Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment

2019 ◽  
Vol 105 (1) ◽  
pp. 106-115 ◽  
Author(s):  
Mai C Arlien-Søborg ◽  
Camilla Grøndahl ◽  
Amanda Bæk ◽  
Jakob Dal ◽  
Michael Madsen ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Disease Control ◽  
Fibroblast Activation Protein ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Type I ◽  
Collagen Turnover ◽  
Fibroblast Activation ◽  
Before And After ◽  
Turnover Markers

Abstract Background Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover. Aim To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control. Methods Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR). Results Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P < 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P < 0.000) and Type III (P < 0.000). Conclusion 1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover. Clinical Trials Registration NCT00647179

scholarly journals Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

2017 ◽  
Vol 235 (2) ◽  
pp. 97-109 ◽  
Author(s):  
Jay W Porter ◽  
Joe L Rowles ◽  
Justin A Fletcher ◽  
Terese M Zidon ◽  
Nathan C Winn ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Citrate Synthase ◽  
Metabolic Effects ◽  
Relative Mass ◽  
Fibroblast Growth Factor 21 ◽  
Wild Type ◽  
Anti Inflammatory ◽  
Running Wheels

Exercise enhances insulin sensitivity; it also improves adipocyte metabolism and reduces adipose tissue inflammation through poorly defined mechanisms. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone-like protein whose insulin-sensitizing properties are predominantly mediated via receptor signaling in adipose tissue (AT). Recently, FGF21 has also been demonstrated to have anti-inflammatory properties. Meanwhile, an association between exercise and increased circulating FGF21 levels has been reported in some, but not all studies. Thus, the role that FGF21 plays in mediating the positive metabolic effects of exercise in AT are unclear. In this study, FGF21-knockout (KO) mice were used to directly assess the role of FGF21 in mediating the metabolic and anti-inflammatory effects of exercise on white AT (WAT) and brown AT (BAT). Male FGF21KO and wild-type mice were provided running wheels or remained sedentary for 8 weeks (n = 9–15/group) and compared for adiposity, insulin sensitivity (i.e., HOMA-IR, Adipo-IR) and AT inflammation and metabolic function (e.g., mitochondrial enzyme activity, subunit content). Adiposity and Adipo-IR were increased in FGF21KO mice and decreased by EX. The BAT of FGF21KO animals had reduced mitochondrial content and decreased relative mass, both normalized by EX. WAT and BAT inflammation was elevated in FGF21KO mice, reduced in both genotypes by EX. EX increased WAT Pgc1alpha gene expression, citrate synthase activity, COX I content and total AMPK content in WT but not FGF21KO mice. Collectively, these findings reveal a previously unappreciated anti-inflammatory role for FGF21 in WAT and BAT, but do not support that FGF21 is necessary for EX-mediated anti-inflammatory effects.

scholarly journals Adipose tissue contribution to plasma fibroblast growth factor 21 and fibroblast activation protein in obesity

2019 ◽  
Vol 44 (2) ◽  
pp. 544-547 ◽  
Author(s):  
Marleen A. van Baak ◽  
Roel G. Vink ◽  
Nadia J. T. Roumans ◽  
Christine C. Cheng ◽  
Andrew C. Adams ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Fibroblast Activation Protein ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Fibroblast Activation

Metabolic effects of one-week binge drinking and fast food intake during Roskilde Festival in young healthy male adults

2021 ◽  
Author(s):  
Mia Demant ◽  
Malte Palm Suppli ◽  
Signe Foghsgaard ◽  
Lise Gether ◽  
Magnus Frederik Gluud Grøndahl ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Binge Drinking ◽  
Fast Food ◽  
Liver Stiffness ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Oral Glucose ◽  
Unhealthy Lifestyle ◽  
Matsuda Index ◽  
Mean Strain

Aims/hypothesis. Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (one week of binge drinking and junk food consumption) in young, healthy males. Methods. Fourteen festival participants (FP) were studied before, during and after one week’s participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline. Results. The FP group consumed more alcohol compared to their standard living conditions (2.0±3.9 vs 16.3±8.3 units/day, p<0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (320±31 vs 376±25 nmol/l×min, p=0.055) and the Matsuda index of insulin sensitivity decreased (6.2±2.4 vs 4.7±1.4, p = 0.054). AUC for glucagon during OGTT increased in the FP group (1,115±114 vs 1,599±183 pmol/l×min, p=0.003) together with fasting fibroblast growth factor 21 (FGF21) (62±30 vs 132±72 pmol/L, p<0.001), growth differentiation factor 15 (GDF5) (276±78 vs 330±83 pg/mL, p=0.009) and aspartate aminotransferase (AST) levels (37.6±6.8 vs 42.4±11 U/l, p=0.043). Four participants (29%) developed ultrasound-detectable steatosis and mean strain elastography-assessed liver stiffness increased (p=0.026) in the FP group. Conclusions/interpretation. Participation in Roskilde Festival did not affect oral glucose tolerance, but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.

scholarly journals FGF21 signaling in glutamatergic neurons is required for weight loss associated with dietary protein dilution

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kyle H. Flippo ◽  
Sharon O. Jensen-Cody ◽  
Kristin E. Claflin ◽  
Matthew J. Potthoff
Keyword(s):  
Body Weight ◽  
Insulin Sensitivity ◽  
Dietary Protein ◽  
Body Weight Gain ◽  
Protein Restriction ◽  
Metabolic Effects ◽  
Whole Body ◽  
Fibroblast Growth Factor 21 ◽  
Dietary Protein Restriction ◽  
Glutamatergic Neurons

Abstract Alterations in macronutrient intake can have profound effects on energy intake and whole-body metabolism. For example, reducing protein intake increases energy expenditure, increases insulin sensitivity and decreases body weight in rodents. Fibroblast growth factor 21 (FGF21) signaling in the brain is necessary for the metabolic effects of dietary protein restriction and has more recently been proposed to promote protein preference. However, the neuron populations through which FGF21 elicits these effects are unknown. Here, we demonstrate that deletion of β-klotho in glutamatergic, but not GABAergic, neurons abrogated the effects of dietary protein restriction on reducing body weight, but not on improving insulin sensitivity in both diet-induced obese and lean mice. Specifically, FGF21 signaling in glutamatergic neurons is necessary for protection against body weight gain and induction of UCP1 in adipose tissues associated with dietary protein restriction. However, β-klotho expression in glutamatergic neurons was dispensable for the effects of dietary protein restriction to increase insulin sensitivity. In addition, we report that FGF21 administration does not alter protein preference, but instead promotes the foraging of other macronutrients primarily by suppressing simple sugar consumption. This work provides important new insights into the neural substrates and mechanisms behind the endocrine control of metabolism during dietary protein dilution.

P715Deletion of fibroblast activation protein decreases experimental atherosclerotic plaque formation and vulnerability

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
S Stein ◽  
J Weber ◽  
S Nusser-Stein ◽  
J Pahla ◽  
H Zhang ◽  
...  
Keyword(s):  
Atherosclerotic Plaque ◽  
Cross Sections ◽  
Aortic Root ◽  
Fibroblast Activation Protein ◽  
Plaque Formation ◽  
Type I ◽  
Plaque Vulnerability ◽  
Fibroblast Activation ◽  
Atherosclerotic Plaque Formation ◽  
Deficient Mice

Abstract Background Fibroblast activation protein (FAP) is a serine protease that is upregulated in sites of tissue remodeling, including arthritis, tumors and atherosclerosis. We have reported that FAP degrades type I collagen in human thin-cap fibroatheromata; its expression is enhanced in advanced human plaques and induced by inflammation. However, the role of endogenous FAP in atherosclerosis remains unknown. Purpose To investigate the effects of constitutive Fap loss-of-function on atherosclerotic plaque formation and vulnerability. Methods and results Male 8-week-old Apoe−/− Fap+/+ and Apoe−/− Fap−/− mice were fed a high-cholesterol diet (1.25% chol) for 12 weeks. En face analyses of thoracoabdominal aortae using Oil Red O (ORO) revealed decreased plaques in Apoe−/− Fap−/− mice (5.7±0.5%; n=21) compared to Apoe−/− Fap+/+ mice (10.7±0.7%; n=24; p<0.0001). In parallel, ORO analyses of serial aortic root cross sections showed diminished plaques in Fap-deficient mice (18.4±3.4% vs 27.6±2.1%). As a surrogate of plaque vulnerability, fibrous cap thickness was increased in Apoe−/− Fap−/− mice (65±6 mm vs 35±3 mm; p<0.01), whereas necrotic core size, plaque macrophages (CD68) and T cells (CD3) accumulation, as well as VCAM1 expression did not differ. These changes were independent of plasma triglycerides, total and LDL-cholesterol levels. Plasma of Fap-deficient mice showed decreased FAP activity compared to Fap wildtype controls. Notably, second harmonics generation in cross sections of aortic root plaques showed that the deposition and density of fibrillar collagens was enhanced in Fap-deficient (25.5±4.4%) compared to control plaques (13.8±2.5%; p<0.05). Consistently, Fap deletion led to an accumulation of uncleaved pre-COL3A1, a proteolytic target of FAP. Conclusions Constitutive Fap deletion decreases experimental atherosclerosis and features of plaque vulnerability. Thus, inhibition of FAP expression or activity may be a promising therapeutic target in atherosclerosis. Acknowledgement/Funding Swiss National Science Foundation, Swiss Heart Foundation

Interleukin-6: a growth factor stimulating collagen synthesis in human tendon

2011 ◽  
Vol 110 (6) ◽  
pp. 1549-1554 ◽  
Author(s):  
Mette Bisgaard Andersen ◽  
Jessica Pingel ◽  
Michael Kjær ◽  
Henning Langberg
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Achilles Tendon ◽  
Collagen Synthesis ◽  
Type I Collagen ◽  
Type I ◽  
Collagen Turnover ◽  
Potential Growth ◽  
Human Tendon ◽  
Turnover Markers

Human connective tissue, e.g., tendon, responds dynamically to physical activity, with collagen synthesis being increased after both acute and prolonged exercise or training. Markers of collagen synthesis and degradation as well as concentration of several potential growth factors have been shown to increase markedly in the peritendinous tissue around the human Achilles tendon following exercise. Of these potential growth factors interleukin-6 (IL-6) showed the largest fold increase, suggesting that IL-6 may be involved in transforming mechanical loading into collagen synthesis in human tendon tissue. In the present study the tissue levels of type I collagen turnover markers [procollagen type I NH2-terminal propeptide (PINP) and C-OOH terminal telopeptide of type I collagen (ICTP)] were measured by the use of microdialysis in peritendinous tissue of the Achilles tendon in 14 male volunteers, who had recombinant human IL-6 (rhIL-6) infused into the peritendinous tissue of the Achilles' tendon in one leg, with the other leg serving as control. Subjects were randomly assigned to either a resting group or an exercise group performing a 1-h treadmill run (12 km/h, 2% uphill) before infusion. In addition to IL-6, serum concentrations of collagen turnover markers PINP, ICTP, and COOH-terminal telopeptide of type I collagen (ICTX) were measured. The peritendinous concentration of PINP rose markedly in response to rhIL-6 infusion in both the exercise and the rest group, demonstrating that infusion of IL-6 significantly stimulates collagen synthesis in the peritendinous tissue in humans. Exercise alone did not result in an increased collagen synthesis. This indicates that IL-6 is involved in the collagen synthesis and supports the hypothesis that IL-6 is an important growth factor of the connective tissue in healthy human tendons.

scholarly journals Fibroblast Activation Protein Targeted Photodynamic Therapy Selectively Kills Activated Skin Fibroblasts from Systemic Sclerosis Patients and Prevents Tissue Contraction

2021 ◽  
Vol 22 (23) ◽  
pp. 12681
Author(s):  
Daphne N. Dorst ◽  
Arjan P. M. van Caam ◽  
Elly L. Vitters ◽  
Birgitte Walgreen ◽  
Monique M. A. Helsen ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Systemic Sclerosis ◽  
Light Exposure ◽  
Collagen Type I ◽  
Fibroblast Activation Protein ◽  
Skin Fibroblasts ◽  
Type I ◽  
Fibroblast Activation ◽  
Tissue Contraction ◽  
Targeted Photodynamic Therapy

Systemic sclerosis (SSc) is a rare, severe, auto-immune disease characterized by inflammation, vasculopathy and fibrosis. Activated (myo)fibroblasts are crucial drivers of this fibrosis. By exploiting their expression of fibroblast activation protein (FAP) to perform targeted photodynamic therapy (tPDT), we can locoregionally deplete these pathogenic cells. In this study, we explored the use of FAP-tPDT in primary skin fibroblasts from SSc patients, both in 2D and 3D cultures. Method: The FAP targeting antibody 28H1 was conjugated with the photosensitizer IRDye700DX. Primary skin fibroblasts were obtained from lesional skin biopsies of SSc patients via spontaneous outgrowth and subsequently cultured on plastic or collagen type I. For 2D FAP-tPDT, cells were incubated in buffer with or without the antibody-photosensitizer construct, washed after 4 h and exposed to λ = 689 nm light. Cell viability was measured using CellTiter Glo®®. For 3D FAP-tPDT, cells were seeded in collagen plugs and underwent the same treatment procedure. Contraction of the plugs was followed over time to determine myofibroblast activity. Results: FAP-tPDT resulted in antibody-dose dependent cytotoxicity in primary skin fibroblasts upon light exposure. Cells not exposed to light or incubated with an irrelevant antibody-photosensitizer construct did not show this response. FAP-tPDT fully prevented contraction of collagen plugs seeded with primary SSc fibroblasts. Even incubation with a very low dose of antibody (0.4 nM) inhibited contraction in 2 out of 3 donors. Conclusions: Here we have shown, for the first time, the potential of FAP-tPDT for the treatment of fibrosis in SSc skin.

scholarly journals SUN-665 Peripheral CB1R Blocker Improves Metabolism in Diet Induced Obese Mice Independent of Hepatic FGF21

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jie Liu ◽  
Grzegorz Godlewski ◽  
Ziyi Liu ◽  
Resat Cinar ◽  
Keming Xiong ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Hepatic Steatosis ◽  
Endocannabinoid System ◽  
Current Data ◽  
Metabolic Effects ◽  
Fibroblast Growth Factor 21 ◽  
Obese Mice ◽  
Wild Type ◽  
Peripheral Tissues ◽  
Selective Blockade

Abstract Obesity is associated with an overactive endocannabinoid system, and selective blockade of CB1R in peripheral tissues, including the liver, reverses HFD-induced metabolic abnormalities by restoring normal lipid and glucose homeostasis. Fibroblast growth factor-21 (FGF21) has emerged as a major endocrine regulator derived from the liver that reduces adiposity and hepatic steatosis and improves glucose tolerance and insulin sensitivity, with changes similar to those induced by CB1R blockade. Here we investigated whether FGF21 mediate the metabolic effects of CB1R blockade in DIO mice. In C57BL/6J wild-type mice, HFD caused a robust increase in hepatic Fgf21 mRNA and serum FGF21 levels, which were reversed by chronic CB1R blockade to levels observed in STD or vehicle-treated hepatocyte-specific CB1R-/- (LCB1-/-) mice, indicating activation of CB1R in the liver is largely involved in HFD-induced “FGF21-resistant” state. In contrast, the expression of the FGF21 receptor Fgfr1 and co-receptor β-klotho (Klb) were dramatically reduced by HFD in both epididymal fat and brain tissue in wild-type mice, and these effects were reversed by peripheral CB1R antagonist JD5037 treatment. To address whether FGF21 mediated the metabolic effects of CB1R blockade, we repeated JD5037 treatment in liver-specific FGF21-/- (FGF21-LKO) mice. Surprisingly, JD5037 treatment was almost equally effective in both HFD-fed wild-type and in FGF21-LKO mice in reducing body weight and hepatic steatosis, attenuating hyperinsulinemia and hyperleptinemia. The current data suggest that peripheral CB1R blockade in obese mice improves insulin sensitivity and energy expenditure independently of hepatic FGF21.

scholarly journals Regulation of Fibroblast Activation Protein by Transforming Growth Factor Beta-1 in Glioblastoma Microenvironment

2021 ◽  
Vol 22 (3) ◽  
pp. 1046
Author(s):  
Evzen Krepela ◽  
Zdislava Vanickova ◽  
Petr Hrabal ◽  
Michal Zubal ◽  
Barbora Chmielova ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Stromal Cells ◽  
Transforming Growth Factor ◽  
Malignant Tumors ◽  
Glioma Cells ◽  
Fibroblast Activation Protein ◽  
Type I ◽  
Fibroblast Activation ◽  
Growth Factor Beta

The proline-specific serine protease fibroblast activation protein (FAP) can participate in the progression of malignant tumors and represents a potential diagnostic and therapeutic target. Recently, we demonstrated an increased expression of FAP in glioblastomas, particularly those of the mesenchymal subtype. Factors controlling FAP expression in glioblastomas are unknown, but evidence suggests that transforming growth factor beta (TGFbeta) can trigger mesenchymal changes in these tumors. Here, we investigated whether TGFbeta promotes FAP expression in transformed and stromal cells constituting the glioblastoma microenvironment. We found that both FAP and TGFbeta-1 are upregulated in glioblastomas and display a significant positive correlation. We detected TGFbeta-1 immunopositivity broadly in glioblastoma tissues, including tumor parenchyma regions in the immediate vicinity of FAP-immunopositive perivascular stromal cells. Wedemonstrate for the first time that TGFbeta-1 induces expression of FAP in non-stem glioma cells, pericytes, and glioblastoma-derived endothelial and FAP+ mesenchymal cells, but not in glioma stem-like cells. In glioma cells, this effect is mediated by the TGFbeta type I receptor and canonical Smad signaling and involves activation of FAP gene transcription. We further present evidence of FAP regulation by TGFbeta-1 secreted by glioma cells. Our results provide insight into the previously unrecognized regulation of FAP expression by autocrine and paracrine TGFbeta-1 signaling in a broad spectrum of cell types present in the glioblastoma microenvironment.

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