

• Merrick D, Sakers A, Irgebay Z, Okada C, Calvert C, Morley MP, Percec I, Seale P. Identification of a mesenchymal progenitor cell hierarchy in adipose tissue. Science. 2019 Apr 26;364(6438):eaav2501. doi: 10.1126/science.aav2501.

  PMID: 31023895 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.

  PMID: 24470260 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.

  PMID: 10593948 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.

  PMID: 17174263 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.

  PMID: 12028401 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.

  PMID: 26663085 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.

  PMID: 31544947 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.

  PMID: 26203859 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.

  PMID: 20081841 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.

  PMID: 20081842 BACKGROUND

Related Links

• Reference number 19

MeSH Terms

Conditions

Fibrosis

Interventions

Growth Hormone; Sodium Chloride; pegvisomant

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pituitary Hormones, Anterior; Pituitary Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds

Study Officials

• Amanda Bæk, MD

  University of Aarhus

  PRINCIPAL INVESTIGATOR

• Jens Otto L Jørgensen, Professor

  University of Aarhus

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: This study aims to uncover physiological in vivo effects of growth hormone (GH). The intervention with GH and Pegvisomant will therefore be used as tools to activate a well-known physiological response. Participants are randomized to receive either control intervention first and then GH intervention, or GH intervention first and then control intervention.

Study Record Dates

• First Submitted: August 9, 2021
• First Posted: August 10, 2021
• Study Start: August 1, 2021
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: May 30, 2023

Record last verified: 2023-05

Locations

DK (1)